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#include "stdhdr.h" #include "digi.h" #include "mesg.h" #include "simveh.h" #include "MsgInc/WingmanMsg.h" #include "find.h" #include "flight.h" #include "wingorder.h" #include "classtbl.h" #include "Aircrft.h" DigitalBrain::BVRProfileType BvrLookup[] = { DigitalBrain::Plevel1a, DigitalBrain::Plevel2a, DigitalBrain::Plevel3a, DigitalBrain::Plevel1b, DigitalBrain::Plevel2b, DigitalBrain::Plevel3b, DigitalBrain::Plevel1c, DigitalBrain::Plevel2c, DigitalBrain::Plevel3c, DigitalBrain::Pbeamdeploy, DigitalBrain::Pbeambeam, DigitalBrain::Pwall, DigitalBrain::Pgrinder, DigitalBrain::Pwideazimuth, DigitalBrain::Pshortazimuth, DigitalBrain::PwideLT, DigitalBrain::PShortLT, DigitalBrain::PDefensive }; void DigitalBrain::ReceiveOrders(FalconEvent* theEvent) { FalconWingmanMsg *wingMsg; FalconWingmanMsg::WingManCmd command; FlightClass *p_flight; AircraftClass *p_from; int fromIndex; short edata[10]; if ( not self->IsAwake() or self->IsDead()) return; //we can't follow orders about how to fly if we're on the ground still if (self->OnGround() or atcstatus >= lOnFinal) return; wingMsg = (FalconWingmanMsg *)theEvent; command = (FalconWingmanMsg::WingManCmd) wingMsg->dataBlock.command; p_flight = (FlightClass*) vuDatabase->Find(wingMsg->EntityId()); p_from = (AircraftClass*) vuDatabase->Find(wingMsg->dataBlock.from); fromIndex = p_flight->GetComponentIndex(p_from); if (curMode == GunsJinkMode or curMode == MissileDefeatMode or curMode == DefensiveModes) { switch (command) { // Commands that change Action and Search States case FalconWingmanMsg::WMRTB: case FalconWingmanMsg::WMClearSix: case FalconWingmanMsg::WMCheckSix: case FalconWingmanMsg::WMBreakRight: case FalconWingmanMsg::WMBreakLeft: case FalconWingmanMsg::WMPosthole: case FalconWingmanMsg::WMPince: case FalconWingmanMsg::WMChainsaw: case FalconWingmanMsg::WMSSOffset: case FalconWingmanMsg::WMFlex: case FalconWingmanMsg::WMShooterMode: case FalconWingmanMsg::WMCoverMode: case FalconWingmanMsg::WMSearchGround: case FalconWingmanMsg::WMSearchAir: case FalconWingmanMsg::WMResumeNormal: case FalconWingmanMsg::WMRejoin: case FalconWingmanMsg::WMAssignTarget: case FalconWingmanMsg::WMAssignGroup: case FalconWingmanMsg::WMWeaponsHold: case FalconWingmanMsg::WMSpread: case FalconWingmanMsg::WMWedge: case FalconWingmanMsg::WMTrail: case FalconWingmanMsg::WMLadder: case FalconWingmanMsg::WMStack: case FalconWingmanMsg::WMResCell: case FalconWingmanMsg::WMBox: case FalconWingmanMsg::WMArrowHead: case FalconWingmanMsg::WMFluidFour: case FalconWingmanMsg::WMVic: case FalconWingmanMsg::WMFinger4: case FalconWingmanMsg::WMEchelon: case FalconWingmanMsg::WMForm1: case FalconWingmanMsg::WMForm2: case FalconWingmanMsg::WMForm3: case FalconWingmanMsg::WMForm4: case FalconWingmanMsg::WMKickout: case FalconWingmanMsg::WMCloseup: case FalconWingmanMsg::WMToggleSide: case FalconWingmanMsg::WMIncreaseRelAlt: case FalconWingmanMsg::WMDecreaseRelAlt: edata[0] = ((FlightClass*)self->GetCampaignObject())->callsign_id; edata[1] = (((FlightClass*)self->GetCampaignObject())->callsign_num - 1) * 4 + self->GetCampaignObject()->GetComponentIndex(self) + 1; edata[2] = -1; edata[3] = -1; AiMakeRadioResponse(self, rcUNABLE, edata); // 2001-07-28 ADDED BY S.G. AI NEEDS TO KNOW WHAT DO TO ONCE HE FINISHES HIS DEFENSE... switch (command) { case FalconWingmanMsg::WMShooterMode: AiGoShooter(); break; case FalconWingmanMsg::WMCoverMode: AiGoCover(); break; case FalconWingmanMsg::WMRejoin: AiRejoin(wingMsg, AI_REJOIN); // 2001-10-23 ADDED AI_REJOIN BY S.G. So the AI knows it comes from the lead //underOrders = FALSE; break; // Commands that affect mode basis case FalconWingmanMsg::WMAssignTarget: case FalconWingmanMsg::WMAssignGroup: AiDesignateTarget(wingMsg); break; } // END OF ADDED SECTION break; case FalconWingmanMsg::WMRaygun: AiRaygun(wingMsg); break; case FalconWingmanMsg::WMBuddySpike: AiBuddySpikeReact(wingMsg); break; case FalconWingmanMsg::WMRadarOn: AiSetRadarActive(wingMsg); break; case FalconWingmanMsg::WMRadarStby: AiSetRadarStby(wingMsg); break; // Transient Commands case FalconWingmanMsg::WMGiveBra: AiGiveBra(wingMsg); break; case FalconWingmanMsg::WMGiveStatus: AiGiveStatus(wingMsg); break; case FalconWingmanMsg::WMGiveDamageReport: AiGiveDamageReport(wingMsg); break; case FalconWingmanMsg::WMGiveFuelState: AiGiveFuelStatus(wingMsg); break; case FalconWingmanMsg::WMWeaponsFree: AiSetWeaponsAction(wingMsg, AI_WEAPONS_FREE); break; case FalconWingmanMsg::WMGiveWeaponsCheck: AiGiveWeaponsStatus(); break; case FalconWingmanMsg::WMSmokeOn: AiSmokeOn(wingMsg); break; case FalconWingmanMsg::WMSmokeOff: AiSmokeOff(wingMsg); break; case FalconWingmanMsg::WMJokerFuel: edata[0] = isWing; edata[1] = 0; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidJoker); break; case FalconWingmanMsg::WMBingoFuel: edata[0] = isWing; edata[1] = 1; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidBingo); break; case FalconWingmanMsg::WMFumes: edata[0] = isWing; edata[1] = 2; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidFumes); break; case FalconWingmanMsg::WMFlameout: edata[0] = isWing; edata[1] = 3; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidFlameout); break; case FalconWingmanMsg::WMGlue: AiGlueWing(); break; case FalconWingmanMsg::WMSplit: AiSplitWing(); break; case FalconWingmanMsg::WMDropStores: AiDropStores(wingMsg); case FalconWingmanMsg::WMECMOn: AiECMOn(wingMsg); break; case FalconWingmanMsg::WMECMOff: AiECMOff(wingMsg); break; // 2002-03-15 ADDED BY S.G. BVR profiles that the player can send to his element case FalconWingmanMsg::WMPlevel1a: case FalconWingmanMsg::WMPlevel2a: case FalconWingmanMsg::WMPlevel3a: case FalconWingmanMsg::WMPlevel1b: case FalconWingmanMsg::WMPlevel2b: case FalconWingmanMsg::WMPlevel3b: case FalconWingmanMsg::WMPlevel1c: case FalconWingmanMsg::WMPlevel2c: case FalconWingmanMsg::WMPlevel3c: case FalconWingmanMsg::WMPbeamdeploy: case FalconWingmanMsg::WMPbeambeam: case FalconWingmanMsg::WMPwall: case FalconWingmanMsg::WMPgrinder: case FalconWingmanMsg::WMPwideazimuth: case FalconWingmanMsg::WMPshortazimuth: case FalconWingmanMsg::WMPwideLT: case FalconWingmanMsg::WMPShortLT: case FalconWingmanMsg::WMPDefensive: if (flightLead and ((AircraftClass *)flightLead)->DBrain()) ((AircraftClass *)flightLead)->DBrain()->SetBvrCurrProfile(BvrLookup[command - FalconWingmanMsg::WMPlevel1a]); fromIndex = self->GetCampaignObject()->GetComponentIndex(self); if (AiIsFullResponse(fromIndex, wingMsg->dataBlock.to)) { edata[0] = fromIndex; edata[1] = 1; AiMakeRadioResponse(self, rcROGER, edata); } else AiRespondShortCallSign(self); break; // END OF ADDED SECTION 2002-03-15 } } else { switch (command) { // Other Commands case FalconWingmanMsg::WMPromote: AiPromote(); break; case FalconWingmanMsg::WMRadarOn: AiSetRadarActive(wingMsg); break; case FalconWingmanMsg::WMRadarStby: AiSetRadarStby(wingMsg); break; case FalconWingmanMsg::WMBuddySpike: AiBuddySpikeReact(wingMsg); break; case FalconWingmanMsg::WMRaygun: AiRaygun(wingMsg); break; // Commands that change Action and Search States case FalconWingmanMsg::WMRTB: AiRTB(wingMsg); break; case FalconWingmanMsg::WMClearSix: AiClearLeadersSix(wingMsg); break; case FalconWingmanMsg::WMCheckSix: AiCheckOwnSix(wingMsg); break; case FalconWingmanMsg::WMBreakRight: AiBreakRight(); break; case FalconWingmanMsg::WMBreakLeft: AiBreakLeft(); break; case FalconWingmanMsg::WMPosthole: AiInitPosthole(wingMsg); break; case FalconWingmanMsg::WMSSOffset: AiInitSSOffset(wingMsg); break; case FalconWingmanMsg::WMPince: AiInitPince(wingMsg, TRUE); break; case FalconWingmanMsg::WMChainsaw: AiInitChainsaw(wingMsg); break; case FalconWingmanMsg::WMFlex: AiInitFlex(); break; case FalconWingmanMsg::WMShooterMode: AiGoShooter(); break; case FalconWingmanMsg::WMCoverMode: AiGoCover(); break; case FalconWingmanMsg::WMSearchGround: AiSearchForTargets(DOMAIN_LAND); break; case FalconWingmanMsg::WMSearchAir: AiSearchForTargets(DOMAIN_AIR); break; case FalconWingmanMsg::WMResumeNormal: AiResumeFlightPlan(wingMsg); break; case FalconWingmanMsg::WMRejoin: AiRejoin(wingMsg, AI_REJOIN); // 2001-10-23 ADDED AI_REJOIN BY S.G. So the AI knows it comes from the lead //underOrders = FALSE; break; // Commands that affect mode basis case FalconWingmanMsg::WMAssignTarget: case FalconWingmanMsg::WMAssignGroup: AiDesignateTarget(wingMsg); break; case FalconWingmanMsg::WMWeaponsHold: AiSetWeaponsAction(wingMsg, AI_WEAPONS_HOLD); break; case FalconWingmanMsg::WMWeaponsFree: AiSetWeaponsAction(wingMsg, AI_WEAPONS_FREE); break; // Commands that modify formation case FalconWingmanMsg::WMSpread: case FalconWingmanMsg::WMWedge: case FalconWingmanMsg::WMTrail: case FalconWingmanMsg::WMLadder: case FalconWingmanMsg::WMStack: case FalconWingmanMsg::WMResCell: case FalconWingmanMsg::WMBox: case FalconWingmanMsg::WMArrowHead: case FalconWingmanMsg::WMFluidFour: case FalconWingmanMsg::WMVic: case FalconWingmanMsg::WMFinger4: case FalconWingmanMsg::WMEchelon: case FalconWingmanMsg::WMForm1: case FalconWingmanMsg::WMForm2: case FalconWingmanMsg::WMForm3: case FalconWingmanMsg::WMForm4: AiSetFormation(wingMsg); break; case FalconWingmanMsg::WMKickout: AiKickout(wingMsg); break; case FalconWingmanMsg::WMCloseup: AiCloseup(wingMsg); break; case FalconWingmanMsg::WMToggleSide: AiToggleSide(); break; case FalconWingmanMsg::WMIncreaseRelAlt: AiIncreaseRelativeAltitude(); break; case FalconWingmanMsg::WMDecreaseRelAlt: AiDecreaseRelativeAltitude(); break; // Transient Commands case FalconWingmanMsg::WMGiveBra: AiGiveBra(wingMsg); break; case FalconWingmanMsg::WMGiveStatus: AiGiveStatus(wingMsg); break; case FalconWingmanMsg::WMGiveDamageReport: AiGiveDamageReport(wingMsg); break; case FalconWingmanMsg::WMGiveFuelState: AiGiveFuelStatus(wingMsg); break; case FalconWingmanMsg::WMGiveWeaponsCheck: AiGiveWeaponsStatus(); break; case FalconWingmanMsg::WMSmokeOn: AiSmokeOn(wingMsg); break; case FalconWingmanMsg::WMSmokeOff: AiSmokeOff(wingMsg); break; case FalconWingmanMsg::WMECMOn: AiECMOn(wingMsg); break; case FalconWingmanMsg::WMECMOff: AiECMOff(wingMsg); break; case FalconWingmanMsg::WMJokerFuel: edata[0] = isWing; edata[1] = 0; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidJoker); break; case FalconWingmanMsg::WMBingoFuel: edata[0] = isWing; edata[1] = 1; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidBingo); break; case FalconWingmanMsg::WMFumes: edata[0] = isWing; edata[1] = 2; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidFumes); break; case FalconWingmanMsg::WMFlameout: edata[0] = isWing; edata[1] = 3; AiMakeRadioResponse(p_from, rcFUELCRITICAL, edata); if ( not isWing) FlightMemberWantsFuel(SaidFlameout); break; case FalconWingmanMsg::WMGlue: AiGlueWing(); break; case FalconWingmanMsg::WMSplit: AiSplitWing(); break; case FalconWingmanMsg::WMDropStores: AiDropStores(wingMsg); // 2002-03-15 ADDED BY S.G. BVR profiles that the player can send to his element case FalconWingmanMsg::WMPlevel1a: case FalconWingmanMsg::WMPlevel2a: case FalconWingmanMsg::WMPlevel3a: case FalconWingmanMsg::WMPlevel1b: case FalconWingmanMsg::WMPlevel2b: case FalconWingmanMsg::WMPlevel3b: case FalconWingmanMsg::WMPlevel1c: case FalconWingmanMsg::WMPlevel2c: case FalconWingmanMsg::WMPlevel3c: case FalconWingmanMsg::WMPbeamdeploy: case FalconWingmanMsg::WMPbeambeam: case FalconWingmanMsg::WMPwall: case FalconWingmanMsg::WMPgrinder: case FalconWingmanMsg::WMPwideazimuth: case FalconWingmanMsg::WMPshortazimuth: case FalconWingmanMsg::WMPwideLT: case FalconWingmanMsg::WMPShortLT: case FalconWingmanMsg::WMPDefensive: if (flightLead and ((AircraftClass *)flightLead)->DBrain()) ((AircraftClass *)flightLead)->DBrain()->SetBvrCurrProfile(BvrLookup[command - FalconWingmanMsg::WMPlevel1a]); fromIndex = self->GetCampaignObject()->GetComponentIndex(self); if (AiIsFullResponse(fromIndex, wingMsg->dataBlock.to)) { edata[0] = fromIndex; edata[1] = 1; AiMakeRadioResponse(self, rcROGER, edata); } else AiRespondShortCallSign(self); break; // END OF ADDED SECTION 2002-03-15 } // end switch } } | Mid | [
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beta-adrenoceptor blockade with diphenylhydantoin (DPH). Diphenylhydantoin (DPH) (20 x 10(-6) to 80 x 10(-6) M/kg) blocked the depressor responses to isoproterenol in spinal, bilaterally vagotomized and atropine pretreated cats; depressor responses to histamine were unaffected; DPH shifted the isoproterenol concentration-response curve to the right in isolated guinea pig tracheal chain preparation, isolated rabbit ileum and isolated perfused heart of frog. The results suggest that DPH has a specific beta-adrenoceptor blocking action and the blockade appears to be competitive in nature as shown by PA2 and PA10 values. | High | [
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"In a beauty market which, as in the first quarter, turned out to be highly contrasted and atypical, the Group has continued to expand, with solid organic growth and differentiated performances across the Divisions. L'Oréal Luxe delivered excellent double-digit growth, substantially outperforming its market. The Consumer Products Division is improving its growth, but is being held back by slowdowns in certain markets worldwide: the United States, Brazil, India and the Middle East. The Active Cosmetics Division accelerated significantly in the second quarter, and sales in the Professional Products Division, although still sluggish, are gradually improving. Across the geographic Zones, Western Europe remains dynamic despite persistent difficulties in the French market, and the New Markets as a whole are posting sustained growth, thanks to the strong contribution of Asia Pacific and solid sales in Eastern Europe. The Group's digital breakthrough is continuing, particularly in e-commerce4, which posted +29.5% growth in the first half and represents 7.0% of total sales. The Group's results are up significantly across the board: operating profit, earnings per share and cash flow. Results by Division are differentiated, logically reflecting the highly contrasted sales in the first half, and our choice to continue investing regularly in each Division so as to build up our positions. Over the full year, the sale of The Body Shop3, and the accretive effect this has on profitability, mean that we will be able to strongly increase our profitability, which for the first time could reach 18% of sales, and also to take the opportunity to strengthen our business drivers in order to accelerate our market share gains and thus our future growth. This strategic choice, combined with the good first-half results, strengthens our confidence in our ability to once again outperform the cosmetics market in 2017, and to achieve growth in both our sales and profits." First-half 2017 sales Like-for-like, i.e. based on a comparable structure and identical exchange rates, sales growth of the L'Oréal Group was +4.3%.The net impact of changes in the scope of consolidation was -2.1%, corresponding to: +1.0% from acquisitions, -3.1% from the sale of The Body Shop. Currency fluctuations had a positive impact of +1.8%. If the exchange rates at 30 June 2017, i.e. €1 = $1.1425, are extrapolated until 31 December 2017, the impact of currency fluctuations on sales would be approximately -0.4% for the whole of 2017.Based on reported figures, the Group's sales at 30 June 2017 amounted to 13.4 billion euros, up by +4.0%. Sales by operational Division and geographic Zone The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop, means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. 2nd quarter 2017 1st half 2017 Growth Growth €m Like-for-like Reported €m Like-for-like Reported By operational Division Professional Products 881.1 +0.3% +1.3% 1,739.3 -0.7% +0.9% Consumer Products 3,160.0 +2.4% +3.6% 6,389.3 +1.9% +3.8% L'Oréal Luxe 1,991.4 +8.9% +12.9% 4,148.5 +10.5% +15.4% Active Cosmetics 531.7 +6.7% +15.4% 1,134.9 +4.6% +11.1% Operational Divisions total 6,564.2 +4.3% +6.8% 13,411.9 +4.3% +7.3% By geographic Zone Western Europe 5 2,066.1 +3.1% +1.7% 4,202.8 +3.0% +1.6% North America 1,907.8 +2.4% +9.4% 3,824.8 +3.1% +10.5% New Markets, of which: 2,590.2 +6.9% +9.4% 5,384.4 +6.2% +9.9% Asia, Pacific 5 1,463.9 +9.2% +10.0% 3,135.4 +8.1% +9.4% Latin America 510.3 +7.1% +12.3% 985.1 +5.9% +14.1% Eastern Europe 427.1 +6.0% +11.5% 908.5 +9.4% +17.4% Africa, Middle East 188.9 -7.6% -5.5% 355.4 -13.2% -10.9% Operational Divisions total 6,564.2 +4.3% +6.8% 13,411.9 +4.3% +7.3% Group total 6,564.2 +4.3% +3.5% 13,411.9 +4.3% +4.0% In the second quarter of 2016 and the first half of 2016, reported Group sales included The Body Shop sales in respective amounts of 198.5 million euros and 398.6 million euros. PROFESSIONAL PRODUCTS At the end of June, the Professional Products Division posted -0.7% like-for-like and +0.9% based on reported figures.Growth has improved slightly, driven by Eastern Europe and Latin America.Hair colour has benefited from the launch of Colorfulhair at L'Oréal Professionnel and the solid performance of Shades EQ at Redken. In haircare, the natural lines Aura Botanica by Kérastase and Biolage R.A.W. by Matrix are maintaining their positive momentum, while the roll-out of new "bonder6" services is continuing. CONSUMER PRODUCTS In the second quarter, the Division posted growth of +2.4% like-for-like. It ended the first half at +1.9% like-for-like, and +3.8% based on reported figures.In a market affected by a clear growth slowdown in the United States, the Division is continuing to win market share in several regions of the world, especially in Western Europe.Make-up remains dynamic, thanks to the success of Infallible Total Cover foundation by L'Oréal Paris, Colossal Big Shot mascara by Maybelline, and NYX Professional Makeup. Hair colour growth is continuing, reflecting the very strong start made by Colorista at L'Oréal Paris, which is reinventing hair colour for Millennials7. Facial skincare is accelerating, thanks to Hydra Genius by L'Oréal Paris, which takes its inspiration from Asia's liquid moisturisers, and the ongoing success of Micellar Cleansing Waters by Garnier.The dynamism of new retail channels such as e-commerce is continuing, opening up new growth opportunities. L'ORÉAL LUXE L'Oréal Luxe is confirming its excellent start to the year, driven by make-up and facial skincare, and has posted first-half growth of +10.5% like-for-like and +15.4% based on reported figures.Lancôme, besides the successful launch of Monsieur Big mascara, is adding to its successes in lip make-up with L'Absolu Rouge and the recent launch of Matte Shaker. Lancôme anti-ageing is growing thanks to its iconic lines Génifique, Absolue and Rénergie. Yves Saint Laurent is expanding, especially in make-up with Volupté Tint-in-Balm, the extension of the Vernis à Lèvres lip make-up range, and the phenomenal Cushion Encre de Peau foundation, and in fragrances with the women's perfume Mon Paris. Giorgio Armani is accelerating its growth, and launching the Emporio Armani fragrance duo. Kiehl's, which is posting double-digit growth, is driven by its Calendula line. The recently acquired brands IT Cosmetics and Atelier Cologne are growing rapidly.The Division is enjoying strong growth in the Asia Pacific Zone, driven by the rebound in China, where its brands are firmly established. It recorded a good first half in Western Europe, especially in Great Britain and Spain. Growth is solid in North America and accelerating in Latin America. L'Oréal Luxe has posted double-digit growth in Travel Retail, and is continuing to forge ahead in e-commerce. ACTIVE COSMETICS At the end of June, the Active Cosmetics Division accelerated at +11.1% based on reported figures and +4.6% like-for-like.Growth at La Roche-Posay is still very dynamic, thanks to the success of its sun protection campaign and the good performances of its franchises Effaclar, Lipikar and Cicaplast. Vichy has launched Minéral 89, its new everyday fortifying repulp booster, with highly promising results a few weeks after launch. SkinCeuticals is continuing to post double-digit growth, with outstanding performances in China, the United Kingdom, France, Russia and Brazil.North America is the number one contributor to the Division's growth, reflecting the successful integration of CeraVe into the Division's portfolio, and the dynamism of the SkinCeuticals and La Roche-Posay brands. Summary by geographic Zone WESTERN EUROPE Western Europe posted growth of +3.0% like-for-like and +1.6% based on reported figures. Growth is particularly sustained in the United Kingdom, Germany and Spain, but sales in France are still being held back by the difficult market conditions. The Consumer Products and L'Oréal Luxe Divisions are outperforming their respective markets. NORTH AMERICA The Zone recorded growth of +3.1% like-for-like and +10.5% based on reported figures. In a mass market sector that has slowed very substantially in the United States, the Consumer Products Division is winning market share in make-up, hair colour and facial cleansing, with key launches in make-up removers at L'Oréal Paris and Garnier and the continuing success of NYX Professional Makeup. At L'Oréal Luxe, IT Cosmetics and Yves Saint Laurent perfumes are posting double-digit growth. The Active Cosmetics Division is also recording double-digit growth, driven by La Roche-Posay, SkinCeuticals and the recent acquisition of CeraVe. NEW MARKETS Asia, Pacific: growth in this Zone amounted to +8.1% like-for-like and +9.4% based on reported figures. In Northern Asia, particularly China and Hong Kong, L'Oréal Luxe is growing strongly, thanks to the brands Lancôme, Yves Saint Laurent and Giorgio Armani. In Southern Asia, growth remains strong across all Divisions, especially in Thailand and Indonesia. In India, sales are being held back by retailer destocking just ahead of the introduction of GST (Goods & Services Tax). Latin America: the Zone recorded growth of +5.9% like-for-like and +14.1% based on reported figures. Growth is particularly strong in Mexico and Argentina. The Brazilian market is still proving difficult. The make-up brands NYX Professional Makeup, Lancôme and Urban Decay are winning market share. The Active Cosmetics Division accelerated in the second quarter in a dynamic market. Eastern Europe: growth in this Zone came out at +9.4% like-for-like and +17.4% based on reported figures. Turkey and Central Europe are posting good growth, with market share gains for most of the Divisions. Russia is slowing, reflecting the trend in its market, with growth at a lower level than last year. Africa, Middle East: sales were down by -13.2% like-for-like and -10.9% based on reported figures. In Saudi Arabia, where the market is still very difficult, the situation of our businesses is gradually improving. The dynamism in Egypt is continuing. Important events during the period 1/4/17 to 30/6/17 On 20 April 2017, the Annual General Meeting of L'Oréal appointed Mr Paul Bulcke as a Director, and renewed the tenure as Directors of Mrs Françoise Bettencourt Meyers and Mrs Virginie Morgon. Furthermore, the Annual General Meeting decided on the distribution of a dividend of €3.30 per share, with a payment date of 3 May 2017. The Board of Directors' meeting, held at the close of the Annual General Meeting, decided, pursuant to the authorisation voted by the Annual General Meeting on 20 April 2016, on the cancellation of 2,846,604 L'Oréal shares acquired within the scope of the share buyback programme decided by the Board of Directors on 9 February 2017. The shares were cancelled on 31 May 2017. The share capital of L'Oréal at 30 June 2017 amounts to 111,993,452 euros, divided into 559,967,260 shares, each with a par value of 0.2 euro. On 20 April 2017, L'Oréal announced the appointment of Mr Nicolas Hieronimus as Deputy CEO, in charge of Divisions. Mr Nicolas Hieronimus will also continue in his role as President of the L'Oréal Luxe Division. On 2 May 2017, L'Oréal USA announced the acquisition of key assets from Four Star Salon Services, a full-service wholesale distributor of products to hair salons in New York, New Jersey and Connecticut. This acquisition will provide SalonCentric with expanded distribution coverage in the United States. On 9 June 2017, L'Oréal announced that it had received a firm offer from Natura Cosmeticos SA to acquire The Body Shop and had entered into exclusive discussions. The offer values The Body Shop at an enterprise value of 1.0 billion euros and, after consultation with the Employee Representative Bodies, remains subject to regulatory approval, notably in Brazil and in the United States. On 27 June 2017, L'Oréal announced the signing of the contract for the sale of The Body Shop to Natura. The proposed sale remains subject to clearance by anti-trust authorities, notably in Brazil and in the United States. First-half 2017 results The limited review procedures of the half-year consolidated accounts have been completed. The limited review report is being prepared by the Statutory Auditors. Operating profitability at 18.9% of sales Consolidated profit and loss account: from sales to operating profit. The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop, means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. See the compared 2016 consolidated profit and loss accounts in the appendix. In € million 30/06/16REPORTED2 As % of sales 31/12/16REPORTED2 As % of sales 30/06/17 As % of sales Change H1-2017 vs. H1-2016 Sales 12,894.6 100.0% 25,837.1 100.0% 13,411.9 100.0% +4.0% Cost of sales -3,561.2 27.6% -7,341.7 28.4% -3,780.5 28.2% Gross Profit 9,333.4 72.4% 18,495.4 71.6% 9,631.4 71.8% +3.2% R&D expenses -414.2 3.2% -849,8 3.3% -425.1 3.2% Advertising and promotion expenses -3,790.9 29.4% -7,498.7 29.0% -3,913.5 29.2% Selling, general and administrative expenses -2,764.7 21.4% -5,607.0 21.7% -2,762.4 20.6% Operating profit 2,363.6 18.3% 4,539.9 17.6% 2,530.4 18.9% +7.1% Gross profit, at 9,631 million euros, has come out at 71.8% of sales, representing a 60-basis-point decline due to the exchange rate impact in the first half. Research and Development expenses, at 425 million euros, have risen by +2.6%. Their relative level is stable at 3.2% of sales. Advertising and promotion expenses have come out at 29.2% of sales, a level slightly below that of the first half of 2016. Selling, general and administrative expenses, at 20.6% of sales, decreased significantly by 80 basis points compared with the first half of 2016, mainly due to the impact of the sale of The Body Shop. Overall, operating profit, at 2,530 million euros, is up by 60 basis points and amounted to 18.9% of sales. Operating profit by operational Division The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop, means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. See the compared 2016 consolidated profit and loss accounts in the appendix. 30/06/16 - Reported 31/12/16 - Reported 30/06/17 €m % of sales €m % of sales €m % of sales By operational Division Professional Products 338.2 19.6% 688.6 20.3% 319.9 18.4% Consumer Products 1,306.8 21.2% 2,417.1 20.2% 1,267.5 19.8% L'Oréal Luxe 767.3 21.3% 1,622.8 21.2% 970.2 23.4% Active Cosmetics 283.3 27.7% 431.5 23.2% 303.5 26.7% Total Divisions before non-allocated 2,695.5 21.6% 5,160.0 20.7% 2,861.1 21.3% Non-allocated8 -309.8 -2.5% -653.9 -2.6% -330.7 -2.5% Total Divisions after non-allocated 2,385.7 19.1% 4,506.1 18.1% 2,530.4 18.9% The Body Shop -22.2 -5.6% 33.8 3.7% Group 2,363.6 18.3% 4,539.9 17.6% 2,530.4 18.9% The L'Oréal Group is managed on an annual basis. This means that half-year operating profits cannot be extrapolated for the whole year. The profitability of the Professional Products Division declined from 19.6% to 18.4%. The Consumer Products Division's profitability decreased from 21.2% to 19.8%. L'Oréal Luxe experienced a very strong improvement in its profitability, with an increase from 21.3% to 23.4%, i.e. +210 basis points. The Active Cosmetics Division remains at a very high profitability level at 26.7%, compared with 27.7% in the first half of 2016. Net profit excluding non-recurring items The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop, means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. See the compared 2016 consolidated profit and loss accounts in the appendix. Net profit The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop, means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. See the compared 2016 consolidated profit and loss accounts in the appendix. After having taken into account the non-recurring items and the impact of the IFRS 5 accounting rule with regards to The Body Shop, net profit after non-controlling interests amounted to 2,037 million euros, a strong increase of +37.7% compared to the first half of 2016. Operating cash flow and balance sheet Gross cash flow amounted to 2,634 million euros, up by +6.8% compared with the first half of 2016. The change in working capital amounted to 362 million euros. As in the first half every year, it increased slightly, particularly because of the impact of the seasonality of part of our business on trade receivables. After payment of the dividend, share buybacks and the acquisition of CeraVe in the United States, the residual cash flow has come out at -1,954 million euros. At 30 June 2017, net debt amounted to 1,492 million euros, compared with a debt of 344 million euros at 30 June 2016. "This news release does not constitute an offer to sell, or a solicitation of an offer to buy L'Oréal shares. If you wish to obtain more comprehensive information about L'Oréal, please refer to the public documents registered in France with the Autorité des Marchés Financiers, also available in English on our Internet site www.loreal-finance.com.This news release may contain some forward-looking statements. Although the Company considers that these statements are based on reasonable hypotheses at the date of publication of this release, they are by their nature subject to risks and uncertainties which could cause actual results to differ materially from those indicated or projected in these statements."This a free translation into English of the First-half 2017 results news release issued in the French language and is provided solely for the convenience of English speaking readers. In case of discrepancy, the French version prevails. Appendices 2 - 6: 1. Like-for-like: based on a comparable structure and constant exchange rates, see details on page 2.2. In the second quarter of 2016 and the first half of 2016, reported Group sales included The Body Shop sales in respective amounts of 198.5 million euros and 398.6 million euros.3. The announcement, on 27 June 2017, of the signing of the contract for the sale of The Body Shop means that the IFRS 5 accounting rule applies to the discontinued operations at 30 June 2017. See the compared 2016 consolidated profit and loss accounts in the appendix.4. Sales achieved on our brands' websites + estimated sales achieved by our brands corresponding to sales through our retailers' websites (non-audited data); like-for-like growth.5. As of 1 July 2016, the Asian Travel Retail business of the Consumer Products Division, previously recorded under the Western Europe Zone, was transferred to the Asia, Pacific Zone. All figures for earlier periods have been restated to allow for this change.6. A formula that protects keratin bonds inside the hair fibre.7. Generation born between 1980 and 2000.8. Non-allocated expenses = Central Group expenses, fundamental research expenses, stock options and free grant of shares expenses and miscellaneous items. As a % of total Divisions sales.9. Net profit excluding non-recurring items after non-controlling interests, does not include capital gains and losses on disposals of long-term assets, impairment of assets, restructuring costs, tax effects and non-controlling interests. At 30 June 2017, net profit excluding non-recurring items of continuing operations.10. Diluted earnings per share, excluding non-recurring items, after non-controlling interests.11. Reported for the first half of 2016 and for the full-year 2016.12. Diluted net profit per share of continuing operations, excluding non-recurring items, after non-controlling interests.13. In the second quarter of 2016 and the first half of 2016, reported Group sales included The Body Shop sales in respective amounts of 198.5 million euros and 398.6 million euros.14. In the first quarter 2017, reported Group sales included The Body Shop sales, which amounted to 197.2 million euros. | Mid | [
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MONTREAL—Prime Minister Justin Trudeau said Canadian companies operating abroad are expected to obey the law after a Bombardier employee in the Swedish offices of the plane and train maker was detained Friday in pretrial custody on suspicion of aggravated bribery. Evgeny Pavlov, a Russian national living in Stockholm, was one of several Bombardier employees “suspected to have been colluding” with Azerbaijan railway authorities “in order to adapt a contract” to fit Bombardier, Swedish prosecutor Thomas Forsberg said. Forsberg said Pavlov worked with Bombardier Transportation Sweden AB. On LinkedIn, Pavlov described himself as “Head of sales, Marketing and Country co-ordinator for the north region.” Pavlov was ordered held in pretrial custody for two weeks to prevent him from fleeing or tampering with evidence. Two others were briefly detained during the week, but were released, Forsberg told The Associated Press. Both remain suspects while the investigation continues. Formal charges have not yet been made. Trudeau was asked about the legal controversy facing Bombardier, a company that the federal government has heavily invested in. “The Canadian government expects Canadian companies and Canadians working abroad to uphold the highest standards of ethical and legal behaviour,” said Trudeau, who was attending a global oil conference in Houston. He said he didn’t believe the case has any bearing on his government’s decision to offer the company’s aeronautics division a $372.5-million loan last month to support its CSeries and Global 7000 jet programs. Read more: Bombardier to get $372.5 million in government loans Metrolinx to Bombardier: ‘Stop blaming others’ for your mistakes “At this point I can’t predict that it will have any impact,” he said. “I think that it’s very clear that this was an entirely separate issue.” Pavlov’s lawyer, Cristina Berger, said her client denies any wrongdoing and it will be up to the Stockholm District Court to decide March 24 whether to remand him in custody. Bombardier Transportation confirmed that employees working in its office in Sweden have been questioned by police and it said it is co-operating with Swedish prosecutors. But it’s “premature” to comment on the outcome of the investigation or court proceedings, the company added. “As always, we are committed to operating in full compliance with all legal rules and requirements and our own high ethical standards,” Claas Belling, a spokesperson for Bombardier Transportation, said in an email. Forsberg said emails seized in October 2016 during a search of Bombardier offices in Sweden were considered evidence in the case. He said the suspicion was that Azerbaijani officials co-operated with Montreal-based Bombardier (TSX:BBD.B) to “receive rewards for having favoured the Bombardier contract.” “Despite the fact that Bombardier was in fifth place in terms of price, it won the contract in 2013 and competitors with better prices were disqualified by the railway authority in Azerbaijan,” Forsberg said. In 2013, Bombardier was part of a consortium awarded a $288-million contract to supply signalling equipment for a 503-kilometre track along a corridor connecting Asia and Europe to Azerbaijan Railways. Bombardier then said it was its “first major signalling contract in Azerbaijan.” Forsberg said Azerbaijani companies made $56 million in earnings from the contract. Karl Moore, professor at Desautels Faculty of Management at McGill University, said he doesn’t think Pavlov’s arrest will affect Bombardier’s ability to win government contracts in Canada. The Quebec and federal governments have placed restrictions on companies whose directors have been convicted of violating the Canadian Criminal Code. Loading... Loading... Loading... Loading... Loading... Loading... “That’s a very small possibility at this point, so I don’t think it’s a big worry,” said Moore on the company’s future ability to win government contracts. “But we’ll see how things unfold.” Michel Nadeau, executive director of the Institute for Governance of Private and Public Organizations, said he too doesn’t think the arrest will affect the company’s relationship with governments in Canada. “I would say it’s part of the daily life of big companies that do business with governments, to be, eventually now and then, accused of corruption,” he said. Nadeau used to be president of the investment arm of Quebec’s pension fund, which in 2015 bought a 30-per-cent stake in the holding company of Bombardier Transportation — the company’s rail division, headquartered in Berlin. With files from The Associated Press Read more about: | Low | [
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Resetting a Serial Port's RTS and DTR Signals when Windows Starts de Joe W4TV You can reset a serial port's RTS and DTR signals on Windows startup by creating a Windows Batch File containing the appropriate command, and then creating a Window Shortcut to this Batch File in the Windows Startup Folder. To reset COM3's RTS and DTR signals, for example, use Windows Notepad to create a Batch File named RESETCOM3.bat that contains To create the required Shortcut, run two instances of Windows Explorer. In the first instance, navigate to the folder in which you created RESETCOM3.bat; in the second instance, navigate to the Windows Startup Folder. Then depress-and-hold the ALT key while dragging RESETCOM3.bat from the first instance of Windows Explorer to the second; when you release the left mouse button, a shortcut to RESETCOM3.bat will appear in the Windows Startup Folder. | Mid | [
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Disney Infinity Combat In The Toy Box Disney released a pair of trailers for its upcoming Disney Infinity just a week ago, and they're back with more. This time, the focus is on combat. Think of the clip below as a sort of mash-up bash-up. The action is set in the game's freeform toy box mode, which means you're going to see familiar faces teaming up in unfamiliar ways. Don't worry – they're made out of plastic, so nobody is going to be (permanently) hurt. | Mid | [
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Jalalabad Airfield, Afghanistan – The Zone 1 Afghan Border Police along with 2nd Brigade Afghan National Civil Order Police delivered school supplies to hundreds of students as part of a community outreach mission, May 25th, at a school in western Jalalabad. A local Afghan schoolgirl smiles after she receives school supplies from Afghan Border Police and 2nd Brigade Afghan National Civil Order Police soldiers during a community outreach mission, May 25, 2013, in Jalalabad, Nangarhar Province, Afghanistan. (U.S. Army photo by Sgt. Jon Heinrich, CT 1-101 Public Affairs) “The mission was basically to put a spotlight on the ABP and ANCOP as they deliver school supplies to the school children across the street,” said U.S. Army 1st Lt. Joseph L. Jenkins, the assistant operations officer with ABP Zone 1 SFAAT, and native to Brandenburg, KY. Jenkins said the supplies consisted of books, backpacks, pencils, notebooks and soccer balls and were donated from the U.S. “They came from all over the place. I got a few from churches,” said Jenkins. “I know my parents sent some stuff.” “Everybody else had family members, church groups and schools bring stuff in,” Jenkins added. “We had about 600 bags worth of stuff sent from all over the country.” The mission began in the morning with the ANSF and U.S. Soldiers taking the supplies out of boxes and loading them onto the police trucks. Everyone then got into formation and conducted a dismounted patrol from the Zone 1 compound to the school across the street where they were greeted by the teachers and students. A local Afghan schoolgirl smiles after she receives school supplies from Afghan Border Police and 2nd Brigade Afghan National Civil Order Police soldiers during a community outreach mission, May 25, 2013, in Jalalabad, Nangarhar Province, Afghanistan. (U.S. Army photo by Sgt. Jon Heinrich, CT 1-101 Public Affairs) The trucks then drove into the school and everyone worked together to take the supplies off the trucks and put them into a tent to be handed out to the students by the ANSF leaders. “They did pretty good,” said U.S. Army Sgt. Christopher Stokes with ABP Zone 1 SFAAT, and native to Louisa, KY. “They were out there smiling, shaking hands, handing out supplies, talking to everybody; it was pretty good.” “They actually took the initiative; standing up and handing out all the school supplies to the kids,” Stokes added. “I thought they did a pretty good job.” “I think it went great,” said Jenkins. “The mission was to hand out school supplies and we handed out rapport-building items. The children were smiling. It was just a great time.” Although the ANSF units do patrols, Jenkins said this kind of mission is still important for the ANSF to maintain their presence in the local community. “This is an opportunity to get out there,” Jenkins said. “Their mission was a show of good will. They (ANSF) were the ones handing everything out. We were just helping to coordinate.” “It was a way for the ABP-ANCOP forces to interact with the locals, and show them we’re friends with them,” said Stokes. After the supplies were handed out, the Coalition Forces said goodbye to the students and made their way back to the Headquarters Zone 1 compound. | High | [
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PlayStation.Blog » Mike Websterhttp://blog.us.playstation.com The official PlayStation Blog for news and video updates on PS3, PS4, PSN, PS Vita, PSPTue, 31 Mar 2015 21:05:17 +0000en-UShourly1http://wordpress.org/?v=4.1PlayStation All-Stars Come To Life in New Short Film From Creators of “Michael”http://blog.us.playstation.com/2012/10/22/playstation-all-stars-come-to-life-in-new-short-film-from-creators-of-michael/ http://blog.us.playstation.com/2012/10/22/playstation-all-stars-come-to-life-in-new-short-film-from-creators-of-michael/#commentsTue, 23 Oct 2012 03:01:15 +0000http://blog.us.playstation.com/?p=88342PlayStation All-Stars: Battle Royale. Last year, we released “Michael,” a campaign which paid homage to you, the gamer. We like to think of PlayStation All-Stars as a continuation of that as it was made as a tribute to gamers, tapping into PlayStation’s legendary history and featuring some of the your most beloved franchises in our first ever cross-over fighting game. We’ve created this short live-action film called “The All-Star” to celebrate PlayStation All-Stars' upcoming launch.]]>Over the past few days we’ve released three short teasers filled with clues and a suspicious 10/23/12 date. As expected, nothing gets past the faithful members of the PlayStation Nation, as you quickly pieced together that these teasers are about PlayStation All-Stars: Battle Royale. Last year, we released “Michael,” a campaign which paid homage to you, the gamer. We like to think of PlayStation All-Stars as a continuation of that as it was made as a tribute to gamers, tapping into PlayStation’s legendary history and featuring some of the your most beloved franchises in our first ever cross-over fighting game. We’ve created this short live-action film called “The All-Star” to celebrate PlayStation All-Stars’ upcoming launch. The film will debut tonight on YouTube at Midnight EST (9:00PM PST), but we wanted to give the PlayStation Nation an advanced screening. Check it out below: “The All-Star” contains an epic battle with four of the most iconic PlayStation characters, but the real star of the film is you, the gamer. We’ve hidden references from each of the storied franchises featured in the game — and a few extras to keep you on your toes. Take to the comments to share your favorites! Be sure to pre-order your copy of PlayStation All-Stars, which launches for PlayStation 3 and PlayStation Vita on November 20th. If you can’t wait until then, put your skills to the test in the PlayStation All-Stars public beta, which is available now for PS Plus members and opens to all PSN users tomorrow. ]]>http://blog.us.playstation.com/2012/10/22/playstation-all-stars-come-to-life-in-new-short-film-from-creators-of-michael/feed/111http://blog.us.playstation.com/wp-content/uploads/2012/10/MichaelFinal.jpg4.26Director, PlayStation First Party Games1110 | Mid | [
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Anthony Weiner Used Congressional Gym for Lewd Photos Rep. Weiner Used Congressional Gym As Backdrop 6/13/2011 4:10 AM PDT BY TMZ STAFF Rep. Anthony Weiner took numerous photos of himself -- clothed and partially nude -- at the House Members Gym and sent them to at least one woman ... raising questions about whether he used Congressional resources in his online exploits. TMZ obtained the pics Weiner took of himself using his Blackberry and a mirror. Congressional sources have confirmed with TMZ ... the backdrop is indeed the House Members Gym in the basement of the Rayburn House Office Building. The pics were taken on both the gym floor and in the locker room. TMZ has confirmed the pics were sent online to at least one woman. The question that's dogged Weiner since his news conference/mea culpa is -- did he use Congressional resources during his cyber affairs? HERE'S THE RUNDOWN Meredith Viera Defends the Killer of Cecil the Lion Jennifer Beals in a Hot-Dog-in-Car Controversy A 'Bachelorette' Star Gets Bashed in the Head with a Brick Zayn Malik is Goin' Solo Thanks to Simon Cowell | Low | [
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--- abstract: 'It is known that the action of Euclidean Einstein gravity is not bounded from below and that the metric of flat space does not correspond to a minimum of the action. Nevertheless, perturbation theory about flat space works well. The deep dynamical reasons for this reside in the non-perturbative behaviour of the system and have been clarified in part by numerical simulations. Several open issues remain. We treat in particular those zero modes of the action for which $R(x)$ is not identically zero, but the integral of $\sqrt{g(x)} R(x)$ vanishes.' address: | I.N.F.N., Gruppo Collegato di Trento\ I-38050 Povo (TN) - Italy\ and\ European Centre for Theoretical Studies in Nuclear Physics and Related Areas\ Villa Tambosi, Strada delle Tabarelle 286\ I-38050 Villazzano (TN) - Italy author: - 'G. Modanese [@byline]' title: Stability Issues in Euclidean Quantum Gravity --- Introduction. {#int} ============= The Euclidean (or “imaginary time") formulation of a quantum field theory offers several aesthetic and substantial advantages. The practical rules for perturbative computations are simpler than in the Lorentzian case and there is no distinction between upper and lower indices. The only relevant Green function of the linearized equations is the Feynman propagator, and there is no need of formal regularization through the $i \varepsilon$ term. From the non-perturbative point of view, if the Euclidean action $S$ is positive definite, then the functional integral is formally convergent thanks to the exponential of $-S/\hbar$. When time-independent quantities are computed in the Euclidean theory, the inverse analytical continuation to real time is not necessary. A well known example are the formulas for the static potential [@sym]. We recall them in some detail in Section \[rec\]. The physical correspondence between an Euclidean functional integral and a statistical system at the temperature $\Theta=\hbar/k_B$ is immediate. We can also easily visualize the dynamics of the system, after suitable discretization, as a Montecarlo evolution: starting from a given field configuration, a new configuration is generated through a small random variation; then the system evolves to the new configuration with probability 1 if its action is smaller, or else with probability $\exp(-\Delta S/\hbar)$, and so on. When the “bare" parameters of the action are changed, the ground state of the system, corresponding to the minimum of the action, changes too (“phases" of the theory). It is possible to insert first some bare parameters into the action, then follow the evolution of the system towards its ground state, and here measure the effective average value of the same parameters. The effective coupling constant, for instance, is usually extracted in this way from the measured potential $U$. An interesting application of this method is the quantum Regge calculus by Hamber and Williams [@hw]. In this case, the physical system under investigation is very peculiar: the Euclidean spacetime, represented by a simplicial manifold and numerically coded in terms of edge lengths and defect angles (see also Section \[how\] below). In order to obtain from this discretized theory a continuum limit, independent of the details of the discretization procedure, one looks in the parameters space of the system for a second-order transition point, where the range of field correlations diverges. Does this Euclidean model of the gravitational field constitute a faithful representation of real spacetime, with its complex causal structure distorted by field fluctuations? This question is still unanswered. While we know for sure that for certain curved manifolds the analytical continuation to Euclidean signature is not valid [@eqg], there are no theorems that do allow this continuation in some special case. All we can do is hope that for weak fluctuations with respect to flat space, the Wick rotation of real time to the imaginary axis still makes sense. Particle physicists do not doubt that the Euclidean Einstein action for weak fields represents a massless spin 2 field correctly and in an unique way. This point of view about gravitation, at variance with the geometrodynamical view of spacetime, has been supported, as is well known, by Feynman, Weinberg and others (see for instance the review by Alvarez [@alv]). No problems have ever been encountered – apart from the familiar non-renormalizability of Einstein action – in Euclidean perturbation theory around flat space. The Euclidean formula for the potential works well, too [@for]. Nevertheless, a serious problem still affects Euclidean quantum gravity, even in the weak field sector: the non positivity of the action. Either if one takes the geometrical point of view (“the Euclidean action is not at a minimum for $R=0$...") or the particle-physicist point of view (“the quadratic part of the action has undefined sign..."), one ends up in the unpleasant situation of studying perturbatively a system around a configuration that does not appear to be a minimum for the action, but rather a saddle point. The feeling is to control only one part of the dynamics of the system, while the other part – which makes the weak field approximation work – remains elusive. The non-perturbative Euclidean quantum Regge calculus based upon Einstein action can be helpful under this respect. It represents a geometrical model whose dynamics is entirely under control, at least numerically. So one can use it to throw some light on the paradoxes of the continuum Einstein action. The short-distance regime of Euclidean quantum gravity is to some extent arbitrary, and a strict connection with real spacetime is quite unlikely in that limit. (We recall that due to the dimensional structure of the gravitational action, field fluctuations are stronger at short distances.) In the large distance limit, however, the connection is much more plausible and thus it can be interesting to see how flat space emerges and keeps stable in the Euclidean Regge calculus. The plan of the paper is the following. In Section \[rec\] we discuss the general formulas which relate, in Euclidean field theory, the static potential of two sources to the vacuum correlations of the field. This also gives us the chance to introduce some basic notations. In Section \[dif\] we deal with the non-positivity of the Euclidean action, and give explicit examples in the weak field approximation. In Section \[zer\] we present a novel issue: the zero-modes of the integral of the scalar curvature. In Section \[how\] we give an interpretation of the numerical results of Regge calculus in view of the stability problem. We stress the importance of the sign of the effective cosmological term, which acts as a volume term. In Section \[ads\] we check the geometrical argument of Section \[how\] in the continuum, doing a stability analysis of anti-de Sitter space. Static potential and Euclidean vacuum correlations. {#rec} =================================================== In Euclidean quantum field theory there is a simple connection between the static potential associated to a bosonic field and the vacuum correlations of the field. This allows signs to be fixed without any ambiguity, which is often crucial in stability issues. Consider a system comprising a quantum field and an external source $J$, and denote by $W[J]=\langle 0^+|0^-\rangle_J$ the vacuum-to-vacuum transition amplitude in the presence of the source. The energy of the ground state of the system is given by $$E_0 = -\frac{\hbar}{T} \log W[J], \label{uno}$$ where $T$ is the temporal range of the source, which eventually tends to infinity. To check this, let us insert a complete set of energy eigenstates $\{|n \rangle \}$ into the amplitude $W[J]$: $$\begin{aligned} \langle 0^+|0^- \rangle_J & = & \langle 0| e^{-HT/\hbar} |0 \rangle \nonumber \\ & = & \sum_n \langle 0| e^{-HT/\hbar} |n \rangle \langle n|0 \rangle \nonumber \\ & = & \sum_n | \langle 0|n \rangle |^2 e^{-E_nT/\hbar} . \label{due}\end{aligned}$$ The smallest eigenvalue among the $E_n$’s corresponds to the ground state, and in the limit $T \to \infty$ its exponential dominates the sum. Thus taking the logarithm of $W[J]$ and multiplying by $(-\hbar/T)$ we obtain the eigenvalue itself. One often considers pointlike sources kept at rest at ${\bf x}_1...{\bf x}_N$, namely $$J(x) = \sum_{j=1}^N q_j \, \delta^3 \left( {\bf x}-{\bf x}_j \right). \label{eq3}$$ In this case the ground state energy corresponds, up to a possible additive constant, to the static potential $U$ of the interaction of the sources, and depends on ${\bf x}_1...{\bf x}_N$. We have $$U({\bf x}_1...{\bf x}_N) = -\frac{\hbar}{T} \log \langle \exp(-S_J) \rangle_0 , \label{a}$$ where $S_J$ is the term in the action containing the coupling to $J$, and the average $\langle ... \rangle_0$ is computed through the functional integral, weighing the field configurations with the factor $\exp(-S_0/\hbar)$. For a scalar field $\phi$, $S_J$ takes the form $$S_J = \int d^4x \, J(x) \phi(x)$$ and $J(x)$ is as in (\[eq3\]). For a gauge field $A_\mu$, the source term is $$\begin{aligned} S_J & = & \int d^4x \, J_\mu(x) A_\mu(x); \\ J_\mu(x) & = & \sum_{j=1}^N q_j \, \delta_{0 \mu} \, \delta^3 \left( {\bf x}-{\bf x}_j \right) .\end{aligned}$$ Therefore $S_J$ reduces to a sum of one-dimensional integrals computed along temporal lines. When the pointlike sources are only two and the field $A_\mu$ vanishes at infinity, $U({\bf x}_1,{\bf x}_2)$ can be also expressed in terms of a Wilson loop. For gravity the source term is $$\begin{aligned} S_T & = & \frac{1}{2} \int d^4x \, \sqrt{g(x)} \, T_{\mu \nu}(x) h_{\mu \nu}(x); \\ \label{lin} T_{\mu \nu}(x) & = & \sum_{j=1}^N m_j \, \delta_{\mu 0} \, \delta_{\nu 0} \, \delta^3({\bf x}-{\bf x}_j).\end{aligned}$$ The leading order contribution to (\[a\]) in the case of two pointlike sources is given in general by an expression of the form $$\begin{aligned} & & U({\bf x}_1,{\bf x}_2) = -\frac{\hbar}{T} \, q_1 q_2 \nonumber \\ & & \times \int_{-T/2}^{T/2} dt_1 \int_{-T/2}^{T/2} dt_2 \, \langle \Phi(t_1,{\bf x}_1)\Phi(t_2,{\bf x}_2) \rangle , \label{dop}\end{aligned}$$ where $\langle ... \rangle$ denotes the free propagator and $\Phi$ corresponds to the field $\phi$ in the scalar case and to the components $A_0$ and $h_{00}$ in the electromagnetic and gravitational cases, respectively (in the latter case, $q_1$ and $q_2$ are replaced by the masses $m_1$ and $m_2$ of the sources). The sign of the correlation $\langle \Phi(t_1,{\bf x}_1)\Phi(t_2,{\bf x}_2) \rangle$ is directly related to that of the potential energy. Some care is needed in order to pick the correct convention for the Euclidean metric. Eq.s (\[uno\]), (\[due\]) hold for the Euclidean metric with signature (-1,-1,-1,-1), which is directly connected to the standard Minkowski metric (1,-1,-1,-1) by the transformation $x_0 \leftrightarrow ix_0$. If the Euclidean metric (1,1,1,1) is used, eq. (\[dop\]) holds with the + sign. This metric is usually preferred and will be employed in the following. In the scalar and electromagnetic case, the correlation is positive. One finds (apart from positive numerical factors and with $c\equiv 1$) $$\langle \phi(x_1)\phi(x_2) \rangle \sim \langle A_0(x_1)A_0(x_2) \rangle \sim \frac{\hbar^{-1}}{(x_1-x_2)^2}; \label{corem}$$ thus the potential is repulsive if $q_1$ and $q_2$ have the same sign, since $$\begin{aligned} & & \int_{-T/2}^{T/2} dt_1 \int_{-T/2}^{T/2} dt_2 \frac{1}{(t_1-t_2)^2+({\bf x}_1 - {\bf x}_2)^2} \nonumber \\ & & \sim \frac{T}{|{\bf x}_1-{\bf x}_2|} .\end{aligned}$$ In the gravitational case, the correlation is negative: $$\langle h_{00}(x_1)h_{00}(x_2) \rangle \sim - \frac{\hbar^{-1}G}{(x_1-x_2)^2}; \label{corgra}$$ being $m_1$ and $m_2$ always positive for physical sources, it follows that the potential is always attractive. The negative sign of the correlation (\[corgra\]) may look counterintuitive. One should never forget, however, that quantum fields are distributions, and the analogy between a quantum functional integral and classical fields at finite temperature has only a limited validity. The positivity of the scalar action and of the electromagnetic action in Feynman gauge are evident in the Euclidean theory: one has namely in momentum space $$\begin{aligned} S_\phi & \sim & \int d^4p \, p^2 \, \tilde{\phi}^*(p) \tilde{\phi}(p) , \\ S_A & \sim & \int d^4p \, p^2 \, \delta_{\mu \nu} \tilde{A}^*_\mu(p) \tilde{A}_\nu(p)\end{aligned}$$ and for the propagators $$\tilde{G}_\phi(p) \sim p^{-2}; \ \ \ \ \ \tilde{G}_{A,\mu \nu}(p) \sim \delta_{\mu \nu} \, p^{-2} .$$ \[We recall that, still apart from positive numerical factors, $\int d^4p \, e^{ipx}p^{-2} \sim x^{-2}$. Compare (\[corem\])\]. Different aspects of the same problem: the action does not have a minimum. {#dif} ========================================================================== The Hilbert-Einstein action for the gravitational field $g_{\mu \nu}(x)$ is usually written in the form $$S = - \frac{1}{8\pi G} \int d^4x \, \sqrt{g(x)} R(x), \label{act}$$ where $R(x)$ is the scalar curvature. Naively one can observe already at this stage that since $R$ is a quantity which can be positive as well as negative and contains the first and second derivatives of the metric, the integrand does not have a definite sign and can grow in both directions if $g_{\mu \nu}(x)$ varies strongly. Hawking showed formally several years ago [@haw] that the Euclidean action is not bounded from below [@nota]. His argument is important also because it does not make any reference to the weak field approximation. Several possible solutions to the unboundedness problem were proposed later on [@unb]. Wetterich suggested recently [@wet] a non-local modification of the effective Euclidean action and showed that the phenomenological implications of such a modified action are almost entirely compatible with cosmology. Without entering into this matter, we just quote here his decomposition of the tensor of the metric fluctuations $h_{\mu \nu}(x) =g_{\mu \nu}(x)- \delta_{\mu \nu}(x)$ in terms of irreducible representations of the Euclidean group in $d$ dimensions: $$\begin{aligned} h_{\mu \nu}(x) &=& b_{\mu \nu}(x) + \partial_\mu a_\nu(x) + \partial_\nu a_\mu(x) \nonumber \\ & & + \left( \partial_\mu \partial_\nu - \frac{1}{d} \delta_{\mu \nu} \partial^2 \right) \chi(x) + \frac{1}{d} \delta_{\mu \nu} \sigma(x) ,\end{aligned}$$ where the tensors $b_{\mu \nu}(x)$ and $a_\mu(x)$ satisfy the conditions $$\partial_\mu a_\mu(x) = 0, \ \ \ \ \partial_\mu b_{\mu \nu}(x) = 0, \ \ \ \ \delta_{\mu \nu} b_{\mu \nu}(x) = 0 .$$ To second order in $h_{\mu \nu}$ one obtains $$\begin{aligned} \sqrt{g(x)} R(x) &=& \frac{1}{4} \partial_\rho b_{\mu \nu}(x) \partial_\rho b_{\mu \nu}(x) -\frac{(d-1)(d-2)}{4d^2} \times \nonumber \\ & & \times \partial_\mu \left[ \sigma(x) - \partial^2 \chi(x) \right] \partial_\mu \left[ \sigma(x) - \partial^2 \chi(x) \right] . \nonumber\end{aligned}$$ Therefore for $d>2$ the action becomes negative semi-definite for configurations in which $b_{\mu \nu}(x)$ is zero. It can be shown that the addition of a gauge-fixing term does not change the situation. Wetterich also observes that even though it is possible to make the action positive definite adding short-distance terms (like the $R^2$ term), the effective action, relevant for large distances, will always keep non positive. In certain cases it can be reasonable to introduce in the theory a cut-off on the momenta, and this will make the scalar curvature bounded. Still, the quadratic part of the action will not be positive-definite. This unpleasant feature does not only concern the small distances sector. It can be exhibited most clearly in harmonic gauge. In this gauge the quadratic part of the Hilbert-Einstein lagrangian in momentum space is simply given by $$\tilde{L}^{(2)}(p) \sim -p^2 \, \tilde{h}^*_{\mu \nu}(p) \, V_{\mu \nu \alpha \beta} \, \tilde{h}_{\alpha \beta}(p) ,$$ where $V_{\mu \nu \alpha \beta}$ is a constant tensor which in particular in dimension 4 is equal to $$V_{\mu \nu \alpha \beta} = \delta_{\mu \alpha} \delta_{\nu \beta} + \delta_{\mu \beta} \delta_{\nu \alpha} - \delta_{\mu \nu} \delta_{\alpha \beta}.$$ Let us rearrange the 10 independent components of the tensor $\tilde{h}$, to build an array $\tilde{h}_i$ ($i=0,1,...,9$), as follows: $\tilde{h}_{00} \to \tilde{h}_0,\ ...\ ,\tilde{h}_{33} \to \tilde{h}_3,\ \tilde{h}_{01} \to \tilde{h}_4,\ ...\ ,\tilde{h}_{23} \to \tilde{h}_9$. We then have $$\tilde{L}^{(2)}(p) \sim -p^2 \, \tilde{h}^*_i(p) \, M_{ij} \, \tilde{h}_j(p) ,$$ where [**M**]{} is a block matrix of the form $${\bf M} = \left[ \begin{array}{cc} {\bf m}(4 \times 4) & {\bf 0}(4 \times 6) \\ {\bf 0}(6 \times 4) & {\bf 1}(6 \times 6) \end{array} \right]$$ and $${\bf m} = \left[ \begin{array}{rrrr} 1 & -1 & -1 & -1 \\ -1 & 1 & -1 & -1 \\ -1 & -1 & 1 & -1 \\ -1 & -1 & -1 & 1 \end{array} \right] .$$ One easily checks that ${\bf m}^2=4 \times {\bf 1}$, thus the propagator of $\tilde{h}_i$ is given by $$\tilde{G}_{h}(p) \sim - p^{-2} \, {\bf M}^{-1} = - p^{-2} \, \left[ \begin{array}{cc} \frac{1}{4}{\bf m} & {\bf 0} \\ {\bf 0} & {\bf 1} \end{array} \right] .$$ As anticipated in Section \[rec\], we see here that the correlation function of $h_{00}$, like the other “diagonal" correlations, is negative. In order to check that the quadratic part of the gravitational action is not positive-definite, we can also rewrite $\tilde{L}^{(2)}(p)$ in matrix form as $$\tilde{L}^{(2)}(p) \sim -p^2 \left\{ 2 {\rm Tr} \, [\tilde{h}^*(p) \tilde{h}(p)] - |{\rm Tr} \, \tilde{h}(p)|^2 \right\}.$$ Denoting now by $\tilde{h}_A(p)$ $(A=0,1,2,3)$ the eigenvalues of the symmetric matrix $[\tilde{h}_{\mu \nu}(p)]$, we have $$\tilde{L}^{(2)}(p) \sim -p^2 \left[ \sum_A |\tilde{h}_A(p)|^2 - \sum_{A \neq B} \tilde{h}^*_A(p) \tilde{h}_B(p) \right] ,$$ or $$\tilde{L}^{(2)}(p) \sim -p^2 \, \tilde{h}^*_A(p) \, m_{AB} \, \tilde{h}_B(p). \label{quad}$$ The eigenvalues of ${\bf m}$ are found to be (2,2,-2,-2). Thus the quadratic form (\[quad\]) has no definite sign. The “zero modes" in the integral of $R$. {#zer} ======================================== It is known that if the metric has Lorentzian signature, then Einstein equations in vacuum admit wave-like solutions. The Riemann tensor $R^\mu_{\nu \rho \sigma}$ propagates in these solutions, while the Ricci tensor $R_{\mu \nu}$ and the curvature scalar $R$ are identically zero. We recall that the Einstein equations in the presence of a source $T_{\mu \nu}$ are (with $c \equiv 1$) $$R_{\mu \nu}(x)- \frac{1}{2} g_{\mu \nu}(x) R(x) = -8 \pi G T_{\mu \nu}(x), \label{ein}$$ and their trace is $$R(x)=8 \pi G {\rm Tr} \, T(x). \label{tra}$$ From (\[tra\]) we see that if $T_{\mu \nu}=0$, then $R=0$, as mentioned; therefore gravitational waves are a set of “zero modes" of the Hilbert-Einstein [*lagrangian*]{} [@pass]. There is, however, another peculiar way to obtain zero modes of the gravitational [*action*]{}. This is due to the non-positivity of this action. Let us consider a solution $g_{\mu \nu}$ of eq. (\[ein\]) with a (covariantly conserved) source $T_{\mu \nu}$ obeying the additional integral condition $$\int d^4x \, \sqrt{g(x)} \, {\rm Tr} \, T(x) = 0. \label{add}$$ Taking into account eq. (\[tra\]) we see that the action (\[act\]) computed for this solution is zero. Condition (\[add\]) can be satisfied by energy-momentum tensors that are not identically zero, provided they have a balance of negative and positive signs, such that their total integral is zero. Of course, they do not represent any acceptable physical source, but the corresponding solutions of (\[ein\]) exist nonetheless, and are zero modes of the action. As an example of an unphysical source which satisfies (\[add\]) one can consider the static field produced by a “mass dipole". Certainly negative masses do not exist in nature; here we are interested just in the formal solution of (\[ein\]) with a suitable $T_{\mu \nu}$, because for this solution we have $\int d^4x \, \sqrt{g} R=0$. Let us take the following $T_{\mu \nu}$ of a static dipole centered at the origin ($m,m'>0$): $$T_{\mu \nu}({\bf x}) = \delta_{\mu 0} \, \delta_{\nu 0} \left[ m f( {\bf x}+{\bf a} ) - m' f( {\bf x}-{\bf a} ) \right] . \label{dip}$$ Here $f({\bf x})$ is a smooth test function centered at ${\bf x}=0$, rapidly decreasing and normalized to 1, which represents the mass density. The range of $f$, say $r_0$, is such that $a \gg r_0 \gg r_{Schw}$, where $r_{Schw}$ is the Schwartzschild radius corresponding to the mass $m$. The mass $m'$ is in general different from $m$ and chosen in such a way to compensate a possible small difference, due to the $\sqrt{g}$ factor, between the integrals $$\begin{aligned} I^+ &=& \int d^4x \, \sqrt{g(x)} f( {\bf x}+{\bf a} ) \ \ \ {\rm and} \nonumber \\ I^- &=& \int d^4x \sqrt{g(x)} f( {\bf x}-{\bf a} ). \label{piu}\end{aligned}$$ The procedure for the construction of the zero mode corresponding to the dipole is the following. One first considers Einstein equations with the source (\[dip\]). Then one solves them with a suitable method, for instance in the weak field approximation. Finally, knowing $\sqrt{g(x)}$ one computes the two integrals (\[piu\]) and adjusts the parameter $m'$ in such a way that $(mI^+ - m'I^-)=0$. Let us implement this procedure to first order. Inside a single mass distribution $mf({\bf x})$, with radius $r_0$ such that $r_0 \gg r_{Schw}$, the gravitational field satisfies a static equation whose linear approximation is of the form $$D h({\bf x}) = m \kappa f({\bf x}), \label{linear}$$ where $D$ is a linear partial differential operator and $\kappa$ denotes, for brevity, $8\pi G$. Let us call $\hat{h}({\bf x})$ the solution of (\[linear\]) with $m\kappa$ replaced by 1. The solution of the linearized Einstein equations with the source (\[dip\]) is, in the region with positive density, $h^+({\bf x})= m\kappa\hat{h}({\bf x}+{\bf a})$. In the region with negative density the solution is $h^-({\bf x})= -m'\kappa\hat{h}({\bf x}-{\bf a}/2)$. Thus in the region with positive density we have $$\sqrt{g(x)} \sim 1 + \frac{1}{2} m \kappa \, {\rm Tr} \, \hat{h} ( {\bf x}+{\bf a} )$$ and in the region with negative density $$\sqrt{g(x)} \sim 1 - \frac{1}{2} m' \kappa \, {\rm Tr} \, \hat{h} ( {\bf x}-{\bf a} ) .$$ The value of the action functional corresponding to this linearized “virtual dipole" metric is $$\begin{aligned} & & - \frac{1}{\kappa} \int d^4x \, \sqrt{g(x)} R(x) = - \int d^4x \, \sqrt{g(x)} \, {\rm Tr} \, T(x) = \nonumber \\ & & = - \int d^4x \, \sqrt{g(x)} \left[ m f( {\bf x}+{\bf a} ) - m' f( {\bf x}-{\bf a} ) \right] = \nonumber \\ & & = - \int d^4x \, \left\{ \left[ 1 + \frac{1}{2} m \kappa \, {\rm Tr} \, \hat{h} ( {\bf x}+{\bf a} ) \right] m f( {\bf x}+{\bf a} ) + \right. \nonumber \\ & & \ \ \ \ - \left. \left[ 1 - \frac{1}{2} m' \kappa \, {\rm Tr} \, \hat{h} ( {\bf x}-{\bf a} ) \right] m' f( {\bf x}-{\bf a} ) \right\} = \nonumber \\ & & = - \int d^4x \, \left[ m f( {\bf x}+{\bf a} ) - m' f( {\bf x}-{\bf a} ) \right] + \nonumber \\ & & \ \ \ \ - \frac{1}{2} \kappa \int d^4x \, \left[ m^2 \, {\rm Tr} \, \hat{h} ( {\bf x}+{\bf a} ) f( {\bf x}+{\bf a} ) + \right. \nonumber \\ & & \ \ \ \ + \left. {m'}^2 \, {\rm Tr} \, \hat{h} ( {\bf x}-{\bf a} ) f( {\bf x}-{\bf a} ) \right]. \label{lunga}\end{aligned}$$ Being $f$ normalized, the first integral of (\[lunga\]) gives $-T(m-m')$, where $T$ is the temporal integration range. We then have $$\begin{aligned} & & - \frac{1}{\kappa} \int d^4x \, \sqrt{g(x)} R(x) = - T(m-m') \nonumber \\ & & \ \ \ \ - \frac{1}{2} \kappa T (m^2+{m'}^2) \int d^3x \, \, {\rm Tr} \, \hat{h}({\bf x}) f({\bf x}).\end{aligned}$$ The integral on the r.h.s. is a number of the order of 1 and will be denoted by $\eta$. The condition for a zero mode now reads $$(m-m') + \frac{1}{2} \eta \kappa (m^2+{m'}^2) = 0$$ and it is satisfied, up to terms of order $\kappa^2$, for $m'=m(1+\eta \kappa m)$. There is no obstacle, in the functional integral, to the formation of a zero mode like this. It can “pop up" at any point in spacetime, or more likely it can be induced by an external localized source, even if weak. The spatial size of the mode can be in principle arbitrarily large. These modes can develop both in Lorentzian and in Euclidean metric. Sometimes it is argued that in the functional integral with real time and with the oscillating factor $\exp(iS/\hbar)$ the non-positivity of the action has no importance. But also in that case the zero modes described above can be present. The only mechanism able to suppress these modes appears to be the presence of an effective volume term with $\Lambda<0$ (see Section \[how\]). How flat space emerges from the quantum Regge lattice. {#how} ====================================================== It can be helpful to recall briefly here the main features of the quantum Regge calculus technique by Hamber and Williams [@hw]. In this approach the Euclidean 4D spacetime is approximated by a simplicial manifold and the curvature, all concentrated at the “hinges", is proportional to the defect angle which one finds when a hinge is flattened out. The system is numerically simulated, with the edge lengths as fundamental variables. At the beginning one puts into the action, as “bare" parameters, $k$ (inverse of the Newton constant) and $a$ (coefficient of the $R^2$ term). Then one looks in the phase diagram of the theory for a second-order transition point. It turns out that the phase diagram is divided in two regions: a “smooth" phase, with average curvature small and negative, and fractal dimension close to 4; and a “rough" phase, singular, collapsed, with average curvature large and positive and small fractal dimension. It is clear that the sign of the curvature plays a crucial role in the stability of the system. The two phases are separated by a transition line. Approaching this line from the smooth phase, the average curvature $\langle R \rangle$ tends to zero. In this way, flat space is obtained in a dynamical way from the smooth phase, without any need of introducing into the theory a flat background by hand. From here, perturbation theory can somehow start. A few data can help to complete the picture. The lattice sites are $16 \times 16 \times 16 \times 16=65,536$, with 1,572,864 simplices. The edge lengths are updated by a straightforward Montecarlo algorithm. Eventually an ensemble of configurations is generated, distributed according to the Euclidean action. The topology is fixed as a four-torus with periodic boundary conditions. A stable, well behaved ground state is found for $k<k_c\sim 0.060$. The system resides in the smooth phase, with fractal dimension four. Six values of $k$ have been investigated: 0.00, 0.01, 0.02, 0.03, 0.04, 0.05. The static potential is attractive and can be fitted by $L^{-1}$, with a small Yukawa factor $\exp(-mL)$. The mass extracted this way is consistent with the exponential decay of the correlations of the scalar curvature. The effective Newton constant can be extimated to $G\sim 0.14$, in lattice units. More exactly, at the beginning one puts $\lambda=1$ in the action. Then one finds for the average edge length $$l_0 = \sqrt{\langle l^2 \rangle} = 2.36, \ \ \ \ {\rm i.e.} \ \ \ \ l_0 = 2.36 \, \lambda^{-1/4}. \label{latt}$$ The critical value of the bare coupling is $$k_c \sim 0.060, \ \ \ {\rm i.e.} \ \ \ k_c ~ 0.060 \, \lambda^{1/2}$$ and the product $G k_c$ is independent of $l_0$ and finite, as hoped. The precision of these data is expected to improve considerably in the next months, thanks to the new dedicated supercomputer AENEAS [@aen]. As far as stability is concerned, the numerical simulations show as mentioned that in the smooth phase the system evolves toward a stable minimum position with $\langle R \rangle <0$. It is not hard to understand intuitively, from the geometrical point of view, [*why*]{} the system is stable in this phase. The effective action is $$S_{eff} = \int d^4x \, \sqrt{g(x)} \left[ \frac{\Lambda}{8\pi G} - \frac{R(x)}{8\pi G} \right] , \label{effa}$$ with $\Lambda \sim \langle R \rangle$. Let us assume that the system is in a configuration with $R(x)=const. =\Lambda$. Now suppose that somewhere a positive fluctuation of $R$ appears. Being proportional to $\exp(-S_{eff})$, the probability of this new configuration is seemingly larger, if we take into account only the second term of the action. The first term, however (the effective cosmological term) can be written as $(\Lambda {\cal V})$, where ${\cal V}$ is the total volume of the system. This volume is maximum when the manifold is flat and all hinges are completely extended. As soon as a curvature fluctuation appears at some point the total volume decreases, and since $\Lambda$ is negative, this tends to suppress the fluctuation. The converse happens, of course, in the collapsed phase, where $\Lambda>0$. Furthermore, this same mechanism will suppress in an even stronger way the zero-modes described in Section \[zer\], since these modes cause no variation of the integral of $R$, but only decrease the volume. The continuum theory is recovered from the lattice only at the transition line, where $\Lambda =0$. This refers, however, to an average computed over all space. More generally, $\Lambda$ scales with the volume $v$ of the averaged region, according to a power law of the form $|\Lambda| G \sim (v^{-1/4}l_0)^\gamma$. Is AdS space a stable minimum of the continuum action? {#ads} ====================================================== As we have seen in the previous Section, the discretized Euclidean action appears to be stabilized by a negative cosmological term. This acts as a volume term and opposes the curvature fluctuations, which tend to diminish the volume of the lattice. Is the geometrical argument offered independent of the Regge lattice regularization? This question suggests a check in the continuum. If eq. (\[effa\]) really has a stable minimum, then that minimum must be a solution of the Euclidean Einstein equations with a negative cosmological constant. Such a solution is known; this is Euclidean anti-de Sitter (AdS) space. Therefore, we can do a stability analysis: is AdS space a stable minimum of the action, with only positive modes in the weak-field expansion in this background? Or is it only a saddlepoint, like flat space? A stability analysis in AdS space is more intricate than in flat space. We must expand the metric with respect to the appropriate background, namely $$g_{\mu \nu}(x) = g^{AdS}_{\mu \nu}(x) + h_{\mu \nu}(x)$$ where $g^{AdS}_{\mu \nu}(x)$ is the solution of the vacuum Euclidean Einstein equations with a negative cosmological term and thus represents a space with constant negative curvature. The form of the metric $g^{AdS}_{\mu \nu}(x)$ depends on the coordinates chosen. We can formally expand the action as $$S[g] = S[g^{AdS}] + \frac{\delta S}{\delta g} [g^{AdS}] \times h + \frac{1}{2} \frac{\delta^2 S}{\delta g^2} [g^{AdS}] \times h^2 + ...$$ The first derivative vanishes at $g^{AdS}$ and to check the stability we must study the sign of the quadratic form $U= \frac{\delta^2 S}{\delta g^2} [g^{AdS}]$. Remembering that the first variation of $S$ gives the Einstein equations, we obtain $$U^{\alpha \beta \mu \nu}(x) = \left[ \frac{\delta S} {\delta g_{\alpha \beta}} \left( R^{\mu \nu} - \frac{1}{2} g^{\mu \nu} R - \Lambda g^{\mu \nu} \right) \right]_{g=g^{AdS}(x)}.$$ The functional derivative of the first two terms corresponds, up to a gauge-fixing, to the usual quadratic form of pure gravity, while the derivative of the cosmological term gives $-\Lambda g^{AdS,\mu \alpha}(x) g^{AdS,\nu \beta}(x)$ [@nota2]. The second variation of $S$ at the extremum must take into account the dependence of $U$ on $x$: $$\delta^2 S = \frac{1}{2} \int d^4x \, \sqrt{g^{AdS}(x)} h_{\alpha \beta}(x) U^{\alpha \beta \mu \nu}(x) h_{\mu \nu}(x).$$ Since the AdS space is homogeneous and we are most interested in localized fluctuations, we could restrict our attention to functions $h_{\mu \nu}(x)$ having support in a small region around the origin. In suitable coordinates we will have $g^{AdS}_{\mu \nu}(x) \sim g^{AdS}_{\mu \nu}(0)= \delta_{\mu \nu}$, but the gauge fixing term constitutes a serious problem, because it must be consistent with the symmetries of the background and with the fact that the fluctuations are localized (compare also Ref. [@tw], for the de Sitter case and related horizon and infrared problems). In conclusion, investigating stability along these lines appears to be very hard. Another possible check concerns the conformal mode. In this case, a weak field expansion is not necessary. For any conformal transformation of the metric of the form $$g_{\mu \nu} \to g'_{\mu \nu}(x) = \Omega^2(x) g_{\mu \nu}(x)$$ the curvature scalar transforms as $$R(x) \to R'(x) = \Omega^{-2}(x)R(x) - 6 \Omega^{-3}(x) \partial^2 \Omega(x)$$ and the action with cosmological term transforms as (we omit the $x$-dependence) $$S \to S' = - \frac{1}{8\pi G} \int d^4x \, \sqrt{g} (\Omega^2 R + 6 \partial_\mu \Omega \partial_\nu \Omega g^{\mu \nu} - \Lambda \Omega^4). \label{stab}$$ Note that $g_{\mu \nu}(x)$ does not need to be constant, and in our case coincides with the AdS metric. We see from (\[stab\]) that for $\Lambda<0$ the conformal mode is [*not*]{} stabilized. On the contrary, it seems that conformal fluctuations can increase the total volume of space and are therefore enhanced. This continuum result is in bold contrast with our intuition of the behavior of the lattice. The contrast could be possibly explained as follows. \(i) It turns out from the numerical simulations that after the simplicial lattice has reached its ground state and has stabilized, the average length $l_0$ of the links (the “bones" of the triangulation) keeps constant and fluctuations are small. This behavior could be due in part to the $R^2$ term or to the volumes in phase space, rather than to the Einstein $R$ term; it signals, anyway, that an effective suppression of the conformal modes has occurred. \(ii) If the lengths of the lattice links are approximately constant, then any increase of the curvature implies an increase of defect angles and thus a diminution of the total volume, as argued in the previous Section. This is easily visualized in two dimensions. Let us consider, for instance, an orthogonal pyramid with a regular polygon as its basis (but here we are only interested in the side surface of the pyramid—the 2D volume). Suppose to keep constant the edges of the pyramid—the links. When the height of the pyramid goes to zero, the side surface is maximum and the defect angle $\delta$, associated to the curvature, is zero. (The defect angle is that obtained by “opening" the pyramid, as if it was made of paper.) The sharper the pyramid, the larger $R \sim \delta$ and the smaller the side surface. The variation of the side surface is of the order of $\Delta {\cal S} \sim - (\Delta \sin \delta) l_0^2$. The 4D analogue is $\Delta {\cal V} \sim - (\Delta \sin \delta) l_0^4$, while the contribution of the curvature to the Einstein action is of the order of $\Lambda (\Delta \delta) l_0^2$. Since in lattice units we have (compare (\[latt\])) $l_0 = \sqrt{\langle l^2 \rangle} >1$ and $|\Lambda|>1$, the lattice prefers to keep the $\delta$’s close to zero. The author would like to thank all the staff of ECT\* for the kind hospitality during completion of this work. E-mail: [[email protected]]{}. K. Symanzik, Comm. Math. Phys. [**16**]{}, 48 (1970). M. Bander, Phys. Rep. [**75**]{}, 205 (1981). H.W. Hamber, Nucl. Phys. [**B 400**]{}, 347 (1993) and ref.s.H.W. Hamber and R. Williams, Nucl. Phys. [**B 435**]{}, 361 (1995). G.W. Gibbons (ed.), S.W. Hawking (ed.), [*Euclidean Quantum Gravity*]{} (World Scientific, Singapore, 1993). E. Alvarez, Rev. Mod. Phys. [**61**]{}, 561 (1989). G. Modanese, Nucl. Phys. [**B 434**]{}, 697 (1995). I.J.Muzinich and S. Vokos, Phys. Rev. [**D 52**]{}, 3472 (1995). S.W. Hawking, in [*General Relativity: an Einstein Centenary Survey*]{}, edited by S.W. Hawking and W. Israel (Cambridge University Press, Cambridge, 1979). See also P. Menotti, [*Non-perturbative quantum gravity*]{}, Nucl. Phys. (Proc. Suppl.) [**B 17**]{}, 29 (1990). In the $R+R^2$ theory the action is positive definite, provided the coefficient $a$ of the $R^2$ term is such that $4a\lambda-k^2>0$ (compare Section \[how\]). Remembering that the $R^2$ term also makes the theory renormalizable, it is easy to understand why the $R+R^2$ action has been chosen, instead of the simple Einstein action, for non perturbative investigations through the Regge discretization. (The unitarity problem does not show up in the non perturbative approach.) It was found, however, that the emergence in the quantum Regge calculus of a stable ground state with zero average curvature does not strictly require the $R^2$ term. See, for instance, J. Greensite, Phys. Lett. [**B 291**]{}, 405 (1992) and references; J. Greensite, Nucl. Phys. [**B 390**]{}, 439 (1993); E. Mazur and E. Mottola, Nucl. Phys. [**B 341**]{}, 187 (1990). C. Wetterich, Gen. Rel. Grav. [**30**]{}, 159 (1998). We note in passing that if the signature of the metric is Euclidean, then the equation $\partial^2 f=0$ does not really admit wave-like solutions. Instead, it has the form of a 4D Poisson equation and its solutions are harmonic functions, which reduce to costants if there are no sources. The status of the project is described at the URL $\langle$http://aeneas.ps.uci.edu/aeneas /index.html$\rangle$. Setting $g^{AdS}_{\mu \nu}(x)=const.=\delta_{\mu \nu}$ we would obtain the known “naive" statement that a cosmological term in weak field approximation amounts to a mass term for the graviton (see for instance [@vel]). It is clear, however, that this statement is not rigorously true, since in AdS space the metric $g^{AdS}$ which minimizes the action is not flat. M.J.G. Veltman, in [*Methods in Field Theory*]{}, Proceedings of the Les Houches Summer School, Les Houches, France, 1975, edited by R.Balian and J. Zinn-Justin, Les Houches Summer School Proceedings Vol.XXVIII (North-Holland, Amsterdam, 1976). N.C. Tsamis and R.P. Woodard, Comm. Math. Phys. [**162**]{}, 217 (1994); Ann. Phys. [**238**]{}, 1 (1995); Phys. Lett. [**B 301**]{}, 351 (1993). E.G. Floratos, J. Iliopoulos and T.N. Tomaras, Phys. Lett., 373 (1987). B. Allen and M. Turyn, Nucl. Phys. [**B 292**]{}, 813 (1987). M. Turyn, J. Math. Phys. [**31**]{}, 669 (1990). I.Antoniadis and E. Mottola, J. Math. Phys. [**32**]{}, 1037 (1991). | Mid | [
0.5545023696682461,
29.25,
23.5
] |
Q: Continuous coloring of a Mandelbrot fractal I've recently started making a small fractal app in Javascript using the famous Mandelbrot bulb $(z = z^2 + c)$. I've been trying to find the best method of coloring the points on the complex plane, and I've come across some very interesting ideas: http://linas.org/art-gallery/escape/escape.html http://en.wikibooks.org/wiki/Fractals/Iterations_in_the_complex_plane/Mandelbrot_set#Real_Escape_Time So I've been focusing on this "normalized iteration count algorithm" and I've run into a small mental hurdle sorting out what needs to be calculated. Basically, I'm confused about the first equation that shows up in that second link. Assuming we have a complex number $Z$ which is the end result of $n$ iterations. I can't quite figure out what "Zx2" or "zy2" is and how how one might add them together or take the square root of their sum. Is that just shorthand for some basic complex operators, or is there something else going on? Basically, my problem is that I'm not particularly good at reading mathematical notation in this area. Anyway...any directional guidance you can offer would be extremely helpful. Thanks in advance! A: Based on the C code given there, Zx is just the real part $\Re z$ and Zy is just the imaginary part $\Im z$. Remember that the complex iteration formula for the Mandelbrot set $z=z^2+c$ when expanded to real variables looks like $x=x^2-y^2+u$ $y=2xy+v$ where $z=x+iy$ and $c=u+iv$. The variables with a 2 appended are the squares, as can be seen from how they were defined, so for instance $|z|=\sqrt{x^2+y^2}$ is sqrt(Zx2+Zy2) which is used for determining how much the iteration diverges (escapes to infinity), which is used by the coloring functions. A: edit: "Zx2" and "Zy2" are defined in the C code in the second code block at this point in your wikibooks link. They are the squares of the real and imaginary parts, respectively, of $z$. I'm not sure if it's exactly the same, but what I've used is: $$n-\log\left(\frac{\log(|z|)}{\log(r)}\right)$$ where $z$ is the result of $n$ iterations and has just escaped as noted by $|z|>r$ (where $r$ is the escape radius). This generates real numbers in $[0,n)$, so you could divide by $n$ to end up with a number in $[0,1)$. | Mid | [
0.572944297082228,
27,
20.125
] |
[Protective effect of myosin light-chain kinase inhibitor on acute lung injury]. To investigate the influence of inhibitor of myosin light-chain kinase (MLCK) on the human pulmonary arterial endothelial cell (HPAEC) challenged with lipopolysaccharide (LPS) and LPS induced of acute lung injury (ALI) in mice. HPAECs were cultured in ECM medium and its passages 4-6 were used. After treatment with inhibitor of MLCK (ML-7) for 60 minutes, the HPAECs were incubated in LPS for another 60 minutes, and then cell viability was measured by the methyl thiazolyl tetrazolium (MTT) assay. Immunofluorescence microscope was used to detect phosphorylated-MLCK (p-MLCK) immunoreactive cells. Twenty female BALB/c mice were randomly divided into two groups. The mice of LPS group were exposed to LPS (1 microg/g) through nasal instillation, and the mice of ML-7 group were pretreated with ML-7 before intranasal instillation of LPS. Wet/dry weight (W/D) ratio of lung, bronchoalveolar lavage fluid (BALF) protein content, myeloperoxidase (MPO) activity and histopathological changes of lung tissue were observed. Immunohistochemistry assays were used to determine the status of MLCK and CD11b immunoreactive cells in lung tissue, and expression of MLCK mRNA in lung tissue was assessed by reverse transcription-polymerase chain reaction (RT-PCR). Expression of MLCK protein in lungs was assayed by Western blotting. Compared with LPS group, increased absorbance (A) value of HPAEC was found in ML-7 group (P<0.01). Immunoreactive cells of p-MLCK were more reduced in the ML-7 group (P<0.05), and W/D ratio of lung, MPO activity and BALF protein content of lung tissue were decreased in ML-7 group (P<0.05 or P<0.01). Histological examination showed that an extensive lung inflammation was seen in mice of LPS group, with an accumulation of a large number of neutrophils, marked pulmonary edema and hemorrhage, but the inflammation and parenchymal hemorrhage was significantly alleviated in ML-7 group. Both MLCK immunoreactive cells located in endothelium and CD11b in infiltrated inflammatory cells were decreased in ML-7 group compared with those in LPS group. Compared with LPS group, MLCK mRNA and protein expressions (A) in ML-7 group were significantly decreased (both P<0.05). ML-7, an MLCK inhibitor, enhances activity of HPAEC induced by LPS and reduces expression of p-MLCK. It also reduces the LPS-induced infiltration of neutrophils in lung tissues, pulmonary edema and expression of MLCK and CD11b protein and MLCK mRNA in lung tissues, demonstrating that inhibition of activation of MLCK, leading to an abatement of phosphorylation of myosin light chain or MLCK, resulting in stabilization of vascular barrier function. The results suggest that MLCK has a crucial role in the pathogenesis of ALI. | High | [
0.660273972602739,
30.125,
15.5
] |
/*****************************************************************************
To be the apostrophe which changed "Impossible" into "I'm possible"!
POC code of chapter 5.6 in book "Vulnerability Exploit and Analysis Technique"
file name : bindshell.c
author : failwest
date : 2006.12.11
description : used to generate PE file and extracted machine code
Noticed : assume EAX point to the beginning of shellcode
can't be executed directly
have to be loaded by shellcode loader
version : 1.0
E-mail : [email protected]
reference :"Writing Small Shellcode", Dafydd Stuttard, NGS white paper, 2005.9.19
http://www.nextgenss.com/research/papers/WritingSmallShellcode.pdf
Only for educational purposes enjoy the fun from exploiting :)
******************************************************************************/
main()
{
__asm{
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
; start of shellcode
; assume: eax points here
; function hashes (executable as nop-equivalent)
_emit 0x59 ; LoadLibraryA ; pop ecx
_emit 0x81 ; CreateProcessA ; or ecx, 0x203062d3
_emit 0xc9 ; ExitProcess
_emit 0xd3 ; WSAStartup
_emit 0x62 ; WSASocketA
_emit 0x30 ; bind
_emit 0x20 ; listen
_emit 0x41 ; accept ; inc ecx
; "CMd"
_emit 0x43 ; inc ebx
_emit 0x4d ; dec ebp
_emit 0x64 ; FS:
; start of proper code
cdq ; set edx = 0 (eax points to stack so is less than 0x80000000)
xchg eax, esi ; esi = addr of first function hash
lea edi, [esi - 0x18] ; edi = addr to start writing function
; addresses (last addr will be written just
; before "cmd")
; find base addr of kernel32.dll
mov ebx, fs:[edx + 0x30] ; ebx = address of PEB
mov ecx, [ebx + 0x0c] ; ecx = pointer to loader data
mov ecx, [ecx + 0x1c] ; ecx = first entry in initialisation order list
mov ecx, [ecx] ; ecx = second entry in list (kernel32.dll)
mov ebp, [ecx + 0x08] ; ebp = base address of kernel32.dll
; make some stack space
mov dh, 0x03 ; sizeof(WSADATA) is 0x190
sub esp, edx
; push a pointer to "ws2_32" onto stack
mov dx, 0x3233 ; rest of edx is null
push edx
push 0x5f327377
push esp
find_lib_functions:
lodsb ; load next hash into al and increment esi
cmp al, 0xd3 ; hash of WSAStartup - trigger
; LoadLibrary("ws2_32")
jne find_functions
xchg eax, ebp ; save current hash
call [edi - 0xc] ; LoadLibraryA
xchg eax, ebp ; restore current hash, and update ebp
; with base address of ws2_32.dll
push edi ; save location of addr of first winsock function
find_functions:
pushad ; preserve registers
mov eax, [ebp + 0x3c] ; eax = start of PE header
mov ecx, [ebp + eax + 0x78] ; ecx = relative offset of export table
add ecx, ebp ; ecx = absolute addr of export table
mov ebx, [ecx + 0x20] ; ebx = relative offset of names table
add ebx, ebp ; ebx = absolute addr of names table
xor edi, edi ; edi will count through the functions
next_function_loop:
inc edi ; increment function counter
mov esi, [ebx + edi * 4] ; esi = relative offset of current function name
add esi, ebp ; esi = absolute addr of current function name
cdq ; dl will hold hash (we know eax is small)
hash_loop:
lodsb ; load next char into al and increment esi
xor al, 0x71 ; XOR current char with 0x71
sub dl, al ; update hash with current char
cmp al, 0x71 ; loop until we reach end of string
jne hash_loop
cmp dl, [esp + 0x1c] ; compare to the requested hash (saved on stack from pushad)
jnz next_function_loop
; we now have the right function
mov ebx, [ecx + 0x24] ; ebx = relative offset of ordinals table
add ebx, ebp ; ebx = absolute addr of ordinals table
mov di, [ebx + 2 * edi] ; di = ordinal number of matched function
mov ebx, [ecx + 0x1c] ; ebx = relative offset of address table
add ebx, ebp ; ebx = absolute addr of address table
add ebp, [ebx + 4 * edi] ; add to ebp (base addr of module) the
; relative offset of matched function
xchg eax, ebp ; move func addr into eax
pop edi ; edi is last onto stack in pushad
stosd ; write function addr to [edi] and increment edi
push edi
popad ; restore registers
cmp esi, edi ; loop until we reach end of last hash
jne find_lib_functions
pop esi ; saved location of first winsock function
; we will lodsd and call each func in sequence
; initialize winsock
push esp ; use stack for WSADATA
push 0x02 ; wVersionRequested
lodsd
call eax ; WSAStartup
; null-terminate "cmd"
mov byte ptr [esi + 0x13], al ; eax = 0 if WSAStartup() worked
; clear some stack to use as NULL parameters
lea ecx, [eax + 0x30] ; sizeof(STARTUPINFO) = 0x44,
mov edi, esp
rep stosd ; eax is still 0
; create socket
inc eax
push eax ; type = 1 (SOCK_STREAM)
inc eax
push eax ; af = 2 (AF_INET)
lodsd
call eax ; WSASocketA
xchg ebp, eax ; save SOCKET descriptor in ebp (safe from
; being changed by remaining API calls)
; push bind parameters
mov eax, 0x0a1aff02 ; 0x1a0a = port 6666, 0x02 = AF_INET
xor ah, ah ; remove the ff from eax
push eax ; we use 0x0a1a0002 as both the name (struct
; sockaddr) and namelen (which only needs to
; be large enough)
push esp ; pointer to our sockaddr struct
; call bind(), listen() and accept() in turn
call_loop:
push ebp ; saved SOCKET descriptor (we implicitly pass
; NULL for all other params)
lodsd
call eax ; call the next function
test eax, eax ; bind() and listen() return 0, accept()
; returns a SOCKET descriptor
jz call_loop
; initialise a STARTUPINFO structure at esp
inc byte ptr [esp + 0x2d] ; set STARTF_USESTDHANDLES to true
sub edi, 0x6c ; point edi at hStdInput in STARTUPINFO
stosd ; use SOCKET descriptor returned by accept
; (still in eax) as the stdin handle
stosd ; same for stdout
stosd ; same for stderr (optional)
; create process
pop eax ; set eax = 0 (STARTUPINFO now at esp + 4)
push esp ; use stack as PROCESSINFORMATION structure
; (STARTUPINFO now back to esp)
push esp ; STARTUPINFO structure
push eax ; lpCurrentDirectory = NULL
push eax ; lpEnvironment = NULL
push eax ; dwCreationFlags = NULL
push esp ; bInheritHandles = true
push eax ; lpThreadAttributes = NULL
push eax ; lpProcessAttributes = NULL
push esi ; lpCommandLine = "cmd"
push eax ; lpApplicationName = NULL
call [esi - 0x1c] ; CreateProcessA
; call ExitProcess()
call [esi - 0x18] ; ExitProcess
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
nop
}
}
| Low | [
0.534351145038167,
35,
30.5
] |
On the Road in Lake George: Bangin Breakfast at Café Vero On the morning our friend Damion was running the Lake George Half Marathon, the weather was not good. As in, it sucked. With some time to kill before he crossed the finish line, Rob and I decided to walk (since Damion had the car) to get some breakfast at Café Vero. The walk was a terrible idea. Café Vero was a great idea. It was cold, windy, and the pouring rain added that extra special touch that we all love. Luckily, Café Vero was about a 10 minute walk away from the hotel. The night before this breakfast venture, I asked around and locals informed me that Vero was the place to go for some morning grub. We walked into a dry, warm, café area. Café Vero roasts their own coffee and that was clear as this place smelled wonderful. My stomach started growling and we were seated in the dining section of the café. Since we were soaked, we asked to be seated right near the fireplace that keeps this place so toasty. Vero really has that hometown feel. One of the things Vero is famous for is their café lattes. Right away I ordered a caramel flavored version. So, you know that cool thing when the coffee experts make something like a heart or a fancy leaf on top of the latte? Yeah. They do that. Maybe this doesn’t add any taste but it sure is cool. I was pleased with the strength of the espresso and it warmed me right up. The caramel was tasty and I didn’t need to add anything to it. Time for breakfast. Our waitress’ dad assisted in my breakfast decision. As I was mulling over the menu, he suggested an omelet or the American Breakfast (a classic two eggs any style with meat and home fries). I always trust the locals so I went with it. My order: a bacon & mushroom omelet with cheese, wheat toast, and home fries. When my order arrived, I marveled at how big and how packed with bacon & mushroom goodness it was. That plate, may it rest in peace, had no chance. As much as I write about burgers and steak, I love breakfast. Café Vero did not skimp on the omelet fillings and I like that. It was one of the better breakfasts I’ve had anywhere. The toast was awesome too. This is not the type of bread that comes from a factory. This was homemade and our waitress told us that it is in fact local but did not know the exact place or baker. The home fries, crispy, well seasoned, and flat out delicious. Even the price was something to smile about. For two café lattes, my omelet extravaganza, and Rob’s American Breakfast, it only came to $23. Good price, good coffee, go there when you’re in Lake George. Café Vero is right on the main drag on Canada Street and can be reached at caffeverocoffee.com/ or 518-668-5800. They even have another location in Albany. | High | [
0.6710013003901171,
32.25,
15.8125
] |
Fast Bounded-Concurrency Hash Tables - nkurz http://backtrace.io/blog/blog/2015/03/13/workload-specialization ====== bbulkow We use this in our project --- [https://github.com/aerospike/aerospike- client-c](https://github.com/aerospike/aerospike-client-c) | Low | [
0.527777777777777,
26.125,
23.375
] |
Chamseddine Harrag Chamseddine Harrag (; born 10 August 1992) is an Algerian footballer who plays for MC Alger in the Algerian Ligue Professionnelle 1. References Category:Living people Category:1992 births Category:Algerian footballers Category:USM El Harrach players Category:NA Hussein Dey players Category:MC Alger players Category:Association football midfielders | High | [
0.6648501362397821,
30.5,
15.375
] |
Q: Validate form with jQuery on submit I have this function when I click on my submit button: $('#signup-button').click(function(event){ var username_check = validateUsernameField(); var email_check = validateEmailField(); var name_check = validateNameField(); var birthdate_check = validateBirthdateField(); event.preventDefault(); if(username_check && email_check && name_check && birthdate_check) { alert('lol'); var formData = $('#FonykerAddForm').serialize(); $.ajax ({ type: 'POST', url: '<?php echo $html->url('/fonykers/add',true); ?>', data: formData, dataType: 'json', success: function(response) { $( "#confirm-dialog" ).html(response.msg).dialog({ autoOpen: false, modal: true, height: 140, title: response.title }); $('#confirm-dialog').dialog('open'); }, error: function (xhr, ajaxOptions, thrownError){ alert('Cualquier vaina'); alert(xhr.statusText); alert(thrownError); } }); } }); I previously call the validate methods on blur events on my fields, and they all work and the validation here seems to work, the problem is that after the if statement nothing happens, the form isn't submitted. Anybody have any idea why? And if not can you think of a better way to validate all my fields before submit? A: The problem was the variables I use in the if statement some were returning undefined so it screwed up the call. I simply replaced checking for the variables to checking for set classes on my DOM elements to see if they have errors and it worked fine. | Mid | [
0.6386138613861381,
32.25,
18.25
] |
200 Sort 17, -5, 1635, -8, -1, 2, -4. -8, -5, -4, -1, 2, 17, 1635 Put -2, 0, -180, -2481 in decreasing order. 0, -2, -180, -2481 Put 0.5, 0.2, -6, 3, -54, -32, 0.1 in descending order. 3, 0.5, 0.2, 0.1, -6, -32, -54 Put -0.862, -1/3, 34, -3/13 in descending order. 34, -3/13, -1/3, -0.862 Sort -3/7, -5, 0.838585 in decreasing order. 0.838585, -3/7, -5 Sort 1, 0, -614, 4681 in descending order. 4681, 1, 0, -614 Sort -40, -3, -512, -4, -5, -2, 3 in increasing order. -512, -40, -5, -4, -3, -2, 3 Sort 4, -377619, 0, 3, -5 in decreasing order. 4, 3, 0, -5, -377619 Sort -4449, 0.2, -7, 3, 0 in descending order. 3, 0.2, 0, -7, -4449 Sort 5800, 259, 38. 38, 259, 5800 Put 0.061, 3/268, -1, 5, -3 in descending order. 5, 0.061, 3/268, -1, -3 Sort 74, 82, 417, -3 in ascending order. -3, 74, 82, 417 Sort 0, -105441, 5 in decreasing order. 5, 0, -105441 Put -28, -5, -9, 4, 12006, 5 in ascending order. -28, -9, -5, 4, 5, 12006 Put -1/6, 1612091, -3 in increasing order. -3, -1/6, 1612091 Put -1, 47, 12, -39, 3, 32, -5 in decreasing order. 47, 32, 12, 3, -1, -5, -39 Sort 4/5, 22.1006, 2, -5, 1/9 in descending order. 22.1006, 2, 4/5, 1/9, -5 Put 1, 6068, 73, -10, 0 in increasing order. -10, 0, 1, 73, 6068 Sort -2, -1879, 7, 2, 4, 0. -1879, -2, 0, 2, 4, 7 Sort 2, 1115, -3, -5, -6, 0, 174 in decreasing order. 1115, 174, 2, 0, -3, -5, -6 Put 0.4, 3/2, 1419/1915 in decreasing order. 3/2, 1419/1915, 0.4 Put 2, 128, -721624 in increasing order. -721624, 2, 128 Put -5, 21.879, -3, 5, -1.1, 0 in decreasing order. 21.879, 5, 0, -1.1, -3, -5 Sort 3, -6, -43, 2, -61, 6 in increasing order. -61, -43, -6, 2, 3, 6 Put -513592, -2, 1, -60 in decreasing order. 1, -2, -60, -513592 Put 3, -517052, -2, -2/9, -1/3 in ascending order. -517052, -2, -1/3, -2/9, 3 Put -5, -253660, 1, -1 in descending order. 1, -1, -5, -253660 Sort -2, 300, 273, 2, 0, -3, 5 in increasing order. -3, -2, 0, 2, 5, 273, 300 Put -5, 11, -6, 3, 1850, -2 in descending order. 1850, 11, 3, -2, -5, -6 Sort 4, -1, -1174, 5, -5, -4 in ascending order. -1174, -5, -4, -1, 4, 5 Put 1054, -9/5, 16 in decreasing order. 1054, 16, -9/5 Sort -167.3, -1/6, -2, 1301, 0.2. -167.3, -2, -1/6, 0.2, 1301 Sort -1, 47, -3, 23, -5, -4 in descending order. 47, 23, -1, -3, -4, -5 Sort 111998, -4, -213 in decreasing order. 111998, -4, -213 Sort 0, -4, -20, 4235, 3 in descending order. 4235, 3, 0, -4, -20 Sort -3275, -1, 1, -132. -3275, -132, -1, 1 Sort -0.52, 4, 5, 8844 in decreasing order. 8844, 5, 4, -0.52 Sort 9, 7, -2/29, 0.044, 5, -1, -2 in increasing order. -2, -1, -2/29, 0.044, 5, 7, 9 Sort 0.14, 1, -4, 58, -34.4 in decreasing order. 58, 1, 0.14, -4, -34.4 Put 10/3, 0.857, 92/3 in decreasing order. 92/3, 10/3, 0.857 Sort 16, -1, 27, 9, 2, -5 in ascending order. -5, -1, 2, 9, 16, 27 Sort 734, 527, -6 in increasing order. -6, 527, 734 Sort -24, 4, 2, -2055, -49 in increasing order. -2055, -49, -24, 2, 4 Put -3, 6, -6.05095 in descending order. 6, -3, -6.05095 Sort -19, -17, -85, -3, 2/29, -2/9. -85, -19, -17, -3, -2/9, 2/29 Put 17, 10212, -34 in descending order. 10212, 17, -34 Sort 1993, -2, -1, -5, 83 in decreasing order. 1993, 83, -1, -2, -5 Put 1, 3, -13, 39, 20, -14 in decreasing order. 39, 20, 3, 1, -13, -14 Put 2/5, 0, -1, -697084 in decreasing order. 2/5, 0, -1, -697084 Sort -3636, 3, -2, -5, -53, -1, -3 in decreasing order. 3, -1, -2, -3, -5, -53, -3636 Sort -5, 10, -2697. -2697, -5, 10 Sort 1, 285, 32, 5, 2. 1, 2, 5, 32, 285 Put 6, 84, -5, -62, -4, 0 in descending order. 84, 6, 0, -4, -5, -62 Sort 495, -51, 5, -2, -1. -51, -2, -1, 5, 495 Put -0.21, -1, 2.52, 5, 0.07 in increasing order. -1, -0.21, 0.07, 2.52, 5 Put 2, 10, 4, -8, -0.04, 1/2 in increasing order. -8, -0.04, 1/2, 2, 4, 10 Sort 2344, 5/8, -2, 1, -5, -4 in decreasing order. 2344, 1, 5/8, -2, -4, -5 Sort 74, 23, 1/2, 11, 2/11, -1/5. -1/5, 2/11, 1/2, 11, 23, 74 Sort 0.6, 2, -2, 30, 0.4, -0.153. -2, -0.153, 0.4, 0.6, 2, 30 Sort -1, -1796668, 0.3, 3 in decreasing order. 3, 0.3, -1, -1796668 Sort -0.4, -193/563, 5, -2/51 in decreasing order. 5, -2/51, -193/563, -0.4 Put 3, -622247, 0, -14 in ascending order. -622247, -14, 0, 3 Put -4097, 3, 47, -1 in descending order. 47, 3, -1, -4097 Sort 2.3, -5, 0.093, 122, 20/7 in increasing order. -5, 0.093, 2.3, 20/7, 122 Sort 8436, -2/3, 0.128, -1/4 in decreasing order. 8436, 0.128, -1/4, -2/3 Put 1, -4, 5, -5, -38070, 2, 4 in descending order. 5, 4, 2, 1, -4, -5, -38070 Put -1147, 1, -20, 1493 in descending order. 1493, 1, -20, -1147 Sort 5, -1/3, 63, 0.2, 0.4, 0.12. -1/3, 0.12, 0.2, 0.4, 5, 63 Sort -1005, -5, 57, 5, -7, 1 in descending order. 57, 5, 1, -5, -7, -1005 Sort -3, -2, -4, -571849, 1, -1 in increasing order. -571849, -4, -3, -2, -1, 1 Put 5, -37, -1/3, -0.5, -1/5, -1/9 in ascending order. -37, -0.5, -1/3, -1/5, -1/9, 5 Sort -169, 1, 347658 in increasing order. -169, 1, 347658 Sort 2062, 5, -15497 in ascending order. -15497, 5, 2062 Put -14, 5, 1154 in increasing order. -14, 5, 1154 Sort -2, 2, 3, 4714, 0, 4, 5. -2, 0, 2, 3, 4, 5, 4714 Sort 2, -2/61, 1722, -1/5, 34, -0.1. -1/5, -0.1, -2/61, 2, 34, 1722 Sort -7, 1/4996, -3/14 in decreasing order. 1/4996, -3/14, -7 Sort -118, -6, 2, -707, -3, -5 in descending order. 2, -3, -5, -6, -118, -707 Sort -83, -3608621, -4 in descending order. -4, -83, -3608621 Put -40, 6, -58, -5 in descending order. 6, -5, -40, -58 Put -30315, 5, -19133 in decreasing order. 5, -19133, -30315 Sort -29, 192, 231, 2, -1 in descending order. 231, 192, 2, -1, -29 Sort -14, 5, 8, 3019, -7 in ascending order. -14, -7, 5, 8, 3019 Put 11, 1, 991, 6, 62, -3 in decreasing order. 991, 62, 11, 6, 1, -3 Sort 50, 1, 0, -0.1, 40, 3/2 in increasing order. -0.1, 0, 1, 3/2, 40, 50 Put 3/5, -10965/16, 3.4 in increasing order. -10965/16, 3/5, 3.4 Sort 5, 12, 6, -2, -119, 23. -119, -2, 5, 6, 12, 23 Sort 10, -2, 5, 43, -43 in increasing order. -43, -2, 5, 10, 43 Sort 274, -4, -378. -378, -4, 274 Sort -3, -4, -8843, 46, 0, 1 in descending order. 46, 1, 0, -3, -4, -8843 Put 690, 14706, -3, 0, 1 in descending order. 14706, 690, 1, 0, -3 Sort 39924, 1, 5, -0.3, 9 in descending order. 39924, 9, 5, 1, -0.3 Put 0, 5, -5, 782, -7 in decreasing order. 782, 5, 0, -5, -7 Sort 26, -8, 2, -35, -3 in descending order. 26, 2, -3, -8, -35 Put -0.04, 0.1, 7964, 5, -5, 0.3 in increasing order. -5, -0.04, 0.1, 0.3, 5, 7964 Sort 2, -106, -1294, 111 in decreasing order. 111, 2, -106, -1294 Sort -988, 738, 6 in descending order. 738, 6, -988 Sort 81, 50, 1, 20 in decreasing order. 81, 50, 20, 1 Sort -38211684, 4, 3, -8 in increasing order. -38211684, -8, 3, 4 Sort -3, 1, 7, 126, -2, -57, 2 in decreasing order. 126, 7, 2, 1, -2, -3, -57 Put 3103, 5, 0.5, -1/3, 4 in decreasing order. 3103, 5, 4, 0.5, -1/3 Put -4, 5, -3/50123 in descending order. 5, -3/50123, -4 Put -6, -9, -18, 1, 4, 3, -344 in increasing order. -344, -18, -9, -6, 1, 3, 4 Put -0.013229, -6, -0.2, 2/5, -1/4 in increasing order. -6, -1/4, -0.2, -0.013229, 2/5 Sort 1, 14.1, 13, 5. 1, 5, 13, 14.1 Sort -4605.8, 9, -5, 1/4, 6/7 in descending order. 9, 6/7, 1/4, -5, -4605.8 Put 2/15, -3/7, 19, 3931, 2/13 in ascending order. -3/7, 2/15, 2/13, 19, 3931 Sort -1/2, -1.02, 541698 in descending order. 541698, -1/2, -1.02 Put -73562, -3, -874 in ascending order. -73562, -874, -3 Put -2, 2, 4, 170, -4, -21, 8 in decreasing order. 170, 8, 4, 2, -2, -4, -21 Sort -3/7, 6, -4, -16666, -5, 4. -16666, -5, -4, -3/7, 4, 6 Put -689, -1, -338, 13, 0 in descending order. 13, 0, -1, -338, -689 Sort -271, -1, 4134, 0, 4. -271, -1, 0, 4, 4134 Sort -5, 2, 3, 4, 601070. -5, 2, 3, 4, 601070 Put -4, 658, 3, 0, -7 in decreasing order. 658, 3, 0, -4, -7 Sort 1, 6, 7, -3, 48, 2, 5. -3, 1, 2, 5, 6, 7, 48 Sort 33, 12, 75061. 12, 33, 75061 Sort -4, -60, -127, 1711 in increasing order. -127, -60, -4, 1711 Sort 402, 1160, 6. 6, 402, 1160 Sort 24, -2, -24, 1, -7, 4, -21. -24, -21, -7, -2, 1, 4, 24 Put 50/21, 0.5, 1048.4 in decreasing order. 1048.4, 50/21, 0.5 Put -3, 2, -35168957, 0 in descending order. 2, 0, -3, -35168957 Sort 313, 155, -2003 in increasing order. -2003, 155, 313 Sort 89205, 74, 4 in ascending order. 4, 74, 89205 Sort 1, -41, 0, -2, 11, 5, 36 in ascending order. -41, -2, 0, 1, 5, 11, 36 Sort -3918, -163, 6. -3918, -163, 6 Sort -990, 5, -1, -19938 in decreasing order. 5, -1, -990, -19938 S | Low | [
0.513513513513513,
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As is known, the balancing of vehicle wheels includes identifying at least a plane which is perpendicular to the wheel axis, called the balancing plane, at which the weights will be applied on the wheel rim. In particular, in order to perform static wheel balancing it is sufficient to identify one balancing plane alone, while in order to perform a dynamic balancing two distinct balancing planes must be identified, reciprocally distanced along the wheel axis. An electronic calculator, connected to a measuring group belonging to the balancing machine, detects the wheel imbalance and calculates the entity of the weights according to the position of the balancing planes, as well as the angular position of the weights in the balancing planes themselves. The identification of the balancing planes is generally done by measuring some geometrical parameters which are characteristic of the wheel hub to be balanced, after the wheel has been mounted on the balancing machine. The geometric parameters are typically the hub diameter at each balancing plane and the distance of each balancing plane from a fixed reference plane of the balancing machine. Usually these measurements are performed by feelers on the balancing machine, which are positioned manually by the operative according to the points on the hub which are comprised in the balancing plane in which he wishes to locate the weights. The displacement of the feeler organs from a predetermined initial position is measured by special electronic systems which transmit the performed measurement to the electronic calculator which then processes the data. Recent research in the field of wheel balancers has been especially directed at obtaining maximum automation of the balancing processes, so as to optimise the results and reduce error as well as manual intervention on the part of the operatives. In this context, balancing machines have been devised which can make a totally automatic reading of the optimal balancing planes at which the weights should be applied on the rims. These balancing machines are generally provided with special pick-up devices which are connected to the electronic calculator and can perform a scan of the hub profile, and acquire for each point thereon the geometric parameters required for the balancing operation. The pick-up devices are generally aimed at detecting the spatial position of the points on the rim without direct contact with the points themselves, such as for example optical devices for measuring distances. In this way, on the basis of the rim profile and other imbalances of the wheel measured by the measuring group, the electronic calculator is able automatically to identify the optimal balancing planes, without any need for feelers and without any direct intervention on the part of the operative. Clearly these balancing machines are very expensive and complicated, and they do not always respond to market demand, where the need to have greater automation is generally accompanied by a need to have accessible prices. Further, the scanning of the rim profile requires a relatively long time, which has an overall effect of slowing down the wheel balancing process. The aim of the present invention is to solve the above-mentioned drawbacks in the prior art, by making available a method and a machine for vehicle wheel balancing, in which the determining of the balancing planes can be done semi-automatically, reducing the operative's manual contribution and improving the precision of the balancing, though remaining within the ambit of a simple, rational and inexpensive solution. | High | [
0.6588785046728971,
35.25,
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Zofia Rydet Zofia Rydet (May 5, 1911 – August 24, 1997) was a Polish photographer, best known for her project "Sociological Record", which aimed to document every household in Poland. She began working on "Sociological Record" in 1978 at the age of 67, and took nearly 20,000 pictures until her death in 1997. Many of the pictures remain undeveloped. The photographs are predominantly portraits of children, men, women, couples, families and the elderly amidst their belongings. Rydet tended to photograph her subjects straight-on, using a wide-angle lens and a flash. Personal life Rydet was born in Stanisławów. She attended the Główna Szkoła Gospodarcza Żeńska in Snopków. As a young woman she had a number of occupations such as working for the Orbis Polish Travel Office and running a stationery shop. In mid-life she returned to her hobby of photography. She joined the Gliwice Photographic Society in 1954 and improved her skills. Work In 1961 Rydet had a major exhibition of photographs called Mały człowiek (Little Man). Rydet's intention for Little Man, was to show that children had good and bad experiences in their life, just like adults. She also wanted to depict how societal issues and policies can affect children. Rydet did not want to show children as a carefree stereotype, but rather as human. In 1965 the works in this exhibition were collected into a book edited by Wojciech Zamecznik. The same year she became a member of the Union of Polish Art Photographers. In Czas prezemianija (The Passage of Time, 1963-1977), Rydet portrays the dignity and grace of old age in a series of intimate portraits. In 1976, Rydet was awarded the Excellence de la Fédération Internationale de l´Art Photographique (EFIAP). In 1978 Rydet began her work on "Zapis Socjologiczny" ("Sociological Record"). The project consists of thousands of informal black and white photographs taken in ordinary households throughout Poland. Rydet died in Gliwice on August 24, 1997. References Category:1911 births Category:1997 deaths Category:20th-century women artists Category:Polish photographers | High | [
0.6749311294765841,
30.625,
14.75
] |
95 B.R. 13 (1988) In re Patrick Dennis FLINN, Debra Catherine Flinn, Debtors. Bankruptcy No. 88-00816. United States Bankruptcy Court, N.D. New York. November 23, 1988. *14 Lee E. Woodard, Syracuse, N.Y., Trustee. UAW Legal Services Plan, Syracuse, N.Y., for debtors; Clifford Forstadt, of counsel. MEMORANDUM-DECISION, FINDINGS OF FACT, CONCLUSIONS OF LAW AND ORDER STEPHEN D. GERLING, Bankruptcy Judge. The Court is called upon to decide whether, when a husband and wife join in a Chapter 7 petition under Title 11, either spouse alone may claim as exempt the entire equity interest in the couple's homestead owned by them as tenants by the entirety. FACTS On June 9, 1988, Patrick Dennis and Debra Catherine Flinn ("Debtors") filed a joint petition under Chapter 7 of the Bankruptcy Code, 11 U.S.C.A. §§ 101-1330 (West 1979 & Supp.1988) ("Code"), pursuant to Code § 302. Their petition recited $64,205.14 in debt and $56,989.00 in property. Pursuant to § 282 and 283 of the New York Debtor and Creditor Law (McKinney's Supp.1988) ("NYD & CL"), the Debtors filed a B-4 Schedule, entitled Property Claimed as Exempt, which listed, among other things, a $2,600.00 equity interest in the couple's homestead and $2,500.00 in cash as property exempted from the Debtors' estate. The Debtors' homestead is owned by them as tenants by the entirety. On July 8, 1988, the Trustee filed an objection to the Debtors' claimed cash and homestead exemptions, alleging that NYD & CL §§ 282 and 283 do not permit them to take exemptions in both a homestead and cash. After a hearing in Syracuse, New York on August 2, 1988, the Court reserved decision. The Debtors were granted a discharge by Order dated August 5, 1988. On September 27, 1988, they filed an amendment to their B-4 Schedule, reducing both their claimed homestead and cash exemptions to $2,100.00 and $54.00, respectively. ARGUMENTS The Trustee maintains that under NYD & CL § 283(2)(a), a debtor is precluded from claiming a cash exemption if he utilizes any portion of the homestead exemption provided for in § 5206 of the New York Civil Practice Law and Rules (McKinney's 1978 & Supp.1988) ("NYCPLR"). He agrees that a husband and wife each have a personal right to claim the allowable property exemptions in their joint petition, thereby in theory permitting one spouse to claim the cash exemption and the other to claim the homestead exemption. However, the Trustee argues that each spouse may only do so to the extent that he or she has an interest in that property. Therefore, because the Debtors in the present case own their residence as tenants by the entirety, bestowing upon each an undivided one-half interest in the whole, each spouse alone may only claim one-half of the entire equity interest in the homestead as exempt property. The Debtors respond that either spouse individually may claim the entire equity interest under the homestead exemption. Relying on In re Arnold, 33 B.R. 765 (Bankr.E.D.N.Y.1983), they characterize a tenancy by the entirety as ownership where "both and each [spouse] own the entire fee." Memorandum Of Law In Opposition To The Trustee's Objections To Claimed Exemptions, p. 2 (filed Aug. 23, 1988). Under this analysis, the Debtors claim that either spouse may claim the entire equity interest as an owner of the whole and that the allocation of exemptions need not be specified in the Chapter 7 petition. JURISDICTIONAL STATEMENT The Court has jurisdiction over this core proceeding under the provisions of 28 U.S. *15 C.A. §§ 1334(b) and 157(a), 157(b)(1), 157(b)(2)(A), (B) and (O) (West Supp.1988). Objections to a debtor's claim of exemptions, a contested matter, are governed by Rules 4003(b), (c), 7052 and 9014 of the Bankruptcy Rules. DISCUSSION Pursuant to Code § 522(b)(1), New York State has "opted out" of the federal property exemption provisions enacted by Congress in Code § 522(d). In its place and pursuant to Code § 522(b)(2), the New York legislature passed Article 10-A, entitled Personal Bankruptcy Exemptions, in the New York Debtor and Creditor Law, effective September 1, 1982. Under § 282 of Article 10-A, a debtor is permitted to exempt real property in a liquidation proceeding to the extent permitted by NYCPLR § 5206. NYCPLR § 5206 authorizes an individual debtor to exempt his or her real property interest up to "ten thousand dollars in value above liens and encumbrances [if] owned and occupied as a principal residence." This provision has been construed to allow an aggregate exemption of $20,000.00 for a homestead, where a joint petition is filed by a husband and wife and each spouse claims an exemption under this provision. See John T. Mather Memorial Hosp. Of Port Jefferson, Inc. v. Pearl, 723 F.2d 193 (2d Cir. 1983). The extent to which the Debtors in the present case may take advantage of the New York "homestead provision" depends upon the nature of their respective property interests in their residence. The reason for this is because the Debtors also wish to apply for a cash exemption. Since, under NYD & CL § 283(2)(a), a single debtor may not claim both the homestead and the cash exemptions, the crucial issue is whether the husband may claim the couple's entire equity interest in the home, thereby permitting his wife to claim the cash exemption. In Butner v. United States, 440 U.S. 48, 99 S.Ct. 914, 59 L.Ed.2d 136 (1979), the Supreme Court observed that "Congress has generally left the determination of property rights in the assets of a bankrupt's estate to state law . . . Unless some federal interest requires a different result, there is no reason why such interests should be analyzed differently simply because an interested party is involved in a bankruptcy proceeding." Id. at 54-55, 99 S.Ct. at 918. As there appears to be no countervailing federal interests in the instant case, the Court will turn to New York state property law to determine the Debtors' rights as tenants by the entirety home-owners. The tenancy by the entirety is codified in § 6-2.2(b) of the New York Estates, Powers and Trusts Law (McKinney's Supp. 1988), which reads that "[a] disposition of real property to a husband and wife creates in them a tenancy by the entirety, unless expressly declared to be a joint tenancy or tenancy in common." New York case law has interpreted this property interest to be "a tenancy whose salient characteristic is the unique relationship between a husband and his wife, each of whom is seized of the whole and not of any undivided portion of the estate (per tout et non per my)." Reister v. Town Bd. of the Town of Fleming, 18 N.Y.2d 92, 95, 271 N.Y.S.2d 965, 967, 218 N.E.2d 681, 682, (1966) (citations omitted). See also 24 NYJur.2d, Cotenancy and Partition §§ 36-40 (1982). Upon the death of one spouse, the whole estate remains in the survivor. See In re Tsunis, 29 B.R. 527, 529-530 (Bankr.E.D.N.Y.1983). The tenancy by the entirety is a legal fiction existing only within the context of the marriage and by which both spouses jointly own the entire property in interests "same and equal." See Secrist v. Secrist, 284 A.D. 331, 334, 132 N.Y.S.2d 412, 415 (4th Dep't 1954); 24 NYJur.2d, supra, Cotenancy and Partition at §§ 41-42. Where one spouse has purchased the property wholly from his or her money, the law implies a gift to the other spouse of one-half the consideration so that each holds as a tenant by the entirety. See Teitelbaum v. Parameswaran (In re Parameswaran), 50 B.R. 780, 782-783 (Bankr.S.D.N.Y.1985); 24 NYJur.2d, supra, Cotenancy and Partition at § 49. *16 "In New York, an entirety interest is composed of a survivorship right, a right to ½ the rents and profits, and a possessory right to an undivided ½ of the fee", although in cases concerning marital domiciles, there is no rent derived. Kirschenbaum v. Feola (In re Feola), 22 B.R. 81, 84 n. 3 (Bankr.E.D.N.Y.1982). In Lover v. Fennell, 14 Misc.2d 874, 179 N.Y.S.2d 1017 (Sup.Ct.1958), the successor in interest by Sheriff's deed of the interest of a husband who had abandoned his wife was deemed to be entitled to one-half of any net rent derived from property the husband, who subsequently died, had owned with the defendant wife as tenants by the entirety. The Lover court also noted that a tenancy by the entirety permits each spouse to share equally in the premises. See id. at 878-879, 179 N.Y.S.2d at 1021-1022. Compare In re Weiss, 4 B.R. 327, 331 (Bankr.S.D.N. Y.1980) (husband's interest in a tenancy by the entirety may be sold under execution upon a judgment against him and the purchaser at such sale becomes a tenant in common with the wife and entitled to share in rents and profits but not occupancy) and In re Feola, supra, 22 B.R. at 84 (noting that while in theory, purchaser of tenant by entireties interest shares property's rents, profits and occupancy as tenant in common, for practical reasons a protective order preventing simultaneous possession accompanies the sale). New York courts have held that, upon the voluntary dissolution of the marriage through an event such as divorce, each ex-spouse, as a tenant in common, is entitled to an equal share of the proceeds from real property that was held by them as a tenancy by the entirety. See Rouse v. Industrial Commr. of State of New York (In re Rouse), 56 B.R. 534, 536 (Bankr.S.D.N. Y.1985); Doyle v. Hamm, 84 Misc.2d 683, 686, 377 N.Y.S.2d 349 (Sup.Ct.1975). See also Secrist v. Secrist, supra, 284 A.D. at 331, 132 N.Y.S.2d at 412. Each spouse is entitled to a one-half share notwithstanding his or her own individual contributions to payments on the property. See Doyle v. Hamm, supra, 84 Misc.2d at 687, 377 N.Y.S.2d at 353; In re Parameswaran, supra, 50 B.R. at 782-783. To protect the other spouse's right of survivorship, neither may dispose of any part of the property held by them as tenants by the entirety without the mutual consent of both. See, e.g., V.R.W., Inc. v. Klein, 68 N.Y.2d 560, 564, 510 N.Y.S.2d 848, 503 N.E.2d 496 (1986); In re Rouse, supra, 56 B.R. at 535-537; Security Trust Co. of Rochester v. Miller, 72 Misc.2d 269, 270, 338 N.Y.S.2d 1015 (Cty.Ct.1972). "Together, and only together, tenants by the entirety can convey their entire estate, and thereby terminate the tenancy." 24 NYJur.2d, supra, Cotenancy and Partition at § 51. Accord Lee Supply Corp. v. Agnew (In re Agnew), 818 F.2d 1284, 1287-1289 (7th Cir. 1987). Against this backdrop, the Court concludes that the Debtors' position in the present case is untenable. Even assuming that both spouses mutually consented to the husband's claimed exemption in the whole equity interest of their homestead, it could not have terminated the tenancy by the entirety estate. Nor could this purported consent or the act of filing, through a theory of constructive disposition and sale, have created a tenancy in common from which each spouse could exercise control over their own equal half and one transfer it to the other. Each spouse may claim exemptions only to the extent of his or her entireties interest in the homestead. "The right of exemption is a personal privilege.". In re Arnold, supra, 33 B.R. at 767. Therefore, Patrick Dennis cannot claim the entire equity interest in the homestead and permit his wife, Debra Catherine, to avail herself of the cash exemption. It does not matter that the Debtors are only claiming $2,100.00 in equity as exempt. Although the amount claimed is well below the $10,000.00 statutory limit per debtor, and could therefore conceivably be claimed by an individual debtor, it is still owned by the Debtors as tenants by the entirety. Since the record is devoid of any division or conveyance to terminate the tenancy by the entirety estate, neither spouse can claim more than their respective, albeit inseparable, interest in the property, which *17 in this case would be one-half, or $1,050.00, each. To find otherwise would frustrate the public policy behind New York State's preservation of the tenancy by the entireties estates and prejudice the creditors in this Chapter 7 by reducing the value of the property of the estate by $1,050.00. Debtor's reliance on In re Arnold, supra, 33 B.R. at 765 is misplaced. Bankruptcy Judge C. Albert Parente held that a husband and wife who file a joint petition may claim both the New York homestead and cash exemptions without specifying in the petition the exemption each spouse is exercising as long as the statutory guidelines are satisfied. However, the court never addressed the nature of the couple's property interest in their home and does not mention whether said homestead was owned by the spouses as tenants by the entirety. Therefore, In re Arnold should be limited to its facts, which, as in this case, do not consider the unique characteristics of the tenancy by the entirety and its effect on a spouse's homestead exemption claim. Accordingly, it is hereby ORDERED: 1. That the Trustee's motion to disallow the Debtors' claimed homestead and cash exemptions under the applicable New York State law is granted. 2. That the Debtors are granted leave to file amendments to their Chapter 7 petition consistent with this Memorandum-Decision, within thirty (30) days of its entry. | Mid | [
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946 A.2d 1256 (2008) 108 Conn.App. 74 STATEWIDE GRIEVANCE COMMITTEE v. Rebecca L. JOHNSON. No. 28279. Appellate Court of Connecticut. Argued February 8, 2008. Decided May 27, 2008. *1258 Rebecca L. Johnson, pro se, the appellant (defendant). Maureen A. Horgan, assistant bar counsel, for the appellee (plaintiff). GRUENDEL, LAVINE and HENNESSY, Js. HENNESSY, J. The defendant, Rebecca L. Johnson, an attorney licensed to practice law in the state of Connecticut,[1] appeals from the judgment rendered on a presentment in which the trial court adjudged her guilty of professional misconduct in violation of rules 1.4(a),[2] 1.5(b) and (c)[3] and 1.15(b)[4] and suspended her from the practice of law for eighteen months. On appeal, the defendant claims that the court (1) did not conduct the presentment proceeding de novo, and (2) violated her due process rights when she was unable to confront and to cross-examine the complainant during the presentment. We affirm the judgment of the trial court. The following facts are relevant to the defendant's appeal. The defendant was duly admitted as a member of the Connecticut bar on or about December 10, 1993. In December, 2001, the complainant, Anthony Amabile, retained the defendant to represent him regarding a claim of employment discrimination against his former employer. The complainant gave the defendant a $750 retainer, and a retainer agreement was signed. The defendant prepared a complaint dated February 19, 2002, and filed it with the Commission on Human Rights and Opportunities (commission). Thereafter, the commission forwarded the complaint to the Equal Employment Opportunity Commission (federal agency) for processing. On April 24, 2002, the federal agency contacted the complainant *1259 by letter, requesting additional information to process the complaint. The federal agency informed the complainant that the information could be given either through an in-person interview at the federal agency or through a questionnaire, but the information had to be received within thirty days or the complaint would be dismissed. The defendant requested the questionnaire, but the federal agency did not send a complete document. On or about May 30, 2002, the defendant requested the missing pages from the federal agency. On June 24, 2002, the full questionnaire was sent to the defendant via facsimile. In July, 2002, the defendant learned that as a result of a prior presentment, she was being disciplined by the courts and was suspended from the practice of law for one year beginning on September 1, 2002. On February 24, 2003, the federal agency sent notice to the defendant that it had dismissed the complainant's claim because the requested information had never been provided. The dismissal notice advised the complainant that he had ninety days from that date to file a lawsuit in either state or federal court. No action was filed on the complainant's behalf. He therefore requested a return of the $750 retainer, but no refund was made. The plaintiff, the statewide grievance committee, presented its case to the court at a hearing on August 4, 2006. The plaintiff called the defendant to testify and also introduced a number of exhibits. The plaintiff filed transcripts of the proceedings before the plaintiff's reviewing committee[5] in the case and a record of past grievances that had been filed against the defendant. The plaintiff rested its case on this evidence. The defendant was allowed a continuance to subpoena witnesses for her defense. When court reconvened in this matter on August 24, 2006, the defendant filed a motion to dismiss on the basis of the alleged denial of her due process rights to a fair trial. This motion was based on her claim that she had been denied the right to cross-examine the complaining witness during the Superior Court presentment proceeding. When asked by the court whether she had the chance to question the complainant at the prior hearing before the reviewing committee, the defendant stated that she had. The court questioned the plaintiff as to the complainant's availability, and the court was informed that the complainant was residing out of state and was unable to make the trip to court. The court denied the motion to dismiss and admitted into evidence the transcript of the complainant's prior testimony and his cross-examination by the defendant. On November 1, 2006, in a memorandum of decision, the court held that the plaintiff had demonstrated by clear and convincing evidence that the defendant was guilty of professional misconduct. The court suspended the defendant from the practice of law for eighteen months to run concurrently with the prior imposed suspension that she was under at that time. It was further ordered that to be readmitted to practice, the defendant must apply for such readmission and show recent participation in a professional ethics course focusing on Connecticut's Rules of Professional Conduct and a course in law office management, both to last a minimum of three hours, and to take and pass the Multistate Professional Responsibility Examination within three years of the application for readmission. Before addressing the defendant's specific claims, our analysis begins *1260 with a review of the legal principles that govern attorney disciplinary proceedings. "An attorney is admitted to the practice of law on the implied condition that the continuation of this right depends on remaining a fit and safe person to exercise it." Statewide Grievance Committee v. Fountain, 56 Conn.App. 375, 377, 743 A.2d 647 (2000). The Rules of Professional Conduct bind attorneys to uphold the law and to act in accordance with high standards in both their personal and professional lives. See Rules of Professional Conduct, preamble. As officers and commissioners of the court, attorneys are in a special relationship with the judiciary and are "subject to the court's discipline." Statewide Grievance Committee v. Fountain, supra, at 377, 743 A.2d 647. It is well established that "[j]udges of the Superior Court possess the inherent authority to regulate attorney conduct and to discipline the members of the bar. . . . It is their unique position as officers and commissioners of the court . . . which casts attorneys in a special relationship with the judiciary and subjects them to its discipline. . . . [T]he judges have empowered the statewide grievance committee to file presentments in Superior Court seeking judicial sanctions against those claimed to be guilty of misconduct. . . . In carrying out these responsibilities . . . the [statewide grievance committee] is an arm of the court. . . ." (Internal quotation marks omitted.) Statewide Grievance Committee v. Whitney, 227 Conn. 829, 838, 633 A.2d 296 (1993), quoting Sobocinski v. Statewide Grievance Committee, 215 Conn. 517, 525-26, 576 A.2d 532 (1990). "A court disciplining an attorney does so not to punish the attorney, but rather to safeguard the administration of justice and to protect the public from the misconduct or unfitness of those who are members of the legal profession." Statewide Grievance Committee v. Fountain, supra, 56 Conn.App. at 378, 743 A.2d 647. Our court recently has clarified the appropriate appellate standard of review for cases involving attorney grievance appeals. In Brunswick v. Statewide Grievance Committee, 103 Conn.App. 601, 931 A.2d 319, cert. denied, 284 Conn. 929, 934 A.2d 244 (2007), this court, after thorough analysis, determined that "the clearly erroneous standard . . . is the preferable standard of review in attorney grievance appeals." Id., at 613, 931 A.2d 319. "A court reviewing an attorney disciplinary proceeding, therefore, retains its inherent authority over the discipline of its officers in those instances when, despite the evidence in the record, it nevertheless is left with a definite and firm conviction that a mistake has been made." Id., at 614, 931 A.2d 319. With that standard in mind, we turn to the defendant's claims. I The defendant claims that the court did not conduct the presentment proceeding de novo. The plaintiff argues that after it initiated the presentment, a de novo evidentiary proceeding was held. We agree with the plaintiff. The grievance review committee and the courts have their own distinct functions in the grievance process. "[G]rievance panels and reviewing committees carry out what are essentially investigative, fact-bound functions that only determine the probability that an act of attorney misconduct has occurred. [T]here is no requirement that, in order to maintain the essential attributes of the judicial power, all determinations of fact in constitutional courts shall be made by judges. . . . For its part, the statewide grievance committee's only function . . . *1261 was to initiate the presentment. . . . The ultimate decision as to whether an act of misconduct had occurred reposed solely with the judge, as did the power to administer an appropriate sanction." (Citations omitted; internal quotation marks omitted.) Statewide Grievance Committee v. Presnick, 215 Conn. 162, 167, 575 A.2d 210 (1990). We conclude that the trial court conducted a de novo evidentiary proceeding on the presentment in this case. II The defendant claims that she was denied due process of law when she was not able to confront and to cross-examine the complainant at the presentment before the court. The plaintiff argues that the court was correct in admitting the transcripts of the reviewing committee hearings into evidence upon the unavailability of the complainant. We agree with the plaintiff. The following facts are relevant to the defendant's claim. The plaintiff offered the transcripts of the reviewing committee's hearings without objection from the defendant. It was only when the defendant was told that the plaintiff was resting after her testimony that she objected to the offer of the complainant's testimony through the transcripts. The defendant was then given a continuance to subpoena the witnesses she wanted to present for her case-in-chief. On the date that was set for resuming the hearing, the defendant had not subpoenaed the complainant and instead went forward with an oral motion to dismiss on the basis of her claim that she was denied her right to cross-examine the complainant. At that hearing, counsel for the plaintiff stated to the court that she had spoken to the complainant since the first hearing and that he lived out of state and was not able to make the trip to court. During a colloquy with the court, the defendant twice admitted that she had cross-examined the complainant at the prior reviewing committee hearing. The court made a finding orally that the complainant was unavailable and that there was no evidence before the court that the reliability or veracity of the complainant had been brought into question. After ruling, the court took a brief recess so that the defendant could consider what evidence she wanted to present in her defense. Representing herself, she then presented her case-in-chief to the court. "We begin our analysis with a review of the legal principles that govern attorney disciplinary proceedings. In part because such actions are adversary proceedings of a quasi-criminal nature . . . attorneys subject to disciplinary proceedings are entitled to due process of law. . . . A license to practice law is a property interest that cannot be suspended without due process. . . . Due process, however, is a flexible concept, and a determination of the particular process that is due depends on the nature of the proceeding and the interests at stake." (Citations omitted; internal quotation marks omitted.) Statewide Grievance Committee v. Botwick, 226 Conn. 299, 306-307, 627 A.2d 901 (1993). Because a grievance hearing is quasi-criminal in nature, we look to criminal law to resolve the defendant's claim. "Under Crawford v. Washington, [541 U.S. 36, 124 S.Ct. 1354, 158 L.Ed.2d 177 (2004)], the hearsay statements of an unavailable witness that are testimonial in nature may be admitted under the sixth amendment's confrontation clause only if the defendant has had a prior opportunity to cross-examine the declarant."[6]State v. Slater, 285 Conn. 162, 169, 939 A.2d 1105 (2008). *1262 The record clearly shows that the defendant had a full and fair opportunity and did in fact cross-examine the complainant at the reviewing committee hearing. Admission of the complainant's prior testimony did not deprive the defendant of due process. The judgment is affirmed. In this opinion the other judges concurred. NOTES [1] The defendant is presently suspended from the practice of law. [2] Rule 1.4(a) of the Rules of Professional Conduct (2003) provides: "A lawyer shall keep a client reasonably informed about the status of a matter and promptly comply with reasonable requests for information." [3] Rule 1.5 of the Rules of Professional Conduct (2003) provides in relevant part: "(b) When the lawyer has not regularly represented the client, the basis or rate of the fee, whether and to what extent the client will be responsible for any court costs and expenses of litigation, and the scope of the matter to be undertaken shall be communicated to the client, in writing, before or within a reasonable time after commencing the representation. This subsection shall not apply to public defenders or in situations where the lawyer will be paid by the court or a state agency. "(c) A fee may be contingent on the outcome of the matter for which the service is rendered, except in a matter in which a contingent fee is prohibited by subsection (d) or other law. A contingent fee agreement shall be in writing and shall state the method by which the fee is to be determined, including the percentage or percentages of the recovery that shall accrue to the lawyer as a fee in the event of settlement, trial or appeal, whether and to what extent the client will be responsible for any court costs and expenses of litigation, and whether such expenses are to be deducted before or after the contingent fee is calculated. Upon conclusion of a contingent fee matter, the lawyer shall provide the client with a written statement stating the outcome of the matter and, if there is a recovery, showing the remittance to the client and the method of its determination." [4] Rule 1.15(b) of the Rules of Professional Conduct (2003) provides: "Upon receiving funds or other property in which a client or third person has an interest, a lawyer shall promptly notify the client or third person. Except as stated in this rule or otherwise permitted by law or by agreement with the client, a lawyer shall promptly deliver to the client or third person any funds or other property that the client or third person is entitled to receive and, upon request by the client or third person, shall promptly render a full accounting regarding such property." [5] See Practice Book § 2-35. [6] Under the United States Supreme Court's decision in Crawford, a testimonial statement is "[a] solemn declaration or affirmation made for the purpose of establishing or proving some fact." (Internal quotation marks omitted.) Crawford v. Washington, supra, 541 U.S. at 51, 124 S.Ct. 1354; State v. Slater, 285 Conn. 162, 170, 939 A.2d 1105 (2008). The complainant's testimony was therefore testimonial. | Mid | [
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Q: force jspm to install newest version I'm trying to update all my jspm dependencies to the newest version, the only "solution" I found is "jspm update", but this only installs the version, which is defined in the package.json Isn't there anyway to automatically update the packages to the really newest version and settings the new version number in the package.json? Cedric A: Jspm uses semver notation for updating the packages. Please make sure you are using the notation correctly. For instance, if you run Jspm update with a [email protected] package definition on the packages.json, the package will not be updated to a new version because the version is locked for 1.0.2. | Low | [
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Payment Details All advertised prices are based on cash purchase or financing from outside bank/lender (Cannot be financed through Volkswagen Credit). We appreciate your interest in our inventory, and apologize we do not have model details displaying on the website at this time. Please fill the form out below and our team will quickly respond, or, please call us at 516-942-7300 for more information. Vehicle Finder Service Contact Info First Name* Last Name* Phone Email* Contact Preference?* Phone Email What Are You Looking For? Type* New Used Year* Mileage (Max)* Price (Max)* Make* Model* Trim* Color* Transmission* Automatic Manual Message By submitting this form, you agree to be contacted with information regarding the vehicle you are searching for. | Low | [
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Now Commenting On: Estrada's role depends on Marcum's status Estrada's role depends on Marcum's status Marco Estrada By / | PHOENIX -- With Shaun Marcum on the comeback trail after starting Spring Training with a stiff shoulder, Marco Estrada may begin to shift his focus from stretching out as a starter to preparing for a bullpen role with the Brewers. Marcum pitched three innings against the Dodgers in his Cactus League debut on Sunday. The right-hander is expected to throw 60 pitches in a Minor League his next time out, putting him on pace to be on the bubble as far as arm stamina by Opening Day, when a starting pitcher is ideally good for at least 75 pitches or five innings, but preferably more. "If we think Marcum is ready, we will not be stretching Marco," manager Ron Roenicke said on Tuesday. "He's already to the point where his next outing he can be at 90 pitches. He's stretched out." Estrada is 2-2 in six games this spring and has posted a 4.50 ERA in 15 innings. If Marcum starts the season in the rotation, Estrada will be prepared for spot starts should the need arise, with the Brewers confident he'd be able to give them four innings to get through a game. "When he gets in a starting mode he mixes up locations really well," Roenicke said. "He's pitched better for us as a starter than he has as a reliever, though I like him as a reliever. "We want him to get back in a mode where we're going to use him two, three innings, maybe one inning. He needs to pitch more often to try and get ready for our bullpen." The Brewers are keeping their options open by starting Marcum in a Triple-A game Sunday, enabling them to backdate his appearance on the disabled list if they decide he needs more time before joining the rotation. "Shaun was fine, he understands," Roenicke said, noting that no red flags have gone up regarding Marcum. "In case we want to give him an extra start [in the Minors once the season starts], we can do it." | Mid | [
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The effect of continuous drug exposure on the immune response to Trichostrongylus colubriformis in sheep. The effect of albendazole (ABZ)-capsule (CRC) administration on parasite establishment and immunity to ABZ-resistant (RES) and -susceptible (SUS) T. colubriformis was measured in Romney lambs. During 12 weeks of twice-weekly dosing with 3000 parasite larvae (L3), eggs were observed in faeces from CRC-treated and untreated lambs given RES L3, but not CRC-treated lambs given SUS L3. Following the period of trickle challenge all lambs were drenched and, 1 week later, dosed with 20000 SUS L3. Resulting worm burdens were higher in control lambs than in those previously treated with CRCs and challenged with SUS, which in turn were higher than those in the CRC-treated or -untreated lambs previously challenged with RES L3. During the period of trickle challenge, the number of peripheral eosinophils and titres of anti-L3 and anti-adult antibody were raised only in those groups given RES L3. There was no effect of CRC administration. Following drench and challenge, antibody titres and eosinophil numbers increased in the control animals but not in those groups which had received previous trickle infection. The results demonstrate that the larval challenge alone resulted in incomplete though substantial protection against subsequent parasite challenge. The use of CRCs may potentially impact on subsequent animal performance and selection for anthelmintic resistance through a reduced level of immunity. | Mid | [
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You are here Unearthing Moku’ula with Emily Erickson '14 Thursday, November 3, 2011 - 5:43pm By Suk-Lin Zhou '14 For Emily Erickson ’14, it wasn’t just the coconut palm trees, sparkling turquoise water, or powdered sugar sand that drew her to Lahaina, Maui, this past summer. It was also the opportunity to help unearth Moku’ula. Erickson was captivated by the various fields of anthropology in her first year at Mount Holyoke—and, in particular, archaeology. Determined to learn more, she decided that a hands-on experience would give her the best introduction to the field. Her curiosity led her to Lahaina, Maui, where she was an archeological volunteer for three weeks at the excavation site for the Friends of Moku'ula. Moku'ula was originally an island in the middle of Mokuhinia, a wetland pond. Home to Kamehameha the Great, Kamehameha II, and Kamehameha III, the island served as the political and spiritual center of the Hawaiian kingdom from 1820 to 1845 and as an oasis of calm during the turbulent whaling days in the Pacific. By 1845, Moku’ula had been abandoned after the arrival of foreign powers and a power shift that moved the capital to the more profitable shores of Honolulu. Over time, the island became stagnant marshlands, and in the early twentieth century, the pond was filled in and made into a park. In the last century, downtown Lahaina’s Malu’ulu o Lele Park was always deemed the "most sacred baseball field in America." Moku’ula is an important part of Hawaiian history, and since 1998, the Friends of Moku’ula have worked to restore the ancient island to its state in the days of Kamehameha III. It is believed that with more understanding of the past, Hawaii can protect its future. Hence, Moku’ula’s motto is: I ka wa mamua ka wa mahope. The future is in the past. When Erickson and her peers arrived at Lahaina, led by Janet Six, a lecturer in anthropology at the University of Hawaii Maui College, they found the island was about three feet under the baseball field. As an archeological volunteer, Erickson helped define the border and core of the hidden island. “At the end of the day, I would be covered in red excavation dirt from head to toe, but I didn’t mind. My peers and I swam in the ocean afterwards, and it was a great way to end the day. It was the perfect balance between work and play,” she said. For Erickson, her summer in Lahaina will be a treasured memory. She found her passion in archeology, discovered ways to utilize knowledge gained from her cultural anthropology and geology classes, uncovered a seal tooth dating back to whaling days, and learned about a new culture. Lahaina is more than just a tourist attraction; it’s a place filled with history and pride in its people. “Archaeology is like a puzzle. In the end, everything came together and our project was a success. I loved my time spent in Lahaina,” she said. Erickson plans to continue her interest in archaeology and hopes that one day she can do fieldwork in the Mediterranean. | Mid | [
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Lost in space: multisensory conflict yields adaptation in spatial representations across frames of reference. According to embodied cognition, bodily interactions with our environment shape the perception and representation of our body and the surrounding space, that is, peripersonal space. To investigate the adaptive nature of these spatial representations, we introduced a multisensory conflict between vision and proprioception in an immersive virtual reality. During individual bimanual interaction trials, we gradually shifted the visual hand representation. As a result, participants unknowingly shifted their actual hands to compensate for the visual shift. We then measured the adaptation to the invoked multisensory conflict by means of a self-localization and an external localization task. While effects of the conflict were observed in both tasks, the effects systematically interacted with the type of localization task and the available visual information while performing the localization task (i.e., the visibility of the virtual hands). The results imply that the localization of one's own hands is based on a multisensory integration process, which is modulated by the saliency of the currently most relevant sensory modality and the involved frame of reference. Moreover, the results suggest that our brain strives for consistency between its body and spatial estimates, thereby adapting multiple, related frames of reference, and the spatial estimates within, due to a sensory conflict in one of them. | Mid | [
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Today during a federal violation hearing it was determined that Deric Lostutter had indeed violated the terms of his release. With this determination he was immediately taken into custody early. He was previously set to surrender himself to prison on May 18, 2017. Had Deric not spent his last few weeks of freedom attempting to intimidate others including a high profile South Florida lawyer, or flipping the bird for Instagram, he may have had these last few days to spend with his baby daughter. Instead he chose to once again thumb his nose at the courts and the orders set forth for him. Typical Deric is typical. Follow @MURTWITNESSONE on Twitter as well for videos and updates. This story is developing and will be updated as more information is received. UPDATE: According to William K Murtaugh who was in the courtroom the judge was very unhappy with Deric. When he asked defense attorney what could be done to keep Deric from further violating if released today, defense could offer no reasonable solution. Judge also went on to predict (that) Deric would violate terms of release within one month of being released from prison. In keeping in true Deric fashion, he allowed his attorney to throw his own wife under the bus by allowing him to argue that Deric had no idea she was posting videos or pictures of him online. . . never mind the fact these were on Instagram which posts automatically to the internet. Defense also argued that this was an attempt by Alexandria Goddard to somehow sink the civil case against her. The judge was having none of it and basically made it known that he didn’t care what others had done – Deric did not have to do what he did and his flipping the bird to the camera was basically an attempt to intimidate others. The judge went on to call Deric and bully, going on to say he liked to threaten others. More updates to come … Read also, Lexington Herald Leader regarding today’s hearing. UPDATE: Deric has been booked into the Grayson County, Kentucky jail awaiting his placement in a Federal Facility. | Mid | [
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Endoscopic sedation: medicolegal considerations. The availability of endoscopy as a diagnostic and therapeutic tool has caused the number of procedures performed in the United States to greatly increase; additionally, the volume and complexity of endoscopic procedures performed under sedation, including difficult procedures performed on frail and severely ill patients, has increased. The goals of endoscopic sedation are to provide patients with a successful procedure and to ensure that they remain safe and are relieved from anxiety and discomfort; agents should provide efficient, appropriate sedation and allow patients to recover rapidly. Sedation is usually both safe and effective; however, complications may ensue. This article will explore medicolegal aspects of sedation, such as the importance of informed consent for sedation, the difficulties of assessing withdrawal of consent in a sedated patient, and the need for sedation monitoring which meets accepted standard of care. Controversies involving GI directed propofol and the use of anesthesia personnel to deliver sedation for endoscopy are also discussed. | Mid | [
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An Hour of Prayer for Life, Peace and Protection with Our Lady of Guadalupe $3.95 Spend an hour praying with Our Lady of Guadalupe. This little booklet contains the story of Our Lady of Guadalupe, prayers, psalms and hymns, the Holy Rosary and prayers of St. Pope John Paul II. Great to use in prayer groups or alone. | Mid | [
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The Latest on the release of videos from cameras worn by Las Vegas police who responded to the deadliest shooting in modern U.S. history (all times local): 5:35 p.m. Officer body-camera video from the deadliest mass shooting in modern U.S. history shows Las Vegas police finding cameras set up on the peepholes of the gunman's hotel suite. Footage made public Wednesday from two officers' body-worn cameras shows an officer gesturing to an open laptop in the room. The officer remarks that the gunman placed a camera in the hallway, which he was watching on his computer. Police say Stephen Paddock killed 58 people and injured hundreds more last October before killing himself as authorities closed in. The clips don't provide a motive for the rampage. In other clips, officers talk about the volume of weapons in the room at a Las Vegas Strip casino-hotel. They also discuss finding some sort of gas mask and that gunman may have expected gas in the room. ___ 5:15 p.m. Newly released police body-camera footage from inside a Las Vegas Strip hotel suite shows the body of the man who authorities say unleashed the deadliest mass shooting in modern U.S. history. Footage made public Wednesday from two officers' body-worn cameras shows Stephen Paddock's body on his back, clad in dark pants and a long-sleeve shirt with a glove on his left hand. An apparent pool of blood stains the carpet near his head as a police SWAT officer walks past. Assault-style rifles are seen in the room, but the view doesn't include a handgun that police say Paddock used to kill himself before officers arrived. Police say Paddock opened fire from the hotel room into a concert crowd on Oct. 1, killing 58 people and injuring hundreds. ___ 5:05 p.m. Officer body-camera video from the deadliest mass shooting in modern U.S. history shows Las Vegas police walking into a casino that's still packed and telling people to get inside and lock the doors. Authorities released footage Wednesday from two officers' body-worn cameras as they responded to gunfire that rained down on a concert crowd from a Las Vegas Strip casino-hotel last fall. A video shows an officer passing people still playing slot machines and telling an employee that "there's a shooter. He's shot and killed multiple people already." In another clip, officers are ordering people to leave the casino and telling an employee, "We need to evacuate the whole casino. Get everyone out of here." ___ 4:30 p.m. Officer body-camera video from the deadliest mass shooting in modern U.S. history shows Las Vegas police at the door of the gunman's suite, and one saying "Breach! Breach! Breach!" before a loud bang and a fire alarm begins to sound. Authorities released footage Wednesday from two officers' body-worn cameras as they responded to gunfire raining down on a concert crowd from a Las Vegas Strip casino-hotel last fall. Officers can be heard shouting to each other to say they have checked parts of the room. A clip shows officers inside a room reading an address off Paddock's driver's license. Another shows officers in a stairwell walking down a hallway behind armored shields and encountering a security guard holding a handgun. ___ 4:25 p.m. Police body-camera video from the deadliest mass shooting in modern U.S. history shows Las Vegas officers busting into the gunman's hotel room and removing a rifle near a broken window. Authorities released footage Wednesday from two officers' body-worn cameras as they respond to gunfire raining down on a concert crowd from a Las Vegas Strip casino-hotel last fall. Video shows officers walk around Stephen Paddock's room, where other weapons are scattered. Police say he killed 58 people and injured hundreds more before killing himself as authorities closed in. Officers talking to each other question if there were any indications of two shooters. ___ 1:55 p.m. A home that the Las Vegas shooter owned in Reno when he carried out the deadliest mass shooting in modern U.S. history sits vacant in an upscale neighborhood. Damage is still visible to the patched-up front door where authorities got in to search the house for potential explosives, weapons and other evidence the day after the Oct. 1 massacre. Washoe County records still list Paddock as the owner. He bought the two-bedroom home for $228,500 in 2013 and lived there at one time with his girlfriend. About a week after the FBI searched the home, police responded to a report that an intruder tried to enter the house through the damaged front door. ___ 1:30 p.m. Las Vegas police have released some officer body-camera video from the deadliest mass shooting in modern U.S. history. Videos made public Wednesday are expected to show what two officers found entering a 32nd-floor hotel room where Stephen Paddock unleashed gunfire on a concert last October. Police say he killed 58 people and injured hundreds more before killing himself as authorities closed in. The footage represents a sample of hundreds of hours of body-camera recordings that police say don't answer why Paddock opened fire. The Associated Press and other media outlets sued to obtain videos, 911 recordings, evidence logs and interview reports. Authorities say more will be released in coming weeks. ____ 12:20 p.m. The first police officer to burst through the door of a Las Vegas hotel suite where a gunman unleashed a hail of bullets on a concert last year didn't activate his body camera. The disclosure made by police lawyers late Tuesday raises questions about whether officers followed department policy during the deadliest mass shooting in modern U.S. history. Police are expected to release body camera videos Wednesday from two other officers who helped clear Stephen Paddock's room. A lawsuit by The Associated Press and other media prompted the videos' release. Paddock opened fire from a 32nd-floor hotel suite on Oct. 1, killing 58 people and injuring hundreds of others. The police department's policy requires officers to activate body cameras during calls that result in interaction with citizens and searches. | Mid | [
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Has this ever been done here before? This is a tough one, as these guys are probably the two biggest villains of their respective universes. I would say that Doom takes this one, but The Joker can certainly be very crafty (And he might have some superpowers as well. There have been some stories where he has had powers.). I think that this is a good one, but I favor Doom. | Low | [
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The U.S. Content of “Made in China” Goods and services from China accounted for only 2.7% of U.S. personal consumption expenditures in 2010, of which less than half reflected the actual costs of Chinese imports. The rest went to U.S. businesses and workers transporting, selling, and marketing goods carrying the “Made in China” label. Although the fraction is higher when the imported content of goods made in the United States is considered, Chinese imports still make up only a small share of total U.S. consumer spending. This suggests that Chinese inflation will have little direct effect on U.S. consumer prices. The United States is running a record trade deficit with China. This is no surprise, given the wide array of items in stores labeled “Made in China.” This Economic Letter examines what fraction of U.S. consumer spending goes for Chinese goods and what part of that fraction reflects the actual cost of imports from China. We perform a similar exercise to determine the foreign and domestic content of all U.S. imports. In our analysis, we combine data from several sources: Census Bureau 2011 U.S. International Trade Data; the Bureau of Labor Statistics 2010 input-output matrix; and personal consumption expenditures (PCE) by category from the U.S. national accounts of the Commerce Department’s Bureau of Economic Analysis. We use the combined data to answer three questions: • What fraction of U.S. consumer spending goes for goods labeled “Made in China” and what fraction is spent on goods “Made in the USA”? • What part of the cost of goods “Made in China” is actually due to the cost of these imports and what part reflects the value added by U.S. transportation, wholesale, and retail activities? That is, what is the U.S. content of “Made in China”? • What part of U.S. consumer spending can be traced to the cost of goods imported from China, taking into account not only goods sold directly to consumers, but also goods used as inputs in intermediate stages of production in the United States? Share of spending on “Made in China” Although globalization is widely recognized these days, the U.S. economy actually remains relatively closed. The vast majority of goods and services sold in the United States is produced here. In 2010, imports were about 16% of U.S. GDP. Imports from China amounted to 2.5% of GDP. Table 1 Import content of U.S. personal consumption expenditures by category Table 1 shows our calculations of the import content of U.S. household consumption of goods and services. A total of 88.5% of U.S. consumer spending is on items made in the United States. This is largely because services, which make up about two-thirds of spending, are mainly produced locally. The market share of foreign goods is highest in durables, which include cars and electronics. Two-thirds of U.S. durables consumption goes for goods labeled “Made in the USA,” while the other third goes for goods made abroad. Chinese goods account for 2.7% of U.S. PCE, about one-quarter of the 11.5% foreign share. Chinese imported goods consist mainly of furniture and household equipment; other durables; and clothing and shoes. In the clothing and shoes category, 35.6% of U.S. consumer purchases in 2010 was of items with the “Made in China” label. Local content of “Made in China” Obviously, if a pair of sneakers made in China costs $70 in the United States, not all of that retail price goes to the Chinese manufacturer. In fact, the bulk of the retail price pays for transportation of the sneakers in the United States, rent for the store where they are sold, profits for shareholders of the U.S. retailer, and the cost of marketing the sneakers. These costs include the salaries, wages, and benefits paid to the U.S. workers and managers who staff these operations. Table 1 shows that, of the 11.5% of U.S. consumer spending that goes for goods and services produced abroad, 7.3% reflects the cost of imports. The remaining 4.2% goes for U.S. transportation, wholesale, and retail activities. Thus, 36% of the price U.S. consumers pay for imported goods actually goes to U.S. companies and workers. This U.S. fraction is much higher for imports from China. Whereas goods labeled “Made in China” make up 2.7% of U.S. consumer spending, only 1.2% actually reflects the cost of the imported goods. Thus, on average, of every dollar spent on an item labeled “Made in China,” 55 cents go for services produced in the United States. In other words, the U.S. content of “Made in China” is about 55%. The fact that the U.S. content of Chinese goods is much higher than for imports as a whole is mainly due to higher retail and wholesale margins on consumer electronics and clothing than on most other goods and services. Total import content of U.S. PCE Not all goods and services imported into the United States are directly sold to households. Many are used in the production of goods and services in the United States. Hence, part of the 88.5% of spending on goods and services labeled “Made in the USA” pays for imported intermediate goods and services. To properly account for the share of imports in U.S. consumer spending, it’s necessary to take into account the contribution of these imported intermediate inputs. We use input-output tables to compute the contribution of imports to U.S. production of final goods and services. Combining the imported share of U.S.-produced goods and services with imported goods and services directly sold to consumers yields the total import content of PCE. Table 1 also shows total import content as a fraction of total PCE and its subcategories. When total import content is considered, 13.9% of U.S. consumer spending can be traced to the cost of imported goods and services. This is substantially higher than the 7.3%, which includes only final imported goods and services and leaves out imported intermediates. Imported oil, which makes up a large part of the production costs of the “gasoline, fuel oil, and other energy goods” and “transportation” categories, is the main contributor to this 6.6 percentage point difference. Figure 1 Import content of U.S. PCE, 2000–2010 Sources: Bureau of Economic Analysis, Bureau of Labor Statistics, Census Bureau, and authors’ calculations. The total share of PCE that goes for goods and services imported from China is 1.9%. This is 0.7 percentage point more than the share of Chinese-produced final goods and services in PCE. This difference is mainly due to the use of intermediate goods imported from China in the U.S. production of services. Figure 1 plots the total and Chinese import content of U.S. PCE over the past decade. The import content of PCE has been relatively constant at between 11.7% and 14.2%. Import content peaked in 2008 at 14.2%, which was probably due to the spike in oil prices at the time. The share of imports in PCE is slightly lower than in GDP as a whole because the import content of investment goods turns out to be twice as high as that of consumer goods and services. The fraction of import content attributable to Chinese imports has doubled over the past decade. In 2000, Chinese goods accounted for 0.9% of the content of PCE. In 2010, Chinese goods accounted for 1.9%. The fact that the overall import content of U.S. consumer goods has remained relatively constant while the Chinese share has doubled indicates that Chinese gains have come, in large part, at the expense of other exporting nations. Broader implications The import content of U.S. PCE attributable to imports from China is useful in understanding where revenue generated by sales to U.S. households flows. It is also important because it affects to what extent price increases for Chinese goods are likely to pass through to U.S. consumer prices. China’s 2011 inflation rate is close to 5%. If Chinese exporters were to pass through all their domestic inflation to the prices of goods they sell in the United States, the PCE price index (PCEPI) would only increase by 1.9% of this 5%, reflecting the Chinese share of U.S. consumer goods and services. That would equal a 0.1 percentage point increase in the PCEPI. The inflationary effects would be highest in the industries in which the share of Chinese imports is highest—clothing and shoes, and electronics. In fact, recent data show accelerating price increases for these goods compared with other goods. However, it does not seem that so far Chinese exporters are fully passing through their domestic inflation. In , prices of Chinese imports only increased 2.8% from . This is partly because a large share of Chinese production costs consists of imports from other countries. Xing and Detert (2010) demonstrate this by examining the production costs of an iPhone. In 2009, it cost about $179 in China to produce an iPhone, which sold in the United States for about $500. Thus, $179 of the U.S. retail cost consisted of Chinese imported content. However, only $6.50 was actually due to assembly costs in China. The other $172.50 reflected costs of parts produced in other countries, including $10.75 for parts made in the United States. Conclusion Figure 2 Geography of U.S. PCE, 2010 Sources: Bureau of Economic Analysis, Bureau of Labor Statistics, Census Bureau, and authors’ calculations. Figure 2 shows the share of U.S. PCE based on where goods were produced, taking into account intermediate goods production, and the domestic and foreign content of imports. Of the 2.7% of U.S. consumer purchases going to goods labeled “Made in China,” only 1.2% actually represents China-produced content. If we take into account imported intermediate goods, about 13.9% of U.S. consumer spending is attributable to imports, including 1.9% imported from China. Since the share of PCE attributable to imports from China is less than 2% and some of this can be traced to production in other countries, it is unlikely that recent increases in labor costs and inflation in China will generate broad-based inflationary pressures in the United States. Galina Hale is a senior economist in the Economic Research Department of the Federal Reserve Bank of San Francisco. Bart Hobijn is a senior research advisor in the Economic Research Department of the Federal Reserve Bank of San Francisco. References Bureau of Labor Statistics. 2010. “Inter-industry relationships (Input/Output matrix).” U.S. Census Bureau. 2011. “U.S. International Trade Data.” Xing, Yuqing, and Neal Detert. 2010. “How the iPhone Widens the United States Trade Deficit with the People’s Republic of China.” Asian Development Bank Institute Working Paper 257. Additional materials Replication files: source data files, GAUSS programs, and Excel files that can be used to replicate results in Table 1. (zip 14.5 mb) | Mid | [
0.577656675749318,
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--- abstract: | The reaction mechanisms of the two-neutron transfer reaction $^{12}$C($^6$He,$^4$He) have been studied at 30 MeV at the TRIUMF ISAC-II facility using the SHARC charged-particle detector array. Optical potential parameters have been extracted from the analysis of the elastic scattering angular distribution. The new potential has been applied to the study of the transfer angular distribution to the 2$^+_2$ 8.32 MeV state in $^{14}$C, using a realistic 3-body $^6$He model and advanced shell model calculations for the carbon structure, allowing to calculate the relative contributions of the simultaneous and sequential two-neutron transfer. The reaction model provides a good description of the 30 MeV data set and shows that the simultaneous process is the dominant transfer mechanism. Sensitivity tests of optical potential parameters show that the final results can be considerably affected by the choice of optical potentials. A reanalysis of data measured previously at 18 MeV however, is not as well described by the same reaction model, suggesting that one needs to include higher order effects in the reaction mechanism.\ author: - 'D. Smalley' - 'F. Sarazin' - 'F.M. Nunes' - 'B.A. Brown' - 'P. Adsley' - 'H. Al-Falou' - 'C. Andreoiu' - 'B. Baartman' - 'G.C. Ball' - 'J.C. Blackmon' - 'H.C. Boston' - 'W.N. Catford' - 'S. Chagnon-Lessard' - 'A. Chester' - 'R.M. Churchman' - 'D.S. Cross' - 'C.Aa. Diget' - 'D. Di Valentino' - 'S.P. Fox' - 'B.R. Fulton' - 'A. Garnsworthy' - 'G. Hackman' - 'U. Hager' - 'R. Kshetri' - 'J.N. Orce' - 'N.A. Orr' - 'E. Paul' - 'M. Pearson' - 'E.T. Rand' - 'J. Rees' - 'S. Sjue' - 'C.E. Svensson' - 'E. Tardiff' - 'A. Diaz Varela' - 'S.J. Williams' - 'S. Yates' title: 'Two-neutron transfer reaction mechanisms in $^{12}$C($^6$He,$^{4}$He)$^{14}$C using a realistic three-body $^{6}$He model' --- [^1] Introduction {#intro} ============ One of the critical ingredients to understand nuclear properties, both in the valley of stability and at the nuclear drip lines, is the pairing effect [@review-pairing]. Pairing is a general term that embodies the correlation between pairs of nucleons, producing for example the well-known mass staggering in nuclear isobars. Pairing is also essential to understanding the formation of two-neutron halos [@Tan13]. Although the importance of pairing for describing nuclear phenomena is well accepted, reaction probes used to measure pairing are still poorly understood. Two-nucleon transfer is the traditional probe to study pairing. The main idea is that the angular distribution for the simultaneous transfer of two nucleons depends directly on the change in angular momentum of the two nucleons from the original to the final nucleus, and therefore provides indirectly information on their relative motion. Experimental studies of two-neutron transfer imply the use of a surrogate reaction. Hence, the interpretation of the results become strongly dependent on the reaction mechanism, since typically the simultaneous transfer of the two nucleons is contaminated by the two-step sequential transfer. Traditionally A$(t,p)$B or B$(p,t)$A reactions have been the most common tools to explore two-neutron correlations (see for example [@decowski; @bjerregaard] for earlier studies and [@wimmer; @potel11] for more recent studies). The advantage of $(t,p)$ is that it allows the study of not only the ground state of B but also of a number of its excited states, accessible through energy and angular momentum matching. Since the triton is a well understood nucleus, it was thought that these reactions would be easier to describe than others using heavier probes [@Gat75; @Iga91]. However, missing factors of 2 or 3 in the cross section normalization (known as the unhappiness factor [@Mer79; @Kun82]) for $(p,t)$ and $(t,p)$ have shown that a simple perturbative description, that does not take into account the intermediate deuteron state correctly has severe limitations [@Tho12]. There are experimental drawbacks as well: (p,t) only permits the study of the ground-state of the original nucleus considered, and $(t,p)$ requires handling of tritium radioactivity, which is challenging in most laboratories. Other two-neutron transfer probes have been considered. The next simplest case after $(t,p)$ would be the ($^{6}$He,$^{4}$He) reaction involving the two-neutron halo nucleus $^{6}$He. The structure of $^{6}$He makes it a very attractive candidate for two-neutron transfer reactions, because of its Borromean nature and its very low two-neutron separation energy ($S_{2n}=0.97$ MeV). Indeed, Chatterjee [*et al.*]{} [@Cha08] recently observed in $^{6}$He on $^{65}$Cu at 23 MeV a large dominance of the two-neutron over one-neutron transfer cross-section and interpreted this in terms of the unique features of the $^{6}$He wavefunction. At present, $^6$He is the best understood two-neutron halo nucleus, with a very significant component where the halo neutrons are spatially correlated (the so-called “di-neutron” component) and an equally important component where the two halo neutrons are anti-correlated (the so-called “cigar” component) (e.g. [@Var94; @Bri10]). Given the comparatively small $^6$He two-neutron separation energy with respect to the one of the triton ($S_{2n}=6.25$ MeV), the two-neutron transfer reaction ($^{6}$He,$^{4}$He) provides not only a higher Q-value overall than its $(t,p)$ counterpart allowing for higher excited states to be populated, but also a more favorable Q-value matching condition for a given two-neutron transfer reaction. It has even been suggested by Fortunato [*et al.*]{} [@For02] that this higher Q-value provides relatively large cross sections to study giant pairing vibrations in heavy-ions. It also provides a different angular momentum matching condition, given that the two active neutrons can exist in a relative p-state as opposed to the situation in the triton. In addition to these two important differences, the Borromean nature of $^6$He [@Zhu93] implies that the sequential transfer can only happen through the continuum states of $^5$He and is likely to leave a softer imprint in the distributions than the sequential process in $(t,p)$ through the deuteron bound state. Experimentally, the major drawback lies in the fact that $^{6}$He is unstable (T$_{1/2}$=807 ms) and therefore the reaction can only be studied using targets made of stable or long-lived isotopes. Theoretically, one difficulty arises from the existence of unbound excited states in $^{6}$He, the first one (2$^{+}$) at 1.8 MeV. With this in mind, what is needed to explore ($^{6}$He,$^{4}$He) is a test-case, where the final state is well understood, such that the focus can be on the reaction mechanism. Given the interest in the halo structure of $^6$He [@Tan85; @Zhu93], there have been many measurements involving the ($^{6}$He,$^{4}$He) vertex. The measurements of the p($^{6}$He,$^{4}$He)t at 151 MeV [@wolski-he6pt151; @giot-he6pt150] resulted in difficulties in the analysis due to the strong interference of the small $t+t$ component in the $^6$He wave function. There were also two measurements on $^4$He($^{6}$He,$^{4}$He)$^6$He, one at E$_{\mathrm{lab}}=29$ MeV [@raabe-he6he4-11] and the other at E$_{\mathrm{lab}}=151$ MeV [@terakopian-he6he4-151]. In this reaction, the transfer channel corresponds to the exchange of the elastic channel, reducing the number of effective interactions necessary to describe the process, but introducing yet another complication, that of appropriate symmetrization. And while Ref [@Cha08] clearly demonstrated a preference for two-neutron over one-neutron transfer, the actual mechanism for the two-neutron transfer was simply assumed to be one-step arising from the di-neutron configuration of the $^{6}$He wavefunction. Our test-case is the reaction $^{12}$C($^{6}$He,$^{4}$He)$^{14}$C, a reaction that populates well-known states in $^{14}$C. Possible intermediate states in $^{13}$C in the sequential transfer are also well known. If we thus assume that our present knowledge of $^6$He is complete, we can focus on the reaction mechanism. $^{12}$C($^{6}$He,$^{4}$He)$^{14}$C was first performed at E=5.9 MeV [@Ost98] and populated the ground state and the first $1^-$ and $3^-$ states in $^{14}$C. Following that measurement, the reaction was remeasured at 18 MeV [@Mil04], populating strongly the $8.32$ MeV $2^+_2$ state in $^{14}$C. At the lowest beam energy, the transfer cannot be treated perturbatively, resulting in an intricate mechanism for the process [@Kro00], in [@Mil04] a reasonable description of the reaction is provided with the simple one-step di-neutron model. In this work, we present new results from the measurement of $^{12}$C($^{6}$He,$^{4}$He)$^{14}$C at $30$ MeV and discuss in detail the reaction mechanisms taking into account not only one-step but also two-step (through intermediate $^{13}$C states) processes. The new model is also applied to the previous study at 18 MeV. In Section \[setup\], we describe the experimental setup and details in the analysis. In Section \[theo\], we briefly summarize the main ingredients used in the reaction theory used to analyze our results. The elastic scattering results are presented in Section \[elas\], followed by the inelastic scattering in Section \[Inelas\] and the transfer results in Section \[tran\]. Finally, in Section \[concl\] we summarize and draw our conclusions. Experimental Setup {#setup} ================== The [$^{12}$C($^6$He,$^4$He)$^{14}$C]{} experiment was performed in direct kinematics at the TRIUMF ISAC-II facility using a combination of the Silicon Highly-segmented Array for Reactions and Coulex (SHARC) [@Dig11] and the TRIUMF-ISAC Gamma-Ray Escape-Suppressed Spectrometer (TIGRESS) [@Hac13]. The $^6$He$^{+}$ beam was produced by impinging a 500-MeV, 75-$\mu$A proton beam upon a 20.63 g/cm$^{2}$ ZrC target, and extracted using a Forced Electron Beam Induced Arc Discharge (FEBIAD) ion source. The 12.24 keV $^{6}$He beam was post-accelerated through the ISAC-I (where the beam was also stripped to 2+) and ISAC-II accelerators to 30 MeV before being delivered to the TIGRESS beam line. A small amount ($<$5%) of $^6$Li contaminant was also transmitted through the accelerator. The beam then impinged upon a 217 $\mu$g/cm$^2$ $^{12}$C target located at the center of the SHARC and TIGRESS arrays. The average beam intensity was estimated to be $\mathrm{I}=8\times10^5$ pps with a total integrated beam current on target of 77 nC over the course of the experiment. ![(color online) Particle identification for the DCD. The $\Delta$E-E plot shows the energy loss in the thin 80 $\mu$m detector ($\Delta$E) plotted against the energy loss in the thick 1mm detector (E). The nuclei unambiguously identified are shown in the figure.[]{data-label="f:ParID"}](figure1.pdf){width="\columnwidth"} ![(color online) Particle identification for the DCD. The $\Delta$E-E plot shows the energy loss in the thin 80 $\mu$m detector ($\Delta$E) plotted against the energy loss in the thick 1mm detector (E). The nuclei unambiguously identified are shown in the figure.[]{data-label="f:ParID"}](figure2.pdf){width="\columnwidth"} The laboratory angular coverage of the SHARC array is shown in Fig. \[f:SHARC\], where each point represents a pixel of detection. The downstream end cap detectors (DCD) consisted of four $\Delta$E-E telescopes made of three 80 $\mu$m Double-Sided Silicon Strip Detectors (DSSSD) and one single-sided 40 $\mu$m $\Delta$E detector, all backed with 1 mm E detectors. Polar angle coverage in the laboratory frame of the DCD was 7$^\circ$-27$^\circ$. The downstream box (DBx) was comprised of four 140 $\mu$m DSSSDs $\Delta$E detectors backed with 1.5 mm E detectors and polar angle coverage of 32$^\circ$-71$^\circ$. The upstream box (UBx) was made of four 1 mm DSSSDs with polar angle coverage of 103$^\circ$-145$^\circ$. Finally, the partial upstream end cap (UCD) consisted of a single 1 mm DSSSD with a polar angle coverage of 148$^\circ$-172$^\circ$. A total of 21 strips out of 752 were not functioning giving a solid angle coverage of the array of $\Omega\approx2\pi$. Additionally, one DCD E ($184^\circ<\phi_{lab}<258^\circ$) detector malfunctioned during the experiment. Particle identification was obtained for three quadrants of DCD and all quadrants of DBx. The DCD $\Delta$E-E provided identification of all the isotopes of charge $\mathrm{Z}\leq3$ as shown in Fig. \[f:ParID\]. In particular, clear separation of the $^4$He and $^6$He isotopes was achieved allowing for a clear identification of the elastic/inelastic scattering from the two-neutron transfer (and fusion-evaporation) channels. Only identification of particles with mass $\mathrm{A}\leq4$ was possible in the downstream box due to the thickness of the $\Delta$E detectors (which stopped the scattered $^6$He beam). For UBx and UCD, identification of the two-neutron transfer channel remained possible because of the high Q-value of the reaction (Q=12.15 MeV). The TIGRESS array was used in high-efficiency mode for $\gamma$-ray detection. The angular coverage of the TIGRESS array was such that there were 7 clover detectors at $\theta_{\mathrm{lab}}=90^\circ$ and 4 clover detectors at $\theta_{\mathrm{lab}}=135^\circ$ with one crystal not operational in the clover at ($\theta_{lab}=135^\circ$,$\phi_{lab}=113^\circ$). Detection of $\gamma$-rays in coincidence with charged-particles was achieved, but the statistics was too low to carry out analyses of $\gamma$-gated angular distributions. In what follows, $\gamma$-ray detection and tagging are not discussed further. Theory {#theo} ====== Reaction mechanisms ------------------- We study two-neutron transfer with the finite-range Distorted Wave Born Approximation (DWBA). The simultaneous two-neutron transfer process is treated to first order, as one step (see e.g. [@oganessian99] for details). The transition amplitude for the process for $^{12}$C($^6$He,$^4$He)$^{14}$C$(2^+)$ can be written as [@oganessian99]: $$T^{post} = \langle \chi_f \: {\cal I}_{^{14}C,^{12}C} | \Delta V | {\cal I}_{^6He,^4He} \: \chi_i\rangle \;, \label{t-matrix}$$ where $\chi_i$ and $\chi_f$ are the initial and final distorted waves between $^6$He-$^{12}$C and $^4$He-$^{14}$C respectively, and ${\cal{I}}_{He}$ and ${\cal{I}}_C$ are the two-neutron overlap functions of the ground state of $^6$He and $^4$He, and the $2^+_2$ state of $^{14}$C and the ground state of $^{12}$C respectively. In the post form [@Tho09], the potential is defined as, $$\Delta V = V_{2n^{12}C}+V_{\alpha^{12}C}-U_i, \label{V}$$ where $V_{2n^{12}C}$ is the potential between the two valence neutrons of the $^6$He and the $^{12}$C, $V_{\alpha^{12}C}$ is the core-core potential and $U_i$ is the entrance channel potential ($^6$He+$^{12}$C). Many analyses of two-neutron transfer data involving $^6$He beams have assumed that the $^6$He system can be described by a two-body wave function of the $\alpha$-particle and a di-neutron cluster, simplifying tremendously the two-neutron overlap function needed in the transfer matrix element (e.g. [@Cha08; @Mil04]). While a full six-body microscopic description [@Bri10; @timofeyuk01] may not provide more than a correction to the overall normalization of the overlap function, the three-body $^6\mathrm{He}$ = $^{4}\mathrm{He}+\mathrm{n}+\mathrm{n}$ wave function is a requirement for a consistent treatment of simultaneous and sequential transfer, present for all but the highest energies E$>$100 MeV. In this work, we use a realistic three-body model for $^{6}$He [@Bri08] which reproduces the binding energy and radius of the ground state. The two-neutron spectroscopic amplitudes for $^{14}$C are obtained from microscopic shell-model calculations, which we describe in more detail below. We assume a standard geometry (radius $r=1.25$ fm and diffuseness $a=0.65$ fm) for the mean field generating the radial form factor including a spin-orbit with the same geometry as the mean field and a strengh of V = 6.5 MeV for the $^{14}$C two-neutron overlap function. The initial and final distorted waves are also important elements of Eq. \[t-matrix\]. One way to constrain these is by using elastic scattering over a wide angular range. For the optical potential in the final channel $^4$He-$^{14}$C, there are many possible data sets from which to draw, and even global parameterizations may be adequate since none of the nuclei involved are of peculiar structure. The same is not true for the initial channel. Separate studies on the elastic scattering of $^6$He on $^{12}$C [@Alk96; @Lap02] at high energies have revealed very significant modifications of the expected optical potential based on the double folding approach, due to large breakup effects inherent to the low S$_{2n}$ of $^{6}$He. Given the strong dependence of the two-neutron transfer cross section on the optical potentials used, it is critical to have elastic scattering data at the appropriate energy for a meaningful analysis. This is presented in Section \[elas\]. At the energies we are interested in, the two-step sequential process must be considered. In this case we need to include the one-nucleon transfer into $^{13}$C: $$T^{post} = \langle \chi_{f1} \; {\cal I}_{^{13}C,^{12}C} | \Delta V_1 | {\cal I}_{^6He,^5He}\; \chi_{i1}\rangle \;, \label{t-matrix1}$$ where the initial state of Eq. \[t-matrix\] is taken into a bound state in $^{13}$C and followed by the second neutron transferring from $^5$He to the final state in $^{14}$C: $$T^{prior} = \langle \chi_{f2}\; {\cal I}_{^{14}C,^{13}C} | \Delta V_2 | {\cal I}_{^5He,^4He} \;\chi_{i2}\rangle \;, \label{t-matrix2}$$ A number of $^{13}$C states contribute to this process, and the needed spectroscopic amplitudes are obtained from microscopic shell model calculations, assuming the same residual interaction and model space as that used for the two-neutron amplitudes. We avoid the explicit inclusion of states in the continuum by modifying the binding energy and level scheme of $^{13}$C. Shell model considerations for carbon overlaps ---------------------------------------------- All structural information for the carbon isotopes relies on recent shell model predictions. The earliest discussion related to the structure of the 2$^+$ 8.32 MeV state in $^{14}$C is based on the gamma decay of its analogue in $^{14}$N at 10.43 MeV [@war60]. There are two 2$^+$ T=1 states in this energy region of $^{14}$N, the 10.43 MeV and a lower one at 9.16 MeV. The possible shell-model configurations for these states relative to a closed shell for $^{16}$O are two-holes in the $p$-shell ($2h$) and four holes in the $p$-shell with two particles in the $sd$ shell ($2p-4h$). The electromagnetic decay required about an equal admixture between these two configurations. The early weak-coupling model of Lie [@lie72] could reproduce this result only by introducing an empirical energy shift in the $2p-4h$ component. Mordechai [*et al.*]{} [@mor78] have used the empirical wave functions of Lie to understand the relative $^{12}$C$(t,p)$$^{14}$C strength to the 7.01 and 8.32 MeV 2$^+$ states. The $(t,p)$ cross section is dominated by the $2p$ ($sd$) part of the transfer, and the mixing results in about equal $(t,p)$ cross sections for these two 2$^+$ states. Here we are able to use the full $p-sd$ model space. In this model space the basis dimension is 982,390 for $J=2$, and the wavefunctions can be obtained with the NuShellX code [@nushellx]. A Hamiltonian for this space was recently developed by Utsuno and Chiba [@uts11] (psdUC). This was used to calculate Gamow-Teller strengths for the $^{12}$B($^{7}$Li,$^{7}$Be)$^{12}$Be reaction. Relative to the original Hamiltonian of Utsuno and Chiba, the $p-sd$ gap had to be increased by one MeV in order to reproduce the correct mixing of states in $^{12}$Be. We calculated the two-particle transfer amplitudes with this same modified psdUC Hamiltonian. The wavefunctions for the two 2$^+$ states in $^{14}$C came out with about the correct mixing between $2h$ and $2p-4h$ that are required to reproduce the gamma decay and the relative $(t,p)$ cross sections. The theoretical energy splitting of 0.51 MeV is smaller than the experimental value of 1.3 MeV. But the most important aspect for the present analysis is that the structure of the 2$^+$ state be consistent with the history of its structure that we have outlined above. Details of the calculations --------------------------- The level scheme relevant for the transfer is shown in Fig. \[f:ModelAssume\] a) with the Q-values listed. A direct transfer from the ground state of $^6$He to the $2^{+}_{2}$ 8.32 MeV state in $^{14}$C is shown with a solid line. The sequential transfer paths, represented by dashed lines, involve single particle overlaps. To reduce the complexity of the reaction theory and associated computational cost, we make a quasi-bound approximation for $^5$He, and take for the $^5$He optical potentials, the same parameters used for $^6$He-$^{12}$C. The binding energy of the quasi-bound $^5$He was assumed to be half the binding energy of $^6$He relative to $^4$He (28.7831 MeV). Similarly, we slightly shifted the intermediate $^{13}$C states, to avoid introducing the continuum in our calculations. The only significant shift introduced was for the high lying $3/2^+$ state. Although the relative spectroscopic amplitudes for the $^{13}$C $3/2^+$ state is weak compared to the most dominant states of 5/2$^+$ and 1/2$^+$, we found that this state has a non-negligible contribution to the cross section. The total transfer calculation is then the coherent sum of all the pathways. Fig. \[f:ModelAssume\] b) shows the final level scheme adopted in our reaction calculation. The indirect route of the unbound 2$^+$ excited state of $^6$He was not considered. Krouglov [*et al.*]{} [@Kro00] observed that in the analysis of the $^6$He+$^{12}$C two-neutron transfer at E$_{\mathrm{lab}}=5.9$ MeV it was of minor importance. ![The level scheme adopted for this two-neutron transfer study. The solid line shows the pathway for simultaneous transfer. The dotted lines show the multiple pathways taken into account in the sequential transfer. The total transfer calculation then takes the coherent sum of all the pathways. The true level scheme is shown in a) and the modified level scheme which was used is depicted in b). []{data-label="f:ModelAssume"}](figure3.pdf){width="\columnwidth"} The transfer calculations were performed using the reaction code [fresco]{} [@Tho88] and the realistic three-body calculations for $^6$He were performed using [efadd]{} [@efadd]. The integration was performed out to 30 fm and the transfer matrix element non-locality was calculated out to 10 fm. The cluster variable for the two-neutron overlap extended to 10 fm and partial waves up to J$_{\mathrm{max}}=33$ were included, for convergence. Results and Discussion ====================== Elastic Scattering {#elas} ------------------ ![(color online) The elastic and inelastic scattering Energy vs. $\theta_{\mathrm{lab}}$ kinematics. The DCD used the straightforward particle ID of the $^6$He ejectiles, while the DBx required coincident detection considerations (see text for details). The kinematic curves for $^6$He and $^{12}$C are shown in black and red respectively with strong population of the $0^+$ ground state and the $2^+$ 4.4 MeV state of $^{12}$C. The slight mismatch in energy of the $^{12}$C expected kinematics is due to increased energy loss from the higher Z and straggling in the carbon target. []{data-label="f:Elastic_E_Theta"}](figure4.pdf){width="\columnwidth"} [l|\*[13]{}[c]{}]{} & r$_{\mathrm{C}}$ & V & r$_{\mathrm{R}}$ & a$_{\mathrm{R}}$ & W & r$_{\mathrm{I}}$ & a$_{\mathrm{I}}$ & V$_{\mathrm{SO}}$ & r$_{\mathrm{SO}}$ & a$_{\mathrm{SO}}$\ $^6$He+$^{12}$C/$^5$He+$^{13}$C & 2.3 & 240.3 & 1.18 & 0.74 & 10.0 & 2.10 & 1.18 & & &\ $^6$Li+$^{12}$C [@Trc90] & 2.3 & 240.3 & 1.18 & 0.74 & 10.0 & 2.10 & 0.78 & & &\ $\alpha$+$^{12,14}$C [@Mik61] & 1.2 & 40.69 & 2.12 & 0.1 & 2.21 & 2.98 & 0.22 & & &\ n+$^{5}$He [@Kee08] & 1.2 & 4.3 & 1.25 & 0.65 & & & & 6 & 1.25 & 0.65\ The elastic scattering angular distribution was extracted for the downstream ($\mathrm{\theta}_{\mathrm{lab}}<90^\circ$) detection system. For $\mathrm{\theta}_{\mathrm{lab}}>90^\circ$, no clear identification of the elastic scattering channel could be achieved. Fig. \[f:Elastic\_E\_Theta\] shows the Energy vs. $\mathrm{\theta}_{\mathrm{lab}}$ in the DCD and DBx for the $^6$He+$^{12}$C elastic and inelastic scattering after cuts on the data. In the DCD, unambiguous identification of the scattered $^6$He was achieved through $\Delta$E-E particle identification. The elastic angular distribution was only extracted past $\theta_{\mathrm{lab}}$=10.7$^\circ$, because of the presence of elastic scattering on a heavy nucleus in the first three polar strips. As mentioned earlier, (in)elastically scattered $^{6}$He do not punch-through the $\Delta$E in the DBx. However, clean identification of the scattering events could still be achieved using kinematics considerations. For this particular reaction, both the scattered $^{6}$He and recoiling $^{12}$C remain confined to the DBx and are detected in a reaction plane intersecting opposite DBx quadrants. Using cuts on the kinematic correlation of the $^{6}$He and $^{12}$C energies, polar angles $\theta$ and azimuthal angles $\phi$, the kinematic loci for $^{6}$He and $^{12}$C were extracted from background and are shown in Fig. \[f:Elastic\_E\_Theta\]. The detection of $^{12}$C in the DBx stops abruptly at $\theta_{\mathrm{lab}}=36^\circ$ due to the $^6$He scattering beyond $\theta_{\mathrm{lab}}=72^\circ$. Monte Carlo simulations using GEANT4 [@Ago03] were performed to determine the detection efficiency arising from these cuts and to normalize the DCD and DBx relative angular distributions. The elastic scattering angular distribution is shown in Fig. \[f:ElasticAngDist\] (top). The absolute cross section was obtained by normalizing the angular distribution to Coulomb scattering at forward angles. Only statistical errors are shown but we estimate a systematic error in the normalization of 25%. The solid line is the optical model obtained from a $\chi^2$ minimization of the $^6$Li+$^{12}$C optical model parameters to better fit the current data set, using the code [sfresco]{}. We found that adjusting only the imaginary diffuseness $a_I$ of the original $^6$Li potential and introducing the correct Coulomb charge, a good description of the $^6$He was obtained (see solid line in Fig. \[f:ElasticAngDist\] (top)). Similar adjustments were performed by Sakaguchi [*et al.*]{} [@Sak11] to the $^6$Li+p optical potential to describe the $^6$He+p scattering. We note that, while our $^6$He scattering is measured out to $\theta_{\mathrm{cm}}<100^\circ$, the elastic scattering data for $^6$Li+$^{12}$C [@Vin84] (see Fig. \[f:ElasticAngDist\] (bottom)) goes out to much larger angles ($5^\circ<\theta_{\mathrm{cm}}<170^\circ$), and these large angles appear to be critical to better constrain the optical potential. The optical model parameters used for the elastic scattering are shown in table \[t:OM-Parameters\]. ![(color online) The elastic scattering angular distribution. The top figure shows $^6$He+$^{12}$C elastic scattering at E$_{\mathrm{lab}}=30$ MeV. The dotted red line is the theoretical cross section calculated using the optical model parameters for the $^6$Li+$^{12}$C at 30 MeV [@Trc90], while the solid line is the theoretical cross section calculated using the optical model parameters of $^6$He+$^{12}$C obtained from the fit to the current data set. The bottom figure shows the $^6$Li+$^{12}$C elastic scattering at E$_{\mathrm{lab}}=30$ MeV with the dotted red line being the optical model parameters for the $^6$Li+$^{12}$C at 30 MeV [@Trc90].[]{data-label="f:ElasticAngDist"}](figure5.pdf){width="\columnwidth"} General features of the scattering can be observed from the $^6$Li+$^{12}$C optical model [@Trc90] at 30 MeV (see Fig. \[f:ElasticAngDist\] (bottom)). However, the current data has a notable shift in minima compared to the $^6$Li+$^{12}$C optical potential. This same effect was observed in the elastic scattering at 18 MeV of $^6$He+$^{12}$C by Milin [*et al.*]{} [@Mil04]. Using the adjusted elastic potential parameters, an analysis was performed for the inelastic scattering to the 2$^{+}$ 4.4 MeV state of $^{12}$C. Inelastic Scattering (2$^{+}$ 4.4 MeV state) {#Inelas} -------------------------------------------- Inelastic scattering of the 2$^+$ 4.4 MeV state of $^{12}$C was observed and is shown in Fig. \[f:Elastic\_E\_Theta\]. The data were extracted and analyzed independently of the transfer model. A quadrupole deformation of $^{12}$C was assumed with a deformation length of $\delta_{l}=-1.34$ fm taken from the analysis of inelastic scattering of $^{12}$C+$^6$Li at 30 MeV [@Ker96]. The coupling strength is calculated within the simple rotor model. A coupled-channel calculation with coupling between the ground state and first excited state of $^{12}$C was assumed. The inelastic angular distribution is shown in Fig. \[f:inelastic\]. The adjustment of the imaginary diffuseness $a_I$ as described in Section \[elas\], has the effect of decreasing the magnitude of the angular distribution at higher angles, improving the agreement with the data. In this work we do not couple the inelastic scattering contributions into the two-neutron transfer. ![The inelastic scattering to the 2$^+$ 4.4 MeV state. An independent model of the transfer was performed with the elastic scattering optical potential described above (see text for details). []{data-label="f:inelastic"}](figure6.pdf){width="\columnwidth"} ${}^{12}$C(${}^6$He,${}^4$He)${}^{14}$C (2$^+$, 8.32 MeV) {#tran} --------------------------------------------------------- The two-neutron transfer was extracted beyond background for all areas of detection except the UCD. Interference with the (p,t) reaction kinematics was observed and this led to the exclusion of events between $10.7^\circ<\theta_{\mathrm{lab}}<19^\circ$. The DCD/DBx relied on particle identification of the alpha particles from the $\Delta$E-E spectrum. Coincident events were selected for the DBx in a similar manner to that discussed in Section \[elas\]. Background in the DBx and UBx was present due to a worsening of the angular resolution which was accounted for and subtracted from the spectrum. The excitation spectrum of the two-neutron transfer for the DCD is shown in Fig. \[f:TwoNExcite\]. The ground state (not shown) is only weakly populated due to Q-value mismatching, and thus is not further discussed. Angular distributions for the closely-spaced $^{14}$C bound states could not be extracted due to the lack of $^4$He-$\gamma$ coincidences. Hence, only the angular distribution for the $2^+_2$ 8.32 MeV state of $^{14}$C could be extracted. ![(color online) The energy excitation spectrum for the two-neutron transfer in the DCD. Separation of the 2$^+_2$ 8.32 MeV of $^{14}$C is clearly observed. A high density of bound states from 6 MeV to 7.3 MeV is observed but cannot be separated without $^4$He-$\gamma$ coincidences. The 8.32 MeV state is located 200 keV above the neutron separation energy ($\mathrm{S}_{n}=8.1$ MeV). []{data-label="f:TwoNExcite"}](figure7.pdf){width="\columnwidth"} The optical potentials used in the transfer calculations are shown in table \[t:OM-Parameters\]. The elastic scattering parameters from \[elas\] were used as the entrance channel and the $^5$He+$^{13}$C interaction potentials. For the exit channel and the core-core potential, $\alpha$+$^{12}$C data at 28.2 MeV [@Mik61] was fit using [sfresco]{}. For the n+$^{12}$C binding potential, we took a standard radius and diffuseness, and adjusted the depth to reproduce the correct binding energy. A Gaussian potential was used for the $\alpha$+n binding potential [@Zhu93] and finally the $^5$He+n binding potential was taken from Keeley [*et al.*]{} [@Kee08]. The $2^+_2$ 8.32 MeV transfer cross-section is shown in Fig. \[f:transfer\]. Note that only statistical errors are included for the data. The reaction calculations agree fairly well with the data, considering no normalization factor is applied to the transfer (no unhappiness factor). The solid black line corresponds to the coherent sum of the sequential and simultaneous transfer, the dotted red line is the simultaneous transfer alone and the dashed blue line is the results of including the sequential transfer contributions only. We performed various sensitivity tests to assess the robustness of our results. We found that taking the intermediate levels as degenerate introduces a reduction of the cross section by no more than $\approx 5\%$. However, the transfer cross section is by far most sensitive to the choice of the optical potentials. Taking a different set of parameters for an optical potential describing the $^6$He+$^{12}$C elastic scattering, resulted in significant effects on the magnitude (up to $50$%) as well as on the shape of the angular distribution. Effects of similar magnitude were seen for changes in the exit optical potential and in the core-core interaction. Less significant were the effects of the geometry used for the binding potentials of $^{12}$C+n/$^{13}$C+n. In all cases the simultaneous two-neutron transfer remained the dominant component. However, the interplay between the simultaneous and sequential transfer provides a better overall agreement with the data. ![(color online) Comparison of the angular distribution of the $^{12}$C($^6$He,$^4$He)$^{14}$C 2$^+$ $\mathrm{E}_{\mathrm{x}}=8.32$ MeV state at $\mathrm{E}_{\mathrm{lab}}$=30 MeV with the current model. The dotted red line is the simultaneous two-neutron transfer accounting for the three-body nature of $^6$He, the dashed blue line is the sequential two-step transfer accounting for the structure of $^{13}$C and $^{14}$C and the solid black line is the coherent sum of the simultaneous and sequential transfer. For comparison, the dot-dashed black line is the simple di-neutron model. See text for details. []{data-label="f:transfer"}](figure8.pdf){width="\columnwidth"} For completeness, we examine the same reaction at 18 MeV [@Mil04]. The entrance channel ($^6$He+$^{12}$C), exit channel ($^4$He+$^{14}$C) and sequential channel ($^5$He+$^{13}$C) were adjusted to those used by Milin [*et al.*]{} [@Obe68]. All structure information introduced in this calculation was kept the same as that used for the analysis of the 30 MeV reaction, for a meaningful comparison. As can be seen, the angular distributions presented in Fig. \[f:MilMod\] show a systematic underestimation of the experimental cross section. ![(color online) Comparison of the angular distribution of the $^{12}$C($^6$He,$^4$He)$^{14}$C 2$^+$ $\mathrm{E}_{\mathrm{x}}=8.32$ MeV state at $\mathrm{E}_{\mathrm{lab}}$=18 MeV with the current model. Refer to Fig. \[f:transfer\] for the description of the lines and the text for details. []{data-label="f:MilMod"}](figure9.pdf){width="\columnwidth"} Comparison with the pure di-neutron model was made for both the 30 MeV data and the 18 MeV data. We use the same binding potentials in Milin [*et al.*]{} [@Mil04], for $^{12}$C+2n and $^4$He+2n, keeping the optical potentials unchanged. In $^6$He, we assumed the two neutrons were transfered from a relative 2S state. The results obtained with the di-neutron model are shown in Figures \[f:transfer\] and \[f:MilMod\] by the dot-dashed line. Applying a renormalization of $\approx 0.3$ to the 30 MeV di-neutron cross section (not shown in the Fig. \[f:transfer\]) produces a distribution that resembles the respective data. The di-neutron model appears to better describe the 18 MeV data, particularly at forward and backward angles without any normalization. Also, a coupled channel analysis of the 18 MeV data [@Boz08] including elastic, inelastic and transfer channels, again based on the simple di-neutron model, produces cross sections in agreement with the data. However, the agreement of the di-neutron model with the 18 MeV data is deceptive. The fact that our simultaneous transfer predictions (dotted lines in Fig. \[f:transfer\] and \[f:MilMod\]) are far from the di-neutron predictions (dot-dashed lines) stress the need for the inclusion of the correct three-body description of the projectile since it introduces important dynamics in the process. While it is reassuring that the best reaction model is able to describe our transfer data at 30 MeV, the factor of 2 mismatch between our best reaction model and the data at 18 MeV, shown in Fig. \[f:MilMod\] calls for further investigation. Ideally, as a first step, one should perform a more thorough study of the optical potential parameter sensitivities at this energy. Next, one should study the effect of inelastic and continuum channels in the reaction mechanism. Such work is, however, well beyond the scope of the present paper. Conclusion {#concl} ========== In summary, the elastic scattering of $^6$He on $^{12}$C at 30 MeV was measured and an angular distribution extracted. Inelastic scattering data was also extracted and analyzed including the quadrupole deformation of $^{12}$C. Qualitative agreement to the data was found, when accounting for full coupling of the ground state and first excited state of $^{12}$C. Data for the two-neutron transfer angular distribution to the $2^+_2$ 8.32 MeV state in $^{14}$C was observed and analyzed, including the simultaneous and the sequential contributions. A realistic three-body structure for $^6$He was taken into account and state-of-the-art shell model predictions were used for the structure of the carbon isotopes. Overall, the reaction model describes the new data without invoking a normalization constant. It was observed that the simultaneous transfer is the dominant reaction mechanism, yet the strong interplay between the intermediate states of $^{13}$C have non-negligible contributions to the final results. This implies that adding the two-step process is required in order to better account for the overall reaction mechanism. Discrepancies observed when adopting the current model to data at 18 MeV show that further theoretical work is required for a general and reliable approach to ($^6$He,$^4$He) reactions. Even with the simultaneous experimental measurement of the elastic scattering, we find that the largest source of uncertainties in the calculation lies in the determination of the optical model potentials. Our sensitivity studies suggest that measurements of the elastic scattering all the way to $170^\circ$ could reduce these uncertainties. This, however, presents some serious experimental challenges. Concerning the reaction theory for the two-neutron transfer, this calls for further developments. Future work should include the study of the effects of the continuum (e.g. the $2^+$ $^6$He resonance, the $^5$He states, etc) in the reaction dynamics. The strong sensitivity to the choice of optical potential parameters may be greatly reduced, if these are derived microscopically. Finally, comparisons to multiple final bound states of $^{14}$C, such as the first $0^+$ and $2^+$ states, would allow a more thorough understanding of the spin dependencies of one-step and two-step processes. We would like to thank the staff of the ISAC-II facility for their efforts in delivering the $^6$He beam. This work was partially supported by the US Department of Energy through Grant/Contract [Nos.]{} DE-FG03-93ER40789 (Colorado School of Mines) and DE-FG52-08NA28552, NSF grant PHY-1068217, and the Natural Sciences and Engineering Research Council of Canada. TRIUMF is funded via a contribution agreement with the National Research Council of Canada. [48]{}ifxundefined \[1\][ ifx[\#1]{} ]{}ifnum \[1\][ \#1firstoftwo secondoftwo ]{}ifx \[1\][ \#1firstoftwo secondoftwo ]{}““\#1””@noop \[0\][secondoftwo]{}sanitize@url \[0\][‘\ 12‘\$12 ‘&12‘\#12‘12‘\_12‘%12]{}@startlink\[1\]@endlink\[0\]@bib@innerbibempty @noop [**]{} (, ) [****, ()](\doibase 10.1016/j.ppnp.2012.07.001) [****, ()](\doibase 10.1016/0375-9474(78)90294-4) [****, ()](\doibase 10.1016/0375-9474(68)90678-7) [****, ()](\doibase 10.1103/PhysRevLett.105.252501) [****, ()](\doibase 10.1103/PhysRevLett.107.092501) [****, ()](\doibase http://dx.doi.org/10.1016/0370-1573(75)90040-X) [****, ()](\doibase http://dx.doi.org/10.1016/0370-1573(91)90078-Z) [****, ()](\doibase 10.1103/PhysRevC.20.2130) [****, ()](\doibase http://dx.doi.org/10.1016/0370-2693(82)90893-0) @noop [ ]{} [****, ()](\doibase 10.1103/PhysRevLett.101.032701) [****, ()](\doibase 10.1103/PhysRevC.50.189) [****, ()](\doibase 10.1016/j.nuclphysa.2010.06.012) [****, ()](\doibase 10.1140/epja/iepja1348) [****, ()](\doibase 10.1016/0370-1573(93)90141-Y) [****, ()](\doibase 10.1103/PhysRevLett.55.2676) @noop [ ()]{} [****, ()](\doibase 10.1103/PhysRevC.71.064311) [****, ()](\doibase 10.1103/PhysRevC.67.044602) [****, ()](\doibase 10.1016/S0370-2693(98)00233-0) [****, ()](http://stacks.iop.org/0954-3899/24/i=8/a=033) [****, ()](\doibase 10.1016/j.nuclphysa.2003.11.011) [****, ()](\doibase 10.1007/s100500070073) [****, ()](http://stacks.iop.org/1748-0221/6/i=02/a=P02005) [ ()](\doibase 10.1007/s10751-013-0905-7) [****, ()](\doibase 10.1103/PhysRevC.60.044605) @noop [**]{} (, ) [****, ()](\doibase 10.1103/PhysRevC.63.054609) [****, ()](\doibase 10.1142/S0218301308011641) [****, ()](\doibase 10.1016/0370-2693(96)00336-X) [****, ()](\doibase 10.1103/PhysRevC.66.034608) [****, ()](\doibase 10.1103/PhysRev.118.733) [****, ()](\doibase http://dx.doi.org/10.1016/0375-9474(72)90499-X) [****, ()](\doibase http://dx.doi.org/10.1016/0375-9474(78)90062-3) [](http://www.nscl.msu.edu/~{}brown/resources/resources.html) [****, ()](\doibase 10.1103/PhysRevC.83.021301) [****, ()](\doibase 10.1016/0167-7977(88)90005-6) @noop [****, ()](\doibase 10.1103/PhysRevC.41.2134) [****, ()](\doibase 10.1143/JPSJ.16.1066) [****, ()](\doibase 10.1103/PhysRevC.77.054602) [****, ()](\doibase 10.1016/S0168-9002(03)01368-8) [****, ()](\doibase 10.1103/PhysRevC.84.024604) [****, ()](\doibase 10.1103/PhysRevC.30.916) [****, ()](\doibase 10.1103/PhysRevC.54.1267) [****, ()](\doibase 10.1103/PhysRev.170.924) [****, ()](\doibase 10.1103/PhysRevC.77.064608) [^1]: Present Address: The National Superconducting Cyclotron Laboratory, Michigan State University, East Lansing, MI 48824, US | Mid | [
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YO MULATTO, WE MUST KEEP AN EYE PEELED KOZ THE PONIES ARE EXPECTED TO INVADE DUE TO REVENGE!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! | Low | [
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--- other: - | The method ``build_instance_info_for_deploy()`` from the ``ironic.drivers.modules.agent`` module was deprecated in the Ocata cycle (version 7.0.0). It is no longer available. Please use the method ``build_instance_info_for_deploy()`` from the ``ironic.drivers.modules.deploy_utils`` module instead. | Low | [
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RNF125 is a ubiquitin-protein ligase that promotes p53 degradation. Although early studies show that Mdm2 is the primary E3 ubiquitin ligase for the p53 tumor suppressor, an increasing amount of data suggests that p53 ubiquitination and degradation are more complex than once thought. Here, we investigated the role of RNF125, a non-Mdm2 ubiquitin-protein ligase, in the regulation of p53. RNF125 physically interacted with p53 in exogenous/endogenous co-immunoprecipitation (IP) and GST-pull down assay, and a C72/75A mutation of RNF125 did not interfere with this interaction. Expression of RNF125 decreased the level of p53 in a dose-dependent manner, whereas knockdown of RNF125 by RNA interference increased the level of p53. As shown by Western blotting and ubiquitin assay, RNF125 ubiquitinated p53 and targeted it for proteasome degradation. Furthermore, RNF125 repressed p53 functions including p53-dependent transactivation and growth inhibition. Our data suggest that RNF125 negatively regulates p53 function through physical interaction and ubiquitin-mediated proteasome degradation. | High | [
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Write a Webserver in 100 Lines of Code or Less Network programming can be cumbersome for even the most advanced developers. REALbasic, a rapid application development (RAD) environment and language, simplifies networking yet provides the power that developers expect from any modern object-oriented language. I'll show you how this powerful environment enables professional developers and parttime hobbyists alike to quickly create a full-featured webserver. Because you may be new to REALbasic's unique features and language, it's a good idea to start with something simple. The goal of writing a webserver in REALbasic is not to replace Apache. Instead, this server will demonstrate how to use REALbasic to handle multiple connections using an object-oriented design. Let's start with some preliminary information about how networking in REALbasic works, as well as a quick walk-through of the HTTP protocol. REALbasic Networking Classes REALbasic includes several networking classes that make development easier, including the TCPSocket, UDPSocket, IPCSocket, and ServerSocket, and they are all event-based. This means that you can implement events in your code that will run when certain things happen, such as when an error occurs or when data is received. This saves you the trouble of having to constantly check the states of sockets. HTTP is a simple protocol that is used to request information (generally files). The HTTP protocol works by having the client, such as a browser, send a request to the server. The server will evaluate the request and reply with either an error or the information requested. The syntax for a request is: (GET | POST) + Space + RESOURCE_PATH + Space + HTTPVersion + CRLF As with most text-based protocols, the ending of a line is a carriage-return and a line-feed concatenated together. This is called a CRLF. An example request that a browser would send for the root file on the server would be: The server can send more data after the end of the two CRLFs, if desired. That is where, for example, the page requested would be written. After all the data is sent, the connection is closed by the server. Building the Server REALbasic provides two classes which will be utilized for the majority of the work. The ServerSocket class automatically handles accepting connections without dropping any, even if they are done simultaneously. The TCPSocket provides an easy mechanism for communicating via TCP. Together, they allow for extremely easy creation of servers. Let's get started by launching REALbasic 5.5. (Get a 10-day free trial here.) Once open, you will be presented with a few windows. To the left is a "Controls" palette, which contains commonly used GUI controls. To the right is the Properties window, which allows you to visually set properties on objects such as windows, controls, or classes. The window that contains the three items, Window1, MenuBar1, and App, is the project window. To utilize the ServerSocket and TCPSocket, they need to be subclassed. When you subclass another class, you gain access to events that the superclass exposes. For example, the TCPSocket itself doesn't actually know what to do with the data once it has been received. So, you subclass the TCPSocket and implement the DataAvailable event so that you can do something when data is received. First, create a new class named HTTPServerSocket whose superclass is ServerSocket. Do this by choosing "New Class" from the File menu. The project window will now have a new item named Class1. Click on it, and notice how the properties window updates to reflect what item is selected. Rename the class to HTTPServerSocket, and select "ServerSocket" from the Super popup menu. While we're here, go ahead and add another class. Rename it to HTTPConnection, and set its superclass to TCPSocket. You can click on the superclass field to the left of the popup arrow, and REALbasic allows you to type in the class name. Start typing TCP, and notice how autocomplete kicks in. Press tab to let autocomplete finish the rest of the name for you. Now, you have the two classes that are needed to make the HTTP server. The HTTPServerSocket class is responsible for creating HTTPConnections, and the HTTPConnection class is responsible for handling the HTTP communications. This is a good time to save the project. Remember where you saved the project at because at the end of this article you will need to put another file beside it. Double click on the HTTPServerSocket class. This will open a code editor window. On the left is the code browser, which helps navigate between methods, events, properties, and constants. All we need to do in the HTTPServerSocket is implement an event. Expand the "Events" section, and select "AddSocket." The AddSocket event is fired when the ServerSocket needs more sockets in its pool. The way servers work is that there is generally a "pool" or collection of sockets that are sitting around. When a connection occurs, the server will hand off the connection to one of the sockets in the pool. The ServerSocket takes care of all the tricky TCP code required to create a server that doesn't drop connections for us. All you need to do is add this code to the AddSocket event: returnnew HTTPConnection That's all that is needed. Close that code editor, and double click on the HTTPConnection class we wrote. Here is a diagram of what will happen once the server receives a request: Each of these tasks will be handled by different methods that we will create. The first task is to determine what resource is being requested. The server will have a string that contains the entire request, and this method will extract a string that represents the path to the resource. The next task will be to take that string and locate that file. The server will then either report an error or send the file. When done sending all the data, the server will close the connection. To accomplish these tasks, three methods will be created. Add a method to the HTTPConnection class by choosing "Edit->New Method..." Create the method as shown: The next method you'll need to create is one that takes the path returned from GetPathForRequest and returns the actual file to us. In REALbasic, files are dealt with through the FolderItem class rather than string paths. This is a huge benefit because not only is this same object used across all platforms, but it is so easy to use. Create a method named GetFolderItemForPath that takes "path as String" and returns a FolderItem. The method's scope can be private because the method only pertains to this class. The last method you need to create is just a convenience method. No matter what type of response the server receives, the response will always have a similar header. To help eliminate repeated code, define one last method named WriteResponseHeader that takes the parameters "statusCode as Integer, response as String" with no return value. This method can also be private. In the code browser, expand the Events section. You will see Connected, DataAvailable, Error, SendComplete, and SendProgress. With HTTP, there isn't anything the server needs to do in the connected event. The client will be sending a request, so the server needs to wait until we have data available. The DataAvailable event is very important because of that. That event fires whenever data has been received. That event is where most of the logic will reside. The Error event is fired when there is a socket-related error, but for this example, socket-related errors will be ignored. Finally, SendComplete and SendProgress can be used to keep the send buffer full without eating up too much memory. Since this server is going to be memory-efficient, you need to keep one variable around. Variables that are on the class level and not created inside a method are called properties. The property that is needed is to store a reference to an already open file so that we can write more data from the file when needed. In REALbasic, there is a class called BinaryStream that is used to read and manipulate files. Although there are other classes for accessing files, the BinaryStream class will do what is needed. Create a property by choosing "Edit->New Property..." In the Declaration field, type "stream as BinaryStream" and change its scope to Private. Click OK when done. | Mid | [
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Last week, two European bison were released in the newly established bison release site at the foothills of Poiana Ruscă Mountains, part of the Southern Carpathians rewilding area. The bison were relocated from the Romanian bison reserve in Brasov county. As part of the larger European bison reintroduction initiative in this region, supported by the European Commission through the LIFE Nature programme, this new bison release site will play an important role in bringing back this species where it once roamed. The first two animals were relocated from the Bison Valley Nature Reserve in Brasov county. An additional two animals from here were transported to the Țarcu Mountains near Armenis, our existing release area, some 50 km further south. These relocations mark the start of the 5th annual bison release that Rewilding Europe is doing in cooperation with WWF Romania, with 19 animals more to follow in the coming week. It took two years of intense preparation before the local authorities and communities in Poiana Ruscă were finally ready to welcome these first bison. The site was carefully selected by the expert teams of Rewilding Europe and WWF Romania as it will support the creation of a genetically and demographically viable European bison population in the Southern Carpathian mountain range. Located in a key wildlife corridor, Poiana Ruscă is strategically positioned to create such conditions and ensure connectivity and genetic diversity in these two sub-populations. “The releases taking place this May bring us closer to our goal of having 100 free roaming European bison in the Southern Carpathians“ says Alexandros Karamanlidis, Regional Manager of Rewilding Europe. “We are extremely grateful to the municipalities of Armeniș and Densuș and many national and international partners for making this possible, and to European Commission for supporting our efforts.” Having been hunted to extinction in Romania around 200 years ago, the European bison made a wild return to the country in 2012 (in the Vanatori Neamt Nature Park). Since 2013, Rewilding Europe and WWF Romania have been working together in the Southern Carpathians rewilding area to establish a free-roaming, viable population of this iconic and key-stone animal. The first two bison releases took place in 2014 and 2015. Since then, additional releases are being done as part of the European Commission – funded LIFE Bison Project. “The opening of the new release site in Poiana Ruscă is the biggest step so far in the joint efforts of our two organizations to ensure a viable bison population in this part of Romania”, explains Marina Druga, LIFE Bison Project Manager. “This can only be done if the species is released in more areas, not just one”. Smooth local transfer The transports that Rewilding Europe and WWF Romania are jointly organising since 2013, involve animals coming from a different range of European countries. However, the release carried out last week was the very first translocation within Romania itself. The journey started in the Bison Valley Nature Reserve, in Brasov county, and was supported by the Romanian Wilderness Society’s bison selection and transport advisors. The journey was just over 350 kilometres and took 8 hours. “The trip is the easy part, but much more demanding are the preparations, from getting the trailer ready, herding the selected bison in position for sedation, taking blood samples to mounting collars and loading “by hand” onto the trailer.” – said Roland Hauptman, Bison Ranger and the one driving the bison to their new homes. Four Bison Rangers, assigned through the LIFE Bison project, made sure that the conditions at the release site are favourable and assisted with the transport. The field team made regular stops during the trip, providing water to cool the bison and to carry out veterinarian checks. Bison on the way In the next two weeks, twelve more bison will arrive at Poiana Ruscă, coming all the way from Springe Bison Reserve in Germany, while seven more animals will be transported from several German reserves and Italian Parco Natura Viva to the Țarcu Mountains release area. The animals will be released into the wild from their enclosure after they have undergone a two-month acclimatisation period. From that moment onwards, they will be monitored by the Bison Ranger team, as is the case with the previously released herds. This is another crucial step for the European bison to become a full part of the these Natura 2000 sites of the Țarcu and Poiana Ruscă Mountains Corridor. The reintroduction of the European bison has a profound impact on the local society, apart from its ecological impact. The species represents a wider vision for the region, that will see wilder nature become an engine for regional development, bringing a new perspective for local communities. This is being made possible through associated efforts in developing nature-based tourism, community development, education, scientific research, technological innovation and conservation efforts that benefit both nature and people. Read more: Read more about the LIFE Bison project here. Learn more about the Southern Carpathians rewilding area here. Visit the Rewilding Southern Carpathians Facebook page here. | Mid | [
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Dante Gabriel Rossetti Dante Gabriel Rossetti was an outstanding British artist and poet of Victorian age, master of painting and graphical arts. Early years Dante Gabriel Rossetti was born on May 12, 1828 in London in a family of Italian political emigrant, poet and scientist. His father, Gabriele Rossetti, a former curator of Bourbon museum in Napoli, belonged to Carbonari, who participated in the revolt of 1820, which was suppressed by Austrian troops after the betrayal of King Ferdinand. In London Gabriele taught native language and literature at King’s College School. In his spare time, he wrote comments on Dante. Rossetti’s mother, Frances Mary Lavinia Polidori, was a daughter of famous translator Milton. There was a cult of Dante in Rossetti’s family, so future artist was called in his honor. Father instilled his passion in his kids – the elder daughter, Maria Francesca, wrote book “The Shadow of Dante”, the youngest, Christina, became a prominent poetess, the younger son, William Michael, – an authoritative critic and brother’s biographer. Dante Gabriel himself wrote a poem in 5 years, in 13 – a dramatic novel, in 15 published his work for the first time. Rossetti translated Dante’s “La Vita Nuova” into English, illustrated the poem and referred repeatedly to it, as the main subject of his art was immortal love. Dante Gabriel enrolled to King’s College School in 9, but his artistic education was fragmentary. He started training under guidance of marine and landscape painter John Sell Cotman and in 1841-1841 studied at Henry Sass’s Drawing Academy. Since 1846 he attended the Antique School of the Royal Academy, but finally decided to leave it and mastered his skills under Ford Madox Brown – an artist of Romanticism, who was also passionate about literature. In the Academy Dante met Millais and Holman Hunt, who helped him to refine technique of oil painting, while they were working over first Pre-Raphaelite paintings. Young artists protested against lifelessness of academism in 19th painting. Their rejection of then-contemporary Victorian culture was strengthen by aversion for industrialization that ruined nature and ousted beauty from everyday life. Being gifted in various fields, with Italian temperament and British pensiveness, Rossetti became the head of “Pre-Raphaelite” brotherhood when he was 18 years. Together with Holman Hunt and Millais, he decided to abandon the Academy and rushed in searches of “inner truth”. The word “brotherhood” itself expressed the idea of closed, secret association, similar to medieval monastic orders. Strive for verity and simplicity together with typical for Romanticism unacceptance of reality led to escapism into more attractive past and world of fantasies. To recreate the manner of Italian Quattrocento artists, brotherhood’s members made scrupulous, bright and clear tonal etudes from nature and painted on wet white priming. They inclined to large-scale canvases that allowed depicting figures and objects life-size. Pre-Raphaelites were also inspired by poetry. John Keat, known for emotionality and individualism, was especially close to impulsive Rossetti. A significant role was played by heritage of re-discovered William Blake: it was Dante Gabriel, who found in the library of the British Museum lithographs of forgotten by that time artist and poet. In 1845 – 1848 the master created only two oil painting in the Pre-Raphaelite manner, close to Hunt and Millais. During that period, he dedicated himself mainly to watercolors – more immediate and spontaneous technique that corresponded to the artist’s character. In his desire to render deeply significant subjects Pre-Raphaelites referred to Bible that gave them themes, full of truth, lofty simplicity, so characteristic for early Christianity and Middle Ages. Perceiving Christianity as the eternal spiritual source that elevate art, Rossetti presented in 1851 his piece “Ecce ancilla domini” (Latin for “Servant of God”), where he showed the Annunciation, at the exhibition in the Royal Academy. His friends also displayed religious scenes – “The Light of the World” by Holman Hunt and “Christ in the home of His Parents” by Millais. “Ecce ancilla domini” was the closest one to the works of old Italian masters by its symbolism. The painter attempted to make a symphony of white and cold hues with minor inclusion of warm tints. During Renaissance epoch, Madonna had been usually depicted as a saint that had nothing in common with vulgar everyday life. Rossetti broke up traditions, when he presented Annunciation realistically. His Madonna is a usual girl, embarrassed and scared with the news told her by the Angel. Such interpretation that insulted many art connoisseurs corresponded to the intention of Pre-Raphaelites to paint veraciously. Public didn’t like “The Annunciation” – its realism was taken with disapproval (Dickens even wrote a pamphlet about the exhibition). The artists was suspected in sympathy to the pontificate. That was the epoch of the “Oxford movement”, aimed at rapprochement to Catholicism, but not with papacy. However, very soon the group received many admirers, particularly among growing middle class of central and north England. Participants of the brotherhood manifested their ideas in “The Germ” magazine, and by the end of 1851 they were widely-known beyond the walls of the Academy. Support of John Ruskin allowed them to gain popularity quickly and Pre-Raphaelites managed to raise the standards in painting and stepped over hardened academic traditions. Artistic manner Rossetti made his most significant works in the 1850s – beginning of the 1860s. Under the influence of William Blake’s poetry and painting, Dante Gabriele elaborated his own manner – symbolical, decorative and full of mystic echoes. The master built his compositions on combination of several large-scale figures on the foreground, expanding format of canvas. Numerous objects and images made up background of a piece that contained deep implications, which forestalled European Symbolism. Personages were drawn rather static, lost in thoughts, yet there inner tension was expressed through gestures and eyes. The painter wasn’t afraid of exaggerating body proportions and unusual angles. Coloring was the base of expressing mood and feelings, mostly of uncertainty and elusiveness. Pure, lucid, unfettered by dark hues, it shaped up a beautiful world of bright colors and sunshine. Rossetti favored minimal chiaroscuro, local applying of paint, without considering lighting and lavish ornamental embedding. Line was the major mean of expression for him: nervously twisted or winding, it modeled delicate and eloquent images. Unlike painting of other Pre-Raphaelites, naturalistic elements were extrinsic to Rossetti’s art. It’s not merely decorative, but monumental. His interest in monumentality was revealed in the work over murals in the Oxford Union library he made with other artists in 1857. That experience wasn’t successful, actually, due to Dante’s bad knowledge of fresco technique, but some excellent drafts on Arthurian subject were preserved till nowadays. Female characters In 1850 Dante Gabriel Rossetti met his muse – Elisabeth, who married him in 10 years. At that period the painter created a touching gallery of female characters, passionate and melancholic, with invariable feeling of Elisabeth’s presence. A significant part of Rossetti’s oeuvre is dedicated to the deal female image, which prototype was the artist’s untimely deceased wife. Her unusual appearance attracted his followers, who consciously rejected professional models, so Elisabeth’s features became a kind of canon of female beauty for Pre-Raphaelites. The woman Dante was mad about died just in two years after their marriage, in 1862. It was an awful personal and creative tragedy for the painter. Rossetti withdrew into himself. Together with her he buried some manuscripts of his poems that would be later published. He had repudiated exhibiting as early as 1851, after the harsh critical attack on Pre-Raphaelites. In the latter period the master based his compositions on picturing of a single figure of a woman, absorbed in her thoughts. This image was inspired by Jane Burden – wife of Dante’s friend William Morris. She was his second muse, glorified in such canvases as “Proserpine” and “Mariana”. Historical and religious painting Inspired by Dante, Rossetti revived the face of the beloved woman on canvases in the figure of Beatrice – “Death of Beatrice”, “Blessed Beatrice”, “Dante’s dream”. Another important line in the author’s legacy were historical and religious scenes – “Giotto painting the portrait of Dante” , “The wedding of Saint George and Princess Sabra” (watercolor), “Helen of Troy”, “Rosa triplex”. His painting and poetic heritage sometimes interflowed – he created paintings to his poetry and vice versa – “The blessed Damosel”, “My Sister’s Sleep”, “A Last Confession”. Rossetti’s pieces of the last period were effected by Eilliam Morris and Edward Burn-Johnes, which is obvious in “The Day Dream” (1880). Illustration and Poetry The master contributed in the book art. Apart from easel painting he illustrated poems of Dante, Shakespeare, Browning, his sister Christina, Swinburne’s “Atlanta in Calydon” and legends about King Arthur by Sir Thomas Malory. The artist designed book-covers, delighting his contemporaries with their elegance and plainness that foresaw the visual language of publications in 1900s. Rossetti also left literature work after himself – translation of old Italian poets, Ciello d’Alcamo, Dante, published two volumes of original poetries and a book of ballades and sonnets (1881), noticeable for melodic language, subtle feeling of rhythm and union of passion and mysticism. Legacy Dante Gabriel Rossetti died in Birchington-on-Sea (Kent) on April 9, 1882His solo exhibition took place only two months after his death and was of great success. Rossetti had a serious impact on the artists of the second half of the 19th – beginning of the 20th cent. Numerous adherents and imitator preserved his tradition, which might be called “rossettism”. | High | [
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Obstructive uropathy, following redo aortobifemoral by-pass surgery. A rare case of obstruction of the right ureter due to encagement between the right iliofemoral and right limb of an aorto-bilateral femoral Dacron graft is described. Patient was managed successfully by ureterolysis, removal of the occluded right iliofemoral graft, omentoplasty and placement of a pig tail catheter along the right ureter. | High | [
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/* -*-C++-*- ***************************************************************************** * * File: AllElemDDLCol.h * Description: a header file that includes all header files * defining classes relating to columns. * * * Created: 9/21/95 * Language: C++ * * // @@@ START COPYRIGHT @@@ // // Licensed to the Apache Software Foundation (ASF) under one // or more contributor license agreements. See the NOTICE file // distributed with this work for additional information // regarding copyright ownership. The ASF licenses this file // to you under the Apache License, Version 2.0 (the // "License"); you may not use this file except in compliance // with the License. You may obtain a copy of the License at // // http://www.apache.org/licenses/LICENSE-2.0 // // Unless required by applicable law or agreed to in writing, // software distributed under the License is distributed on an // "AS IS" BASIS, WITHOUT WARRANTIES OR CONDITIONS OF ANY // KIND, either express or implied. See the License for the // specific language governing permissions and limitations // under the License. // // @@@ END COPYRIGHT @@@ * * ***************************************************************************** */ #include "ElemDDLColDef.h" #include "ElemDDLColDefArray.h" #include "ElemDDLColDefault.h" #include "ElemDDLColHeading.h" #include "ElemDDLColName.h" #include "ElemDDLColNameArray.h" #include "ElemDDLColRef.h" #include "ElemDDLColRefArray.h" #include "ElemDDLColViewDef.h" #include "ElemDDLColViewDefArray.h" // // End of File // | Mid | [
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Sleep patterns and fatigue in parents of twins. To examine patterns of postpartum parental sleep and levels of fatigue at 2, 12, and 20 weeks following hospital discharge of newborn twins. Descriptive longitudinal pilot study. Recruitment from 2 hospital postpartum units. Data collected in parents' homes. Eight primiparous parents caring for twins delivered at 33 to 38 weeks gestation. Home visits to deliver and retrieve study equipment: wrist actigraphy and sleep diaries to measure sleep, standardized instrument to measure fatigue, and an investigator-developed form to measure demographics and related variables. Fathers had significantly less night sleep (5.4 hours) and less 24 hour sleep (5.8 hours) than mothers (6.2 and 6.9 hours, respectively) at 2 weeks after twins were discharged. Sleep efficiency increased significantly over time in a linear fashion for both parents. Morning and evening fatigue levels were not significantly different between parents and remained constant over time. Pilot data suggest that mothers and especially fathers of twins experience sleep disturbances after discharge of their twins. Further study is needed to more fully describe the evolution of sleep patterns and clarify factors that influence sleep in parents of twins. | Mid | [
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; Experiment 3 ; ; Measure frequency on PB6 input. ; Use Timer 2 to count pulses. ; User Timer 1 to set time period. ; Output value to screen. ; Enhancement would be to make this interrupt driven but want to keep it simple for now. ; Example: ; Input was 100KHz ; Counted $13AE pulses = 5038 * 20 Hz = 10,076 Hz ; If wanted to convert to Hz, good sample rates might be 16, 32, or 64 since could multiply by shifting it. ; Input was an audio signal generator and then through a 74LS04 inverter to make sure levels were TTL. .org $0280 .include "6522.inc" ECHO = $FFEF ; Woz monitor PRBYTE = $FFDC ; Woz monitor CR = $0D ; Carriage return COUNT = 49998 ; 20 Hz sample rate LDA #$00 STA IER ; disable all interrupts LDA #%00100000 STA ACR ; T1 single shot PB7 disabled, T2 pulse count mode LOOP: LDA #<COUNT ; Set count for T1 STA T1CL ; Set low byte of count LDA #>COUNT STA T1CH ; Set high byte of count LDA #$FF ; Set count for T2 STA T2CL ; Set low byte of count LDA #$FF STA T2CH ; Set high byte of count WAIT: LDA T1CH ; wait for timer T1 to count down to zero BNE WAIT LDA T1CL BNE WAIT LDA T2CH ; get high byte of T2 count EOR #$FF JSR PRBYTE ; print it LDA T2CL ; get low byte of T2 count EOR #$FF JSR PRBYTE ; print it LDA #CR JSR ECHO ; print newline JMP LOOP ; repeat forever | Mid | [
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Ruston says two permits on the way to Point Ruston The city of Ruston says it plans to let the developers of Point Ruston move forward on a key piece of their project, but it wasn’t at all clear the divide between the adversaries was close to being bridged. Developers of the $1.2 billion project have complained of facing years of government obstruction to their construction plans in the city of 749 residents. City leaders and state and federal environmental officials accuse Point Ruston of running roughshod over regulations. With the sides at an impasse, Point Ruston has sought to become fully absorbed by Tacoma, where more than half of the project already sits. The request brought leaders of both cities before a state House committee Wednesday. That’s where Ruston announced plans to issue permits for a road and a parking garage. Ruston Mayor Bruce Hopkins said later Wednesday that the permit for the garage was ready to pick up but that Point Ruston lawyers had raised some concerns about conditions attached to it. “I think we’re there in principle, and now it’s just crossing the t’s and dotting the i’s,” Hopkins said. That clashed with the view from Point Ruston developers’ legal representative, Loren Cohen, who said he knew of no permits. Cohen called it “more of the same stall tactics and inaction.” Construction on both projects had started without city approval, Hopkins said, and the affected portion of Yacht Club Road has already been built, so a forthcoming permit would be a formality. Ruston officials have said the road wasn’t wide enough to allow access by fire trucks, but Hopkins said Wednesday the permit could be issued with the understanding the road must allow fire-truck access once buildings go up alongside it. The parking garage, the only structure under construction on the Ruston side of the development, has been contentious. Ruston City Councilman Jim Hedrick told lawmakers an agreement reached among the parties in November had provided for the garage to move forward, until developers rejected the deal. Developers say there was no permit offered and that it was city officials who backed out of a deal. The city issued a stop-work order on the garage at 5101 Grand Loop in December. The city has contended that plans for the garage didn’t comply with a master land-use plan for the project. But on Wednesday, Hopkins said the city can be flexible on those issues now that there is an understanding the permit is solely for the garage, with no authority for surrounding buildings that had showed up in previous permit applications. That’s what the conditions spell out, he said. ANNEXATION The controversy was aired Wednesday in the House Local Government Committee, with testimony from representatives of Tacoma, developers and a building-trades union on the need to get construction going. “Four years, no permits in a timely manner, is a record I can’t understand,” Point Ruston consultant Tim Thompson said. Hedrick said Ruston needs the development, too. “I don’t even know if we can survive with Point Ruston,” he said. “I know we can’t survive without them.” The hearing was an unusual one. Public hearings at the Legislature usually weigh the good and bad of a bill up for consideration – in this case, House Bill 2074, which is scheduled for a potential vote Thursday in the committee. Hedrick told lawmakers the bill is a threat to keep Ruston at the negotiating table. It could be filled in, he said, “with other language that would be a unilateral takeover of the town of Ruston — not the entire town of Ruston, just the part that raises the almighty buck.” Tacoma Mayor Marilyn Strickland said the bill is a “tool” to make sure the parties are bargaining in good faith. “This is not some hostile takeover,” Strickland said, and later added: “This is not big, bad Tacoma trying to trample on the town of Ruston.” The words officially set down on paper aren’t particularly contentious. First Tacoma Rep. Jake Fey and three fellow local Democrats introduced House Bill 2074 as a “title-only bill” with no real content. Then committee chairman Dean Takko, D-Longview, offered a proposed new version that doesn’t prevent Ruston or other cities from saying no to annexation — it just requires them to say no twice. Under Takko’s proposal, property owners trying to secede from a city could appeal a city council’s rejection. The appeal would go right back to the same council, which would then have to take 90 days to consider the appeal. Fey said the change “extends the time clock” to buy more time for negotiations. Hopkins said it seems like a waste of money. Why all this attention to the proposal now, when it may not be in its final form? Lawmakers are trying to keep the bill alive. Bills that don’t advance out of committee by Friday are technically dead for the year. Never miss a local story. Sign up today for unlimited digital access to our website, apps, the digital newspaper and more. | Low | [
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Small College Notebook: Undefeated season an unstated goal BRUNSWICK – Each passing second in the third period felt like a splinter pushed deeper under its skin. The Bowdoin College men’s hockey team was getting closer to losing its first game of the season, its 10-game win streak and its ranking among the best in the country. The University of New England, a young program with a losing record this season, was Tuesday’s opponent, playing on the road and out of its league. The Nor’easters had a one-goal lead. Additional Photos Behind the Bowdoin bench, Terry Meagher checked his team’s pulse. All coaches of unbeaten teams want to see how their players respond when things are going badly. Now in his 30th season at Bowdoin, Meagher was no different. Bowdoin rallied to score twice in the last period. Harry Matheson got the game winner, taking a pass from Tim McGarry, who had scored earlier in the game. Bowdoin won 4-3 to remain the lone unbeaten team in Division III hockey. “There’s a fine line between self-confidence and a degree of hubris and balalancing that off with humility,” said Meagher on Wednesday. “Looking at my team, I knew they wouldn’t give up but they also had a lot of respect for the other guys. You could feel all that going through the line afterward, shaking hands. The other guys knew they gave us their best game.” Bowdoin has a legacy of championship seasons and winning seasons. Perfect seasons? That’s not something Meagher or McGarry cared to talk about late Wednesday afternoon. Meagher’s record at Bowdoin in an enviable 487 wins, 224 losses and 48 ties. Yet he has never coached an undefeated season. “Well, I guess it does at the end of the season. But going undefeated isn’t something we set out to do. We were fortunate to have a game like last night. It was a bit of a wake-up call.” They had come back from a road trip against tough New England Small College Athletic Conference opponents Hamilton and Amherst. Friday, Wesleyan comes to the Sid Watson Arena on the Bowdoin campus, followed by Trinity on Saturday. UNE, an ECAC East conference team with a 3-9-0 record, was sandwiched in between the NESCAC action. After opening the season with a win, Bowdoin tied Middlebury 4-4, back on Nov. 17. Eleven straight victories have followed. Meagher all but shrugs. His players made a commitment, he says. The unbeaten season reflects a “reasonable skill set, leadership and team culture.” The streak is secondary to the readiness he wants his team to have for the stretch run to the conference playoffs and a bid to the NCAA tournament. After 30 years Meagher is still known to those outside the Bowdoin community for the intensity he brings to hockey. He’s all-in, all the time. But he’s not above making a friendly wager. He and McGarry made a bet last season. If the defenseman scored 10 goals, Meagher would wear the Irish driving cap McGarry favors on the bench during games. “I was stuck on nine for four games,” said McGarry, who grew up in Kennett Square, a suburb of Philadelphia. Meagher, conscious of the bet, would yell at his player to pass, pass, pass when the puck was on his stick near the opponent’s goal. In Bowdoin’s last game of the regular season, McGarry got his 10th goal and knew immediately what it meant. Meagher wore the cap in the playoffs. He believes no one looked better. “Winning is fun,” said Meagher. “But sometimes it’s not fun winning. It’s hard, in real time, to think about how much fun we’re having when there’s work to be done.” • The Bowdoin women’s hockey team has also been winning. The women are 9-1-1 and were ranked seventh in the country when polls came out on Monday. The men were ranked fourth . . . Bryan Hurley (Watertown, Mass.) set a school record with 17 assists in Tuesday night’s 88-64 win over the University of Maine-Presque Isle as the Bowdoin College men’s basketball team shot 60 percent from the Morrell Gymnasium floor. The Bowdoin men have won seven straight for an 8-2 record going into Friday night’s game at home with conference foe Tufts. ST. JOSEPH’S COLLEGE Junior forward Lindsay Moore (Barrington, N.H.) averaged 16.0 points and 13 rebounds in two games last week to earn Great Northeast Athletic Conference recognition . . . Steve Simond’s 35-point effort in a loss to Norwich University was a career high and the first time a St. Joseph’s player has scored 35 points since Travis Seaver’s 36-point performance against Thomas College on Jan. 19, 2000. UNIVERSITY OF SOUTHERN MAINE Senior Jordan Grant (Concord, N.H.) has been a consistent contributor to the women’s basketball team success. Grant averaged 14.3 points, 7.75 rebounds, 1.2 assists and 3.5 steals in a 4-0 week for the Huskies. The 5-11 senior had a career-high 22 points in a win against D’Youville. In a home win vs. the University of New England, Grant finished two assists shy of a triple-double with 19 points, 11 rebounds and eight helpers along with two steals and three blocked shots. On the road at Keene, Grant notched her fifth double-double of the season with a solid 10-point, 10-rebound performance, adding two assists and two steals. She was 92.5 percent from the free throw line over four games, making 25 out of 27 shots. Grant is the Huskies’ second-leading scorer, averaging 12.1 points per game, and their top rebounder, averaging 8.3 caroms per game. She is shooting a solid 45.6 percent (57 for 125) from the field and 74.6 percent (50 for 67) from the free throw line. She leads the team in steals with 39 and has 30 assists. • Junior guard Conor Sullivan (Scarborough) has led the men’s basketball team to a 3-3 mark. Sullivan averaged 15.3 points, 6.7 rebounds, 3.3 assists, 1.8 steals and 1.2 blocks per game while shooting a 47.0 percent (38 for 81) from the field. Sullivan set a career-best total during the week, scoring 21 points in a 93-83 road loss to Salem State University. In a key Little East Conference battle, Sullivan had 19 points, five rebounds, five assists and three steals in a road win at Keene State, marking the first victory over the Owls on their home court since 1979. Here at MaineToday Media we value our readers and are committed to growing our community by encouraging you to add to the discussion. To ensure conscientious dialogue we have implemented a strict no-bullying policy. To participate, you must follow our Terms of Use. Click here to flag and report a comment that violates our terms of use. | Mid | [
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Detroit students walkout against school closures and deteriorating conditions By Lawrence Porter 27 April 2012 Students protesting in Clark Park, across the street from Western International High School Over 200 students at two high schools in Detroit’s southwestern neighborhood, Southwestern High and Western International, walked out of class on Wednesday to protest the closure of Southwestern, the poor conditions at Western, and the growth of charter schools. Students from Western said they walked out of school just before 11 a.m. in sympathy with the students at Southwestern High School, which is among nine schools slated for closure next year in the Detroit Public Schools district. “Our walkout at Western was inspired by the walkout at Southwestern and it was in solidarity with it, but it was also against the conditions in our school system,” stated Freddie Burse, one of the leaders of the walkout. Freddie said the students organized the event themselves via Facebook after a student heard that there was going to be a walkout at Southwestern. “The purpose of the demonstration was to make our voices heard and to speak up on our education system because we feel there are a lot problems there,” continued Burse. “We are also opposed to the growth of charter schools. The main one here is Caesar Chavez. The privatization of schools is the death of the school system.” Several students said they were especially upset with the announcement that Southwestern High School would be closed next year. Natalie Rivera “It’s about trying to save Southwestern High School,” stated Natalie Rivera, a junior at Western, as she and several hundred students gathered in Clark Park with students from her school and Southwestern. “We are tired of the closing of the schools. We want them to stop. “Southwestern students walked out so we felt we should walk out in solidarity. We want all of the schools to join together,” continued Rivera. “We don’t even have proper books in the school. We have to learn with old stuff that is not updated. The teachers take their own money to pay for the stuff we need.” The walkouts at Western International and Southwestern are the third student walkouts in the last month in Detroit. Last month students at Denby High school walked out after the announcement that the school will be placed in the new statewide district for what are being billed as low-performing schools—the Education Achievement Authority (EAA). Another spontaneous protest took place at Fredrick Douglass Academy when 50 students walked out because they did not have teachers. After protesting that they wanted an education, the students were suspended for a day. The Detroit school system has been decimated by the actions of a series of Emergency Managers—state-appointed directors that take over a school district in financial distress, that have been appointed by both Democratic and Republican governors—the systematic defunding of the system by state and federal administrations and the collapse of city property tax revenues, the archaic basis of public education funding in the US. Avonte Latham The present Emergency Manager, Roy Roberts, appointed by Republican Governor Rick Snyder, is implementing the closure of Southwestern. Roberts, a former General Motors executive, has outlined a plan to model a new school district dominated by charter schools similar to the New Orleans Recovery School District created after Hurricane Katrina. The charter school policy is in line with President Barack Obama’s Race to the Top educational initiative. Avonte Latham, a junior involved in the walkout, said the government should provide more financial assistance to the Detroit school district. “I feel Michigan needs to give more money for schools. This is holding things back by closing schools,” charged Avonte. Gabriela Alcazar “I don’t think they should be closing schools every year. They are forcing people to leave Michigan. When they decided to close Southwestern HS we decided to take a stand. Enough is enough. They are taking the schools out of the DPS system and putting them in a new system. It’s not right.” Several students and their supporters said the closure of Southwestern would have a major impact on the choices for schools next year. Gabriela Alcazar, a community activist who attended the protest, said the students at Southwestern have been given two choices for schools that will only make matters worse. “If Southwestern is closed the student will either go to Western or Northwestern,” stated Alcazar. “Southwestern is already overstretched with 1,200 students. Northwestern is 15 miles away.” The author recommends: Detroit schools manager names schools to close this fall [10 February 2012] Jerry White campaigns in Detroit against school closings [14 February 2012] Detroit school czar targets 15 schools, 600 teachers [21 March 2012] School districts throughout Detroit area face cuts [18 May 2011] | Mid | [
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Electrocardiographic and electrophysiological characteristics of premature ventricular complexes associated with left ventricular dysfunction in patients without structural heart disease. The mechanism responsible for premature ventricular complex (PVC)-mediated left ventricular (LV) dysfunction remains unclear. We sought to determine the electrocardiographic and electrophysiological characteristics of PVC-mediated LV dysfunction. One hundred and twenty-seven patients who underwent radiofrequency catheter ablation (RFCA) for frequent PVCs (PVCs burden ≥10%/24 h) and had no significant structural heart disease were investigated. Left ventricular dysfunction (ejection fraction < 50%) was present in 28 of 127 patients (22.0%). The mean PVC burden (31 ± 11 vs. 22 ± 10%, P < 0.001), the presence of non-sustained ventricular tachycardia (53.6 vs. 33.3%, P = 0.05), and the presence of a retrograde P-wave following a PVC (64.3 vs. 30.3%, P = 0.001) were significantly greater in those with LV dysfunction than in those with normal LV function. The cut-off PVC burden related to LV dysfunction was 26%/day, with a sensitivity of 70% and a specificity of 78%. The PVC morphology, QRS axis, QRS width, coupling interval, the presence of interpolation, and PVC emergence pattern during exercise electrocardiogram were not significantly different between the two groups. The origin sites of PVCs, the acute success rate, and the recurrence rate during follow-up after RFCA were similar. In a multivariate analysis, the PVC burden (odds ratio 2.94, 95% confidence interval 0.90-3.19, P = 0.006) and the presence of retrograde P-waves (odds ratio 2.79, 95% confidence interval 1.08-7.19, P = 0.034) were independently associated with PVC-mediated LV dysfunction. A higher PVC burden (>26%/day) and the presence of retrograde P-waves were independently associated with PVC-mediated LV dysfunction. | High | [
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FDA approves new cervical cancer screening technology for review UPDATE: This post originally titled: “FDA approves new cervical cancer screening technology,” incorrectly implied that the FDA had approved the screening technology. In actuality, it has only been approved for review. “Receiving the ‘suitable for filing’ letter from the FDA is the first significant milestone in the regulatory review process and means that our application was sufficiently complete and is ready for substantive review,” said Mark L. Faupel, Ph.D., President and CEO of Guided Therapeutics. “This brings us one step closer to realizing our goal of improving the early detection of cervical disease and reducing the false positives and unnecessary biopsies that result with the current standard of care.” — Guided Therapeutics, Inc. recently received a premarket approval from the FDA for a new technology that could improve the manner in which cervical cancer is screened and tested. The new device, called LightTouch uses biophotonic technology which claims to be painless and can detect cancer earlier than the current methods of cervical cancer screening. According to Biomedreports: Biophotonic technology uses light to create images of cervical cells’ biochemical and morphological changes. LightTouch does not require laboratory testing and analysis, which would not only save time but money. Additionally, it is designed to provide immediate results, is more accurate than pap smears and HPV tests, and painless. Early detection is a major component in reducing the mortality of cervical cancer. Pap smears, HPV tests and vaccines should not be disregarded. It is important for women of all ages to get frequently tested. However LightTouch, if it is as effective as Guided Therapeutics states, could change the face of cervical cancer detection. | High | [
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'Dear Evan Hansen.' 'War Paint.' 'Hello, Dolly!' 'Come From Away.' 'Natasha, Pierre & The Great Comet of 1812.' 'Hamilton.' 'A Doll's House Part 2.' 'The Lion King.' 'Groundhog Day.' 'The Phantom of the Opera.' 'The Book of Mormon.' 'Anastasia.' 'Wicked.' 'Bandstand.' 'Oslo.' 'Cats.' 'Indecent.' 'Charlie and the Chocolate Factory.' 'Marvin's Room.' 'Miss Saigon.' 'A Bronx Tale.' 'On Your Feet!' 'Chicago.' 'Beautiful: The Carole King Musical.' 'Waitress.' '1984.' 'Aladdin.' 'Kinky Boots.' 'The Play That Goes Wrong.' 'School of Rock.' New Jersey Governor Chris Christie went viral for all the wrong reasons over July 4 weekend—the former Republican presidential candidate was photographed hanging out with his family on a completely empty beach that was closed due to a state government shutdown. The pictures inspired countless memes which made Christie the butt of the joke. But the best memes of all emerged this weekend thanks to Stephen Wallem. The actor, who’s appeared on Nurse Jackie, Horace and Pete and Difficult People, took it upon himself to Photoshop Christie and his beach chair into every current Broadway show—and the results are absolutely tremendous. Wallem told the Observer that he got the idea for the memes while in bed with a cold on Saturday. He has several friends in Broadway shows, so he decided to give Christie the theatrical treatment. “It’s all completely absurd and silly,” Wallem said. “I had no goal behind launching into it other than getting my mind off my coughing and wheezing. I’m thoroughly tickled that people got a kick out of them.” Flip through the slides above to get a kick out of Christie lunching with Bette Midler, ogling Josh Groban and more. | Mid | [
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Pages Tuesday, September 18, 2007 pre-election business some business will do quite well this time of the year. yesterday, several school children were given 5 exercise books each. the children were expressly told at school to tell their parents that those books were bought for them by the president! i wonder why presidents buy school books in the second week of third term. however some children are even cleverer than the president and told their parents that the books are from the free primary education program. the program is a Kenya government initiative and not the presidents sponsorship. talk of sharp kids! Anyway book vendors will love it if this will be the way back to power. other business that will do well include sugar business since the man announced that the quota against duty free sugar will be extended by 4 more years. that news will be very sweet to MSC share holders. i dont know whether it will be good to the farmers who normally have to wait for 18 months to be given their meager earnings. but graphic designers will soon be going to town with posters , t-shirts and the like as will be hooligans defacing the posters of rivals. election time is boom time. even taxis and other luxury vehicles will enjoy. taxis will even be even happier with the return of the alcoblow. talking of taxis, i saw that in dubai, they have tried to solve the public transport crisis using taxis. i stood 1 hour in a queue waiting for a taxi! i have never seen such a thing. even though the taxis were well kept, professionally driven and even have GPS installed, they simply don't solve the public transport crisis. in fact they worsen it by introducing traffic jams. and so Dubai which now proudly has the worlds tallest man made physical structure, is working on the only known solution to public transport - the metro. by the way did you know you could buy Kenya in Dubai? then u could be president without having to declare a party of national unity. but i digress. kengen will report a reduction in profit in the neighborhoods of 35%. i think thats massive for a company which has literally no competition and a huge demand for its products. mtu amelala kazini! other ways to make money this electioneering period is to compose songs in praise of the contestants or follow them up and provide a back up crowd. campaigns are anxious moments and one can almost pay to be given that assurance that he is going to win. Otherwise if you want to quit your job to become the CEO of a state corporation or a PS, then the time to lick boots is now! | Mid | [
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Stats Krcolerde Ironcry was summoned from the depths of hell. Forced to feed upon the tainted blood of the diseased, and bound to earth by a conjuror whose name is uknown, he is doomed to walk the darkened allies of plagued cities inciting his judgment upon the weak and the decrepit. He feels a deep pain on our world, a pain that is unimaginable, like a flaming blade trying to rip its way out from the inside, and only the diseased and sickly blood can sooth it. He has hideous but uniform features and lives his life cloaked in a robe dyed the deepest of reds to hide his true appearance. His most shocking features are his blank eyes that stare into your soul, and his hollow horns, which he keeps covered at all times as if the wind upon them felt like a cold chill in a deep cavity. Forever he is bound to walk in our world, forever he is doomed to exile from the most reclusive pits of hell. | Low | [
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Q: python - How to get all the tags before a certain text in a webpage with beautifulsoup? My website has so many <p> tags. I want to have all of the <p> tags which are written before a certain unique text in the web page. How can I achieve this? <p>p1</p> <p>p2</p> <p>p3</p> <span class="zls" id=".B1.D9.87.D8.A7.DB.8C_.D9.88.D8.A"> certain unique text </span> <p>p4</p> <p>p5</p> So I want to get the list of [p1,p2,p3] but I don't want p4 and p5. A: Apart from what sir t.m.adam has already shown, you can go like this as well to get the text out of those p tags appearing before the class zls: from bs4 import BeautifulSoup html_content = ''' <t>p0</t> <y>p00</y> <p>p1</p> <p>p2</p> <p>p3</p> <span class="zls" id=".B1.D9.87.D8.A7.DB.8C_.D9.88.D8.A"> certain unique text </span> <p>p4</p> <p>p5</p> ''' soup = BeautifulSoup(html_content, 'lxml') for items in soup.select(".zls"): tag_items = [item.text for item in items.find_previous_siblings() if item.name=="p"] print(tag_items) Output: ['p3', 'p2', 'p1'] | High | [
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Art from Mega Man 7, Mega Man X, and Mega Man X7/Mega Man Knowledge Base Best, Worst, Weirdest Best, Worst, Weirdest focuses on three installments of a long-running video game series to explore its strengths, its failings, and where it got lost. Prev Next View All Buried beneath his milquetoast but iconic international title, the secret to Mega Man’s success is right there in his original Japanese name—Rockman. Rock ’n’ roll is an alchemical formula that can be added to and subtracted from to create wild new expressions, a familiar base with replicable rules that naturally lend themselves to experimentation and embellishment. Similarly, Rockman is a form, and his 30 years as a fixture in video game canon comes from formal elegance. The character and his attendant games offer an almost infinite opportunity for riffing on a central theme, for making small textural changes to create something outwardly similar but new. All Mega Man games are the same to the untrained ear, but Mega Man 2 wasn’t just the foundation for a cynical, abused video game cash crop. It was The Beatles’ “Love Me Do,” a catalyst for both a series that’s been fruitful on its own and a model for countless others ever since. We keep playing Mega Man games for the same reason we keep buying rock records not called Rubber Soul: There’s always a new way to do it, even when that new thing is called something else. Since Keiji Inafune—illustrator of the original Mega Man who went on to become the series’ producer for more than two decades—departed Capcom in 2010, official Mega Man games have been restricted to archival releases. Meanwhile, other studios like Yacht Club, Batterystaple, and Inafune’s own Comcept have made games like Shovel Knight, 20XX, and Mighty No. 9 that are Mega Man games in all but name. After all, power-pop bands kept writing would-be Beatles songs for decades, and Paul McCartney started a fruitful solo career. (Mighty No. 9 is the Wings of the Mega Man universe.) Like the former Beatle, Mega Man has missed as much as it’s hit over the decades, with putrid spin-offs and erratic experiments sandwiched between canonized classics and modern successors. Best: Mega Man X (1993) By the end of 1993, Mega Man had already gone through its first arc of wild success and audience disinterest. The 1987 original directed by Akira Kitamura established the series’ formula. That first game was inspired, full of the emotive music, demanding action, and wide-eyed cartoon art that have remained signatures in all the series’ peaks. But it was also rough around the edges. It was Mega Man 2 and 3 that polished the formula while creating an impressionistic storytelling style that made Mega Man 2, in particular, a staple. Mega Man 4, 5, and 6 were released on the NES through 1993, a period that saw many developers turning to more powerful 16-bit machines. While still good, all three felt rote and partially hampered by some questionable additions. First was the needless lengthening of the game by the introduction of new villains (all of them just working for Dr. Wily), and then there’s the Mega Buster, a charged shot that gave Mega Man a stronger base weapon but resulted in an irritating whine dominating the game’s aural landscape. Kitamura’s formula had gone as far as it could at the time. Rather than simplifying it, though, Inafune embellished even more when transitioning the games to the Super NES and came away with the best in the series: Mega Man X. Sequels tend to drown when weighed down by the belief that quality is born of quantity, but Mega Man X is the rare example where more of everything is ultimately a net positive. The simple, suggestive sprite art of the NES games is replaced by detailed, thickly colored characters like X, Mega Man’s descendant who can feel and think for himself. The implicit narrative evolves into an anime melodrama with surprisingly effective (if cliché) beats, like the long dead Dr. Light leaving hidden messages and combat upgrades for X or the sacrifice of Zero, X’s David Lee Rothbot-with-a-laser-sword role-model. The run, jump, and shoot action gains new texture thanks to added complexity, but where additions like a robot-dog helper and the Mega Buster diluted what worked in the NES games, Mega Man X’s growth made it more fun to play. Finding X’s long-lost armor, which granted skills like the ability to destroy walls with his head or dash forward, layered welcome new goals into the straightforward survival gauntlets his predecessor suffered through. Even simple moves like jumping against a wall to climb upward felt like magic, a staccato touch on top of the old Mega Man beat. The art, the crushing rock music in stages like Central Highway—a story-centric tutorial stage rather than a robot master rush, another new wrinkle—and the world of sentient robots trying to overthrow mankind culminate in a game that feels like far more than the sum of its parts, and things people held dear about Mega Man 2 and 3 were sacrificed in the process. Those games were paintings of an alien world that you have to dance through, and they could be profoundly moving, as Mega Man 2’s haunting tone poem of an ending proves. Mega Man X wove that world into a textural whole, a complete place with history and humanity. The earlier games had grace, but Mega Man X’s fullness elevates it even now. Unfortunately, its propensity for tinkering resulted in the series’ worst game 10 years later. Worst: Mega Man X7 (2003) After X carved a path for spin-offs and all kinds of experimentation, Capcom went nuts for the better part of a decade. The original Mega Man returned in a handful of bizarre sequels (more on those later), as well as digital board games, a text adventure, arcade fighting games, and even one of the worst soccer games ever made. Even more Mega Men messed with the original games’ structure. The superb Mega Man Legends dug deeper into lore and character customization by reimagining the hero as a spelunking treasure hunter thousands of years into the future of the series. Mega Man Battle Network stripped away the reflex-based action and adapted the rock-paper-scissors interplay between robot master abilities into a strategic card game, something 2002’s Mega Man Zero tried to reintegrate into a side-scrolling action game to limited success. (Rather than a deck of computer chip cards, Zero collected Cyber-elves, an attempt to infuse a Pokémon-style patina into the Mega Man blueprint.) Meanwhile, Capcom continued to produce Mega Man X games, to increasingly poor results, the nadir of which was Mega Man X7. Screenshot: Mega Man X7 Everything about Mega Man X7 feels wrong. Rather than commit to a fully 3-D perspective, X7 uncomfortably shifts between a cramped overhead perspective of poorly drawn polygonal characters, a familiar profile view that lacks the precise feel of the older games, and more open 3-D arenas that are awkward to navigate thanks to loose, fiddly controls. Mega Man characters had started speaking by the mid-’90s, but the voices in X7 were a grating nightmare. Just try sitting through the infamous boss fight with Flame Hyenard and try not to pull your hair out the 70th time he yells “Burn to the ground!” That’s to say nothing of Axl, the new playable character who is not technically anyone’s stepchild but does sport a shock of red hair that looks stolen from a One Piece character, which certainly speaks to the era in which X7 was born. While Legends, Battle Network, Zero, and all the other experiments deviated from the basic form in significant ways, they were united in sourcing their inspiration in the original. The goofy world-building of Legends is the keyboard-laced prog-rock theatrics of Dream Theater compared to the grizzled Led Zeppelin heavy metal of the first Mega Man X. X7, meanwhile, was a muddy attempt to adapt the series’ world into something more contemporary and potentially popular on Sony’s PlayStation 2. Mega Man was thriving on the small stage of the Game Boy Advance, but Capcom chose to force Mega Man X into a shape better suited to a TV-based console landscape where games like Devil May Cry were finding huge success. Name alone doesn’t make Mega Man games what they are, and X7 is the model for why. Weirdest: Mega Man 7 (1995) After the success of Mega Man X, Capcom abandoned the original series for two years before bringing it back in an unrecognizable form with Mega Man 7. The simple, primary-colored world of the NES games and the hyper-detailed, tempered landscape of X were gone. In its place was a bubbly world that looked like a cross between Inafune’s stubby Famicom box art and Western animation, particularly late ’80s and early ’90s Disney shows like DuckTales (appropriate, considering Capcom adapted those series into video games). There’s an even greater emphasis on explicit story than in the X games, with Mega Man paired up with a mechanic named Auto and a nemesis named Bass who has his own evil robot dog named Treble. From the North American and European box art of Mega Man 7/Capcom Database The odd change in style resulted in a change in the action as well. The big bulbous Mega Man of MM7 controls more slowly than the tiny sprite of old, making for a languorous trek through levels that were more detailed but also more cramped. The larger characters and slower pace change the combat into something more comedic than surreal and desperate. And it really does seem like Mega Man 7 is playing for laughs. In the introductory stage, for example, Auto hands Mega Man the wrong helmet, prompting a comedic pause as the hero sits there wearing the construction hat of the series’ iconic Met enemies. It’s as corny as a Monterey Jack cheese pun in Chip ’N Dale Rescue Rangers. The thing is, Mega Man 7 isn’t a comedy at all. Mega Man wins the day like always after pushing through Dr. Wily’s giant castle, but then things get weird. As Wily surrenders himself, Mega Man holds up his little blaster arm and threatens to shoot the evil scientist in the face. “You forget, Mega Man,” says Dr. Wily, “robots cannot harm humans.” “I am more than a robot!” the blinking, buoyant blue robot responds. “Die Wily!” The tonal whiplash is worse than shifting from “Blackbird” to “Piggies” on The Beatles, only there’s no precedent in the game or even the series for such a pitch black move as having Mega Man threaten to murder someone. The game closes with an absolutely tremendous rock song blaring as Mega Man storms away from Wily’s flaming castle. Where in the hell did this game come from? Mega Man 7 is more childish in tone and aesthetic than all of the NES games, and then, right at the end, it suddenly gets even darker than Mega Man X. That ending, coupled with the cartoon style and pace, makes Mega Man 7 a hard left turn compared to the storybook action of the originals and the anime melodrama of X. There’s nothing else in Mega Man history so confused. The developers themselves were confounded when looking back on it. “There are so many things about this title that I have regrets about,” said designer Yoshihisa Tsuda in the Mega Man Official Complete Works, “and even at the time, we all found ourselves wishing for another month or so to work on it.” In fairness to Tsuda, Mega Man 7 was made in just a few months, but that hardly explains the drastic change in art, pacing, and story. Even Mega Man 8 and the final Super NES game, Mega Man & Bass, softened the hard shifts between darkness and slapstick while adapting the rounded Saturday morning visuals of MM7 into something closer to the pastel palette of the originals. That look was abandoned as the series went on, an artistic phase whose legacy is in proving how far the original character could be bent inside the Mega Man form before he broke. Now that form is in the hands of other artists and characters. While 2008’s Mega Man 9 showed that there was still hunger for NES-style games, Shovel Knight, for example, found new room for variation on Mega Man’s structure, using the hero’s signature spade to explore side-scrolling action around melee moves and rethinking how death works as a penalty. Whether Capcom itself will return to the form is a mystery. Mega Man Legacy Collection, the recent NES anthology, and a guest appearance in Super Smash Bros. For Wii U are the only official Mega Man games since Inafune left the company, though the characters live on in the Archie comics series. With a new cartoon on the way—starring a nasty new Mega Man who looks like a refugee from an early ’00s Esurance commercial—rumor is Capcom will try its hand at a brand new game. Whether or not it sounds like a cover band after all these years will depend on how it plays. Purchasing via Amazon helps support The A.V. Club. | High | [
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Shop Announcement: Welcome to Botanic Isles on Folksy, real Scottish flower and nature jewellery. We hand pick and hand press botanical elements from all over Scotland to bring our customers the best and most unique jewellery. "For those that would rather have flowers in their hair than diamonds around their neck..." ♥ We send all orders first class and signed for from the UK. ♥ 5% of all online sales goes to Hessilhead Wildlife Rescue in Beith, Scotland. ♥ All our items come beautifully presented in Botanic Isles's own luxury stamped packaging. We love to create one of a kind, bespoke items for our customers. If you have an idea of something you would like preserved into jewellery send a message our way. DELIVERY INFO: We send all orders first class and signed for with the Royal Mail. ABOUT BOTANIC ISLES: At Botanic Isles, every single botanical element is hand picked and hand pressed by me. I collect a wide variety of flora from all over Scotland's highlands and islands to bring my customers the best and most unique jewellery. This item comes beautifully presented in a white gift box. Personal touches are everything to me, if I can customise your order for you in any way by changing the length of chain, adding a charm, initial or birthday number do not hesitate to ask. Perfect as a gift or as a treat for yourself, this item is perfect for any age or occasion. The chain is 18" and sits elegantly just below the collar bones. GIFT WRAPPING: I am happy to gift wrap items and send them to an alternative address at no extra charge. The gift box is absolutely ideal for gifts. Returns Policy You have 14 days, from receipt, to notify the seller if you wish to cancel your order or exchange an item. Unless faulty, the following types of items are non-refundable: items that are personalised, bespoke or made-to-order to your specific requirements; items which deteriorate quickly (e.g. food), personal items sold with a hygiene seal (cosmetics, underwear) in instances where the seal is broken. | Mid | [
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Q: CSS layout help - Multiline address I'm trying to display an address right aligned in the footer of my page like this: 1234 south east Main St. Nowhere, ID 45445 (555) 555-5555 in my markup I have this: <address> 1234 south east Main St. Nowhere, Id 45445 (555) 555-5555 </address> How can I get this to layout properly without inserting <br /> in each line using css? A: hey try to use this use this .address { white-space:pre; text-align:right; } | High | [
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Q: Nested function in Angular2 using TypeScript I am migrating from Angular 1 to 2, and I have nested functions in JavaScript: function normalizeDoc(doc, id) { function normalize(doc){... I removed the "function" but now I get errors from TypeScript. import { Injectable } from '@angular/core'; @Injectable() export class PouchSeed { constructor( ) { } normalizeDoc(doc, id) { normalize(doc) { doc = angular.copy(doc); Object.keys(doc).forEach(function (prop) { var type = typeof doc[prop]; if (type === 'object') { doc[prop] = normalize(doc[prop]); } else if (type === 'function') { doc[prop] = doc[prop].toString(); } }); return doc; }; var output = normalize(doc); output._id = id || doc._id; output._rev = doc._rev; return output; }; Errors: Typescript Error ';' expected. src/providers/pouch-seed.ts normalizeDoc(doc, id) { normalize(doc) { doc = angular.copy(doc); Typescript Error Cannot find name 'normalize'. src/providers/pouch-seed.ts normalizeDoc(doc, id) { normalize(doc) { Typescript Error Cannot find name 'angular'. src/providers/pouch-seed.ts normalize(doc) { doc = angular.copy(doc); Is it ok to nest methods like this? What's the reason for the ";" error? A: If you add es2016 and es2017 libraries to your compiler, in tsconfig.json: "compilerOptions": { "lib": [ ..., "es2016", "es2017" ] } You can use Object Spread, Object.entries and TypeScript deconstructing: export class PouchSeed { constructor() { } normalizeDoc(doc, id) { const normalize = o => Object.entries(o) .map(([key, value]) => ({ [key]: typeof value === 'object' ? normalize(value) ? typeof value === 'function' : value.toString() : value })) .reduce((acc, value) => ({ ...acc, ...value }), {}); return { ...normalize(doc), _id: id || doc._id, _rev: doc._rev }; }; } | Mid | [
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The Hottest Online Talk Radio Station Main Menu See Derrick Rose’s Incredible Game-Winner In Five Different Angles This is one that’s going to live with us for a long time, if for no other reason than it showed what an awesome thing faith is. Derrick Martell Rose was to always be our basketball savior, no one else. For those of us who didn’t waver in our belief or who at least never wavered in our support of him, this moment came swift and sweet and sent us into that special kind of sports euphoria that is absolutely drug-like. And it was the coolest guy in the room, D-Rose, carried off court by his comrades saying and not-saying “yeah, I thought you knew…” We did, man. We’re sorry for acting new, but its nothing like seeing it go down again, hitting every molecule of nylon. Swish. Kanye has to keep that as his album name now as we all bless the backboard and continue to remember this image. We can do it…he can do it…and next time it is done let him walk off again like its nothing new while we do ALL the celebrating. | Low | [
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Structural and functional properties of cytochrome c oxidase from Bacillus subtilis W23. The terminal component of the electron transport chain, cytochrome c oxidase (ferrocytochrome c: oxygen oxidoreductase) was purified from Bacillus subtilis W23. The enzyme was solubilized with alkyglucosides and purified to homogeneity by cytochrome c affinity chromatography. The enzyme showed absorption maxima at 414 nm and 598 nm in the oxidized form and at 443 nm and 601 nm in the reduced form. Upon reaction with carbon monoxide of the reduced purified enzyme the absorption maxima shifted to 431 nm and 598 nm. Sodium dodecylsulfate polyacrylamide gel electrophoresis indicated that the purified enzyme is composed out of three subunits with apparent molecular weights of 57 000, 37 000 and 21 000. This is the first report on a bacterial aa3-type oxidase containing three subunits. The functional properties of the enzyme are comparable with those of the other bacterial cytochrome c oxidases. The reaction catalyzed by this oxidase was strongly inhibited by cyanide, azide and monovalent salts. Furthermore a strong dependence of cytochrome c oxidase activity on negatively charged phospholipids was observed. Crossed immunoelectrophoresis experiments strongly indicated a transmembranal localization of cytochrome c oxidase. | High | [
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Essential sketch comedy shows June 17, 2013 DANIELLE LEVITT/COMEDY CENTRAL/NYT 1of29 Chappelle's Show: During its brief time on air, Chappelle's Show gave us some of the most brilliantly incisive and hilarious commentary on race mainstream America has seen since Richard Pryor, as well as legions of fratboys telling strangers that they are Rick James, b-----. Dave Chappelle pulled the plug on his cash cow after two seasons, opting to spend his time hiding from drunk white people who loudly quote his sketches at him. (Captions by Joe Mathlete) DANIELLE LEVITT/COMEDY CENTRAL/NYT 1of29 Chappelle's Show: During its brief time on air, Chappelle's Show gave us some of the most brilliantly incisive and hilarious commentary on race mainstream America has seen since Richard Pryor, as well as legions of fratboys telling strangers that they are Rick James, b-----. Dave Chappelle pulled the plug on his cash cow after two seasons, opting to spend his time hiding from drunk white people who loudly quote his sketches at him. (Captions by Joe Mathlete) | High | [
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package com.xabber.android.ui.widget; import android.app.PendingIntent; import android.content.Context; import android.content.Intent; import android.content.pm.ShortcutInfo; import android.content.pm.ShortcutManager; import android.graphics.Bitmap; import android.graphics.drawable.Icon; import android.os.Build; import androidx.annotation.RequiresApi; import com.xabber.android.data.extension.avatar.AvatarManager; import com.xabber.android.data.extension.muc.MUCManager; import com.xabber.android.data.message.CrowdfundingChat; import com.xabber.android.data.roster.AbstractContact; import com.xabber.android.ui.activity.ChatActivity; import java.util.ArrayList; import java.util.List; import java.util.UUID; public class ShortcutBuilder { public static void updateShortcuts(Context context, List<AbstractContact> contacts) { if (Build.VERSION.SDK_INT >= Build.VERSION_CODES.N_MR1) { List<ShortcutInfo> shortcuts = new ArrayList<>(); int added = 0; for (AbstractContact contact : contacts) { if (added == 4) break; else if (!contact.getUser().equals(CrowdfundingChat.getDefaultUser())) { shortcuts.add(createShortcutInfo(context, contact)); added++; } } ShortcutManager manager = context.getSystemService(ShortcutManager.class); if (manager != null && !shortcuts.isEmpty()) { manager.setDynamicShortcuts(shortcuts); } } } public static Intent createPinnedShortcut(Context context, AbstractContact contact) { if (Build.VERSION.SDK_INT >= Build.VERSION_CODES.O) { ShortcutManager manager = context.getSystemService(ShortcutManager.class); if (manager != null && manager.isRequestPinShortcutSupported()) { ShortcutInfo shortcutInfo = createShortcutInfo(context, contact); Intent callbackIntent = manager.createShortcutResultIntent(shortcutInfo); PendingIntent successCallback = PendingIntent.getBroadcast(context, 0, callbackIntent, 0); manager.requestPinShortcut(shortcutInfo, successCallback.getIntentSender()); return null; } } Intent intent = new Intent(); intent.putExtra(Intent.EXTRA_SHORTCUT_INTENT, ChatActivity.createClearTopIntent(context, contact.getAccount(), contact.getUser())); intent.putExtra(Intent.EXTRA_SHORTCUT_NAME, contact.getName()); intent.putExtra(Intent.EXTRA_SHORTCUT_ICON, getAvatar(contact)); return intent; } @RequiresApi(api = Build.VERSION_CODES.N_MR1) private static ShortcutInfo createShortcutInfo(Context context, AbstractContact abstractContact) { return new ShortcutInfo.Builder(context, UUID.randomUUID().toString()) .setShortLabel(abstractContact.getName()) .setLongLabel(abstractContact.getName()) .setIcon(Icon.createWithBitmap(getAvatar(abstractContact))) .setIntent(ChatActivity.createClearTopIntent(context, abstractContact.getAccount(), abstractContact.getUser())) .build(); } private static Bitmap getAvatar(AbstractContact abstractContact) { Bitmap bitmap; if (MUCManager.getInstance().hasRoom(abstractContact.getAccount(), abstractContact.getUser())) bitmap = AvatarManager.getInstance().getRoomBitmap(abstractContact.getUser()); else bitmap = AvatarManager.getInstance().getUserBitmap(abstractContact.getUser(), abstractContact.getName()); return AvatarManager.getInstance().createShortcutBitmap(bitmap); } } | Mid | [
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Elective induction of labor: friend or foe? Elective induction of labor is defined as labor induction in the absence of a clear medical indication. Whether elective labor induction at 39 weeks is a reasonable option for obstetric practice has been a hotly debated topic for decades. Historically, labor induction in low-risk nulliparous women has been discouraged due to the belief that this intervention increases the risk for cesarean delivery without a clear benefit. This review discusses the observational and randomized data that have informed this debate, focusing on recent studies that have reshaped how we think about elective labor induction at 39 weeks of gestation. | High | [
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In IMT2000-TDD, a midamble, which is a pilot sequence, is inserted in the center of a time slot. Multiplexed signals from multiple users arrive at the receiving end, and the receiving end performs correlation operation using midambles different for each signal, thereby creating delay profiles on a per midamble basis, detecting paths and subjecting these to rake-demodulation or JD-demodulation, and acquiring the received data. To acquire the received data on a per user basis, it is necessary to detect the timing of each user's top path in delay profiles. Now, there is processing referred to as frame tracking for tracking the frame timings. By virtue of this frame tracking processing, the top path in a delay profile is detected on a per user basis, and the received data is demodulated by adjusting the timing in accordance with the top path. Usually, tracking processing is performed using a common channel that all users share. On this common channel, a signal is multiplexed with a user signal. At the receiving end, following user-specific delay profiles, delay profiles of the common channel are created. Now, when the receiving party moves while engaged in communication, and when, for instance, the receiving party moves out from behind a building while communicating, the receiving party is then able to receive direct waves from the base station apparatus after moving out from behind the building. Consequently, new peaks by the direct waves might appear before the peaks by the delay waves. If these peaks by the direct waves can be selected as paths and used for rake combining, the quality of the received signal after the rake combining can be improved. So, when paths such as above are detected, tracking processing is performed such that the top path is changed to a path by a direct wave. On the other hand, a mobile apparatus receives multiplexed transmission data from multiple users. Consequently, when there is a new path before the top path, there is a possibility that the correlation operation result at a timing before the top path shows the component of another user signal using a midamble corresponding to a circulation amount as of just before. That is, the communication schemes of IMT2000-TDD use midambles that are created on a per channel basis by cyclically shifting the basic midamble. Consequently, the correlation operation result at a timing before the top path and the correlation operation result of a channel using a midamble shift corresponding to a circulation amount as of just before may show the same component. However, with a typical receiving apparatus, when there is a new path before the top path in a delay profile, by tracking processing, this new path is always set as the new top path. Consequently, when the new path happens to be another user's delayed wave or the like, the reception is done at wrong timings and this may disable communications. | Mid | [
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Effect of hypoxia-inducible factor-1alpha silencing on the sensitivity of human brain glioma cells to doxorubicin and etoposide. Multidrug resistance (MDR) is a significant problem underlying the poor prognosis associated with gliomas. Hypoxia-inducible factor-1alpha (HIF-1alpha) is thought to induce the genes expression involved in MDR. To evaluate the effect of silencing HIF-1alpha in human glioma T98G cells, cells were transfected with HIF-1alpha-small interference RNA (HIF-1alpha-siRNA) and cultured under hypoxic conditions. The effect of HIF-1alpha-siRNA on HIF-1alpha and multidrug resistance-associated protein 1 gene (MRP1) and protein levels was determined. Silencing rates of HIF-1alpha were 90%, 85%, and 88% at 24, 48, 72 h post-transfection, respectively. Corresponding rates of HIF-1alpha protein were 74.5%, 61.1% and 59.1%. MRP1 protein levels decreased by 7.6%, 36.8% and 45.2%. HIF-1alpha-siRNA transfected cells were significantly more sensitive to doxorubicin and etoposide compared to non-transfected cells. These findings suggest that the HIF-1alpha plays a role in mediating chemotherapeutic drug resistance in glioma cells. HIF-1alpha silencing may prove to be an effective therapeutic means of treating gliomas. | Mid | [
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Introduction {#s1} ============ Neurogenesis is extremely limited in the adult brain. In most mammals, specialized astrocytes in the subventricular zone (SVZ) and hippocampal dentate gyrus (DG) are stem cells and generate new neurons continuously, but apart from that, the brain's ability to replace lost neurons is very limited. However, in response to an experimental stroke or excitotoxic lesion, some astrocytes in the mouse striatum can generate neurons ([@bib16]; [@bib17]). This neurogenic response is regulated by Notch signaling and can be activated even in the uninjured mouse striatum by deleting the Notch-mediating transcription factor *Rbpj* ([@bib16]). Striatal astrocytes undergo neurogenesis by passing through a transit-amplifying cell stage. But it is not known whether these astrocytes become bona fide neural stem cells. If they do, this could have far-reaching implications for regenerative medicine. Astrocytes make up a large fraction of all brain cells (10--20% in mice) ([@bib33]) and are distributed throughout the central nervous system. They would thus represent a very abundant source of potential neural stem cells that might be recruited for therapeutic purposes. Although certain injuries and *Rbpj* deletion can both trigger neurogenesis by astrocytes, it almost exclusively does so in the striatum. And even within the striatum, primarily the astrocytes in the medial striatum readily activate neurogenic properties ([Figure 1a](#fig1){ref-type="fig"}). This suggests that neurogenic parenchymal astrocytes either occupy an environmental niche favorable to neurogenesis or that only they have an inherent neurogenic capacity. In order to recruit astrocytes for therapeutic neurogenesis, a first step is to understand the mechanisms underlying this process. If these mechanisms are understood, they could potentially be targeted to induce localized therapeutic neurogenesis throughout the central nervous system. ![Neurogenesis by striatal astrocytes can be reconstructed using single-cell RNA sequencing.\ (**a**) Deletion of the gene encoding the Notch-mediating transcription factor *Rbpj* activates a latent neurogenic program in striatal astrocytes ([@bib16]). Nuclei of Dcx^+^ neuroblasts are indicated by red dots. Not all striatal astrocytes undergo neurogenesis, shown by the restricted distribution of Dcx^+^ neuroblasts and the fact that many recombined astrocytes (gray) remain even 2 months after *Rbpj* deletion. (**b**) We performed single-cell RNA sequencing using two protocols. For the AAV-Cre dataset, we deleted *Rbpj* exclusively in striatal astrocytes using a Cre-expressing AAV and sequenced the transcriptomes of recombined cells five weeks later. (**c**) Dimensionality reduction using UMAP captures the progression from astrocytes, through proliferating transit-amplifying cells, to neuroblasts. Panel (**d**) shows markers for the different maturation stages.](elife-59733-fig1){#fig1} Here, we generated two separate single-cell RNA sequencing datasets to study neurogenesis by parenchymal astrocytes in mice. We found that, at the transcriptional level, *Rbpj-*deficient striatal astrocytes became highly similar to SVZ neural stem cells and that their neurogenic program was nearly identical to that of stem cells in the SVZ, but not the DG. Interestingly, astrocytes in the non-neurogenic somatosensory cortex also initiated a neurogenic program in response to *Rbpj* deletion, but all stalled prior to entering transit-amplifying divisions and failed to generate neuroblasts. In the striatum, too, many astrocytes halted their development prior to entering transit-amplifying divisions. We found that stalled striatal astrocytes could be pushed into transit-amplifying divisions and neurogenesis by an injection of epidermal growth factor (EGF), indicating that it is possible to overcome roadblocks in the astrocyte neurogenic program through targeted manipulations. Taken together, we conclude that parenchymal astrocytes are latent neural stem cells. We posit that their intrinsic neurogenic potential is limited by a non-permissive environment. Recruiting these very abundant latent stem cells for localized therapeutic neurogenesis may be possible but is likely to require precise interventions that guide them through their neurogenic program. Results {#s2} ======= Transcriptome-based reconstruction of neurogenesis by striatal astrocytes {#s2-1} ------------------------------------------------------------------------- To understand the cellular mechanisms underlying neurogenesis by parenchymal astrocytes, we decided to perform single-cell RNA sequencing of striatal astrocytes undergoing neurogenesis in vivo. To this end, we generated two separate single-cell RNA sequencing datasets, each with complementary strengths. For the first dataset, which we call the Cx30-CreER dataset, we used Connexin-30 (Cx30; official gene symbol *Gjb6*)-CreER mice to delete *Rbpj* and activate heritable *tdTomato* or *YFP* expression in astrocytes throughout the brain. This method targeted up to 100% of astrocytes in the striatum (tdTomato expression in 92 ± 10% of glutamine synthetase^+^, S100^+^ cells; mean ± S.D.; *n* = 6 mice). These mice also target neural stem cells in the SVZ, but no other brain cell types ([@bib16]). *Rbpj* deletion in healthy mice was chosen as the means by which to activate the neurogenic program of astrocytes. That is because (1) it constitutes a single, precisely timed trigger throughout the brain, (2) it mimics the endogenous stimulus of reduced Notch signaling by which stroke induces neurogenesis by astrocytes ([@bib16]), and (3) it does not induce potentially confounding cellular processes like reactive gliosis or cell death. Striatal tdTomato^+^ cells were isolated by flow cytometry from mice homozygous for the *Rbpj* null allele 2, 4 and 8 weeks after tamoxifen administration, and from control mice with intact *Rbpj*, 3 days after tamoxifen administration (hereafter called ground-state astrocytes) ([Figure 2---figure supplement 1a--d](#fig2s1){ref-type="fig"}). Sequencing libraries were prepared using Smart-seq2 ([@bib21]). In addition to parenchymal astrocytes, Cx30-mediated recombination also targets SVZ neural stem cells, whose progeny might be sorted along with striatal astrocytes and, thus, confound our results. We therefore generated a second single-cell RNA sequencing dataset, for which labeling of cells was restricted to the striatum. Striatal astrocytes were selectively recombined via injection of an adeno-associated virus (AAV) expressing Cre under the control of the astrocyte-specific GFAP promoter into the striatum of *Rbpj*^fl/fl^; R26-loxP-Stop-loxP-tdTomato mice ([Figure 1b](#fig1){ref-type="fig"}). We isolated tdTomato^+^ cells 5 weeks after virus injection, a time point at which Ascl1^+^ astrocytes, transit-amplifying cells and neuroblasts are all present ([@bib16]). We sequenced these cells using 10X Chromium by 10X Genomics. Despite the GFAP promoter, the AAV-Cre dataset also contained oligodendrocytes and some microglia ([Figure 1---figure supplement 1](#fig1s1){ref-type="fig"}). These were excluded from the final dataset based on our previous finding that they are not involved in a neurogenic program ([@bib16]). The AAV-Cre dataset contained a somewhat higher proportion of transit-amplifying cells than the Cx30-CreER dataset ([Figure 2---figure supplement 1f](#fig2s1){ref-type="fig"}), likely because the AAV-Cre dataset only contained cells from 5 weeks after *Rbpj*-KO, near the peak of transit-amplifying divisions ([@bib16]). We first asked whether we could reconstruct striatal astrocyte neurogenesis computationally using the AAV-Cre dataset. Using Uniform Manifold Approximation and Projection (UMAP), we found that the sequenced cells indeed included *Rbpj-*deficient astrocytes (*Cx30*^+^), activated astrocytes and transit-amplifying cells (*Egfr*^+^, *Ascl1*^+^, *Mki67*^+^, *Dcx*^+^) and neuroblasts (*Dcx*^+^), up until the migratory neuroblast stage (*Nav3*^+^) ([Figure 1c--d](#fig1){ref-type="fig"}). We conclude that it is possible to use single-cell RNA sequencing to study the transcriptional mechanisms underlying the astrocyte neurogenic program. Neurogenesis by astrocytes is dominated by early transcriptional changes associated with metabolism and gene expression {#s2-2} ----------------------------------------------------------------------------------------------------------------------- We were interested in the transcriptional changes that take place as astrocytes first initiate the neurogenic program. For this question, we primarily used the Cx30-CreER dataset, which included astrocytes both at ground state and at 2, 4 and 8 weeks after *Rbpj* deletion ([Figure 2a](#fig2){ref-type="fig"}). Furthermore, the Cx30-CreER mice allowed us to study the neurogenic process in the uninjured brain, without the potentially confounding effects of a needle injection. Two weeks after *Rbpj* deletion, astrocytes had upregulated genes mostly related to transcription, translation and metabolism ([Figure 2b](#fig2){ref-type="fig"}, S1g, [Supplementary file 1](#supp1){ref-type="supplementary-material"}). To study in detail how gene expression changed over the course of neurogenesis, we next reconstructed the differentiation trajectory of these astrocytes computationally using Monocle ([@bib37]; [Figure 2---figure supplement 2](#fig2s2){ref-type="fig"}; Methods). This analysis captured the progression from astrocyte to neuroblast in pseudotime ([Figure 2c](#fig2){ref-type="fig"}). The pseudotemporal axis reflected neurogenesis, as revealed by plotting along pseudotime the expression of genes that are dynamically induced in canonical neurogenesis ([Figure 2d](#fig2){ref-type="fig"}). This analysis confirmed the previous finding that neurogenesis by parenchymal astrocytes involves transit-amplifying divisions ([@bib16]; [@bib18]), and does not occur through direct transdifferentiation, a process during which intermediate stages of differentiation are skipped ([@bib3]). {ref-type="fig"} for cell state definitions). (**d**) Pseudotime captures the neurogenic trajectory of astrocytes, as shown by plotting the expression of classical neurogenesis genes along this axis. (**e**) Gene clustering and GO analysis shows distinctive dynamics of functional gene groups with example genes shown in (**f**). Genes involved in lipid and carbohydrate metabolism are upregulated initially but downregulated as cells enter transit-amplifying divisions. Genes involved in transcription and translation are expressed at steadily increasing levels. Accordingly, the number of genes detected per cell increases initially (**g**) -- an increase not explained by a mere increase in cell size (**h**). A gene cluster with remarkable dynamics contains genes involved in synapse organization (**e**), presumably important for both astrocytes and neurons. (i) All these findings are supported by a pseudotemporal analysis of the AAV-Cre dataset. The AAV-Cre dataset, however, only contains cells from the 5-week time point and thus does not show changes that happen early in the neurogenic program. (TA cells, transit-amplifying cells).](elife-59733-fig2){#fig2} In order to better understand the transcriptional changes that take place as striatal astrocytes initiate neurogenesis, we used Monocle's gene clustering algorithm, which clusters genes whose expression levels vary similarly along pseudotime ([Figure 2e](#fig2){ref-type="fig"}). These gene clusters were then characterized using the gene ontology (GO) tool DAVID ([@bib11]). This approach enabled us to see which biological processes changed as differentiation proceeded ([Supplementary file 2](#supp2){ref-type="supplementary-material"}). We found that, as astrocytes initiated their neurogenic program, genes associated with metabolism, particularly lipid (e.g. *Fabp5*, *Fasn*, *Elovl5*) and carbohydrate metabolism (e.g. *Gapdh*, *Aldoa*, *Aldoc*) were at first upregulated but dramatically downregulated as cells entered transit-amplifying divisions ([Figure 2e--f](#fig2){ref-type="fig"}, \[*Cluster 1*\]). This suggested that the neurogenic program requires high metabolic activity to prepare for transit-amplifying divisions. In addition to these metabolic genes, the expression of genes involved in the regulation of transcription (e.g. mRNA splicing genes *Snrpb*, *Srsf5*, *Srsf3*) and translation (e.g. ribosomal subunits *Rpl17*, *Rpl23*, *Rps11*) progressively increased throughout the neurogenic process ([Figure 2e--f](#fig2){ref-type="fig"}, \[*Cluster 2*\]). Accordingly, we found that the number of genes detected per cell increased in the initial stages of neurogenesis ([Figure 2g](#fig2){ref-type="fig"}): pre-division astrocytes expressed 1.4 times as many genes as ground-state astrocytes (p=10^−12^; 95% C.I. 1.3--1.5; Materials and methods). In theory, such an increase in the number of detected genes could be an artifact caused by a simultaneous increase in cell size; however, no cell size increase was observed during this early phase of neurogenesis, as measured by flow cytometer forward scatter ([Figure 2h](#fig2){ref-type="fig"}). The changes to metabolism and gene expression activity described above were the two dominating transcriptional changes that occurred early in the neurogenic process of astrocytes. At the peak of metabolic gene expression, astrocytes initiated transit-amplifying divisions ([Figure 2e](#fig2){ref-type="fig"}; Materials and methods). Accordingly, they upregulated genes associated with cell division (e.g. *Ccnd2*, *Ccng2*, *Cdk4*; [Figure 2e--f](#fig2){ref-type="fig"}, \[*Cluster 3*\]). Finally, as they exited transit-amplifying divisions, cells upregulated classical marker genes of neuroblasts (e.g. *Cd24a*, *Dcx*, *Dlx1/2*, *Tubb3 \[βIII tubulin\]*; [Figure 2e--f](#fig2){ref-type="fig"}, \[*Cluster 3*\]), indicative of early neuronal commitment and differentiation. Interestingly, one group of genes showed a remarkable pattern of initial downregulation followed by upregulation as cells developed into neuroblasts ([Figure 2e--f](#fig2){ref-type="fig"} \[*Cluster 4*\], S4a). This gene group consisted mainly of genes encoding proteins localized to synapses (e.g. *Cplx2*, *Ctbp2*, *Shank1*, *Chrm4, Bdnf*). This suggested that synapse maintenance was compromised very early as astrocytes initiated neurogenesis, but also that some of the same genes are important for synapse maintenance in both astrocytes and neurons. The gene expression changes described above were confirmed in the AAV-Cre dataset, using a differential expression analysis along pseudotime ([Figure 2i](#fig2){ref-type="fig"}). But because the AAV-Cre dataset only contained cells isolated 5 weeks after *Rbpj* deletion, this dataset did not contain ground-state astrocytes and could not capture changes that happened early in the neurogenic program. Astrocytes gradually lose astrocyte features as they enter the neurogenic program {#s2-3} --------------------------------------------------------------------------------- Throughout the initial phase of neurogenesis and up until the point where cells entered transit-amplifying divisions, astrocytes maintained normal astrocyte morphology and expression of common marker genes (e.g. *Aqp4*, *S100b*, *Slc1a2 \[Glt1\], Glul*) ([Figure 2---figure supplement 3b--c](#fig2s3){ref-type="fig"}, [Video 1](#video1){ref-type="video"}). They never showed signs of reactive gliosis (e.g. morphological changes or upregulation of *Gfap*), indicating that reactive gliosis is not required for neurogenesis by astrocytes in vivo. As the astrocytes entered the neurogenic program, they did eventually lose their typical branched morphology; however, they did so only gradually, and only after entering transit-amplifying divisions. In fact, they retained rudiments of astrocytic processes for several transit-amplifying cell divisions ([Figure 2---figure supplement 3c](#fig2s3){ref-type="fig"}, [Video 1](#video1){ref-type="video"}). As an additional sign that they originated from parenchymal astrocytes, many clustered transit-amplifying cells retained trace levels of the astrocyte marker protein S100β, even though they no longer expressed the *S100b* gene. S100β protein is found in parenchymal astrocytes but not in SVZ stem cells ([Figure 2---figure supplement 3d--g](#fig2s3){ref-type="fig"}). Accordingly, we did not detect any S100β protein in SVZ transit-amplifying cells ([Figure 2---figure supplement 3d--g](#fig2s3){ref-type="fig"}). This suggests that the low levels of S100β protein seen in striatal transit-amplifying cells were lingering remnants of their parenchymal astrocyte origin. It indicates that trace levels of S100β protein can function as a short-term lineage-tracing marker for transit-amplifying cells derived from parenchymal astrocytes. ###### Gradual loss of astrocyte morphology in astrocyte-derived transit-amplifying cells. Striatal astrocytes retain their branched astrocyte morphology (see YFP signal) even after they have initiated transit-amplifying divisions in vivo. Shown are several examples of different Ascl1^+^ astrocytes and astrocyte-derived transit-amplifying cells at various stages of transit-amplifying divisions. EdU indicates that these cells had divided within the 2 weeks leading up to the analysis (Materials and methods). Note that astrocyte processes gradually become less branched and more retracted the longer transit-amplifying divisions proceed. A recent study in *Drosophila melanogaster* showed that many quiescent neural stem cells are halted in the G~2~ phase of the cell cycle ([@bib19]). However, we analyzed EdU incorporation in dividing striatal astrocytes. We found some single astrocytes that had not yet divided but were EdU^+^ ([Figure 2---figure supplement 3c](#fig2s3){ref-type="fig"}). This suggested that these astrocytes initiated the cell cycle by synthesizing DNA and thus had not been suspended in the G~2~ phase. Parenchymal astrocytes are located upstream of a neural stem cell state and acquire a transcriptional profile of neural stem cells upon their activation {#s2-4} -------------------------------------------------------------------------------------------------------------------------------------------------------- We were interested in a direct comparison between neurogenic parenchymal astrocytes and adult neural stem cells to see how their neurogenic transcriptional programs relate to one another. A number of published single-cell RNA sequencing datasets exist for mouse neural stem cells generated by 10X Chromium or Smart-seq2. We first analyzed our AAV-Cre dataset together with a previously published 10X Chromium dataset for SVZ neural stem cells and their progeny ([@bib41]). A UMAP analysis of these cells together with our AAV-Cre dataset revealed that the striatal astrocytes and their progeny clustered closely together with the corresponding stages of SVZ cells ([Figure 3a--b](#fig3){ref-type="fig"}). This indicated that neurogenesis in these two brain regions proceeds through the same general developmental stages. Particularly interesting was the observation that our 'Astrocyte Cluster 2' grouped closely together with SVZ neural stem cells ([Figure 3b](#fig3){ref-type="fig"}), indicating that these cells are transcriptionally similar. {ref-type="fig"}, S5b) shows that striatal astrocytes initiate neurogenesis with a phase of metabolic gene upregulation, whereas SVZ stem cells permanently reside on this metabolic peak. (**f**) Signaling entropy, a reliable proxy for differentiation potency, increases in *Rbpj*-deficient astrocytes to reach the same levels as in SVZ stem cells (**g**). (**h**) Prior to entering transit-amplifying divisions, striatal astrocytes are in their most stem cell-like state, having upregulated many markers of neural stem cells (each dot is one cell. Note the bursting expression pattern of many of these genes). (**i**) Some classical markers, however, are not upregulated.](elife-59733-fig3){#fig3} Because our AAV-Cre dataset only contained cells isolated 5 weeks after *Rbpj* deletion, this dataset could not reveal how striatal astrocytes in their ground state relate to SVZ stem cells. We therefore next turned to our Cx30-CreER dataset and analyzed these cells together with SVZ cells from another previously published Smart-seq2 dataset ([@bib14]; [Figure 3c](#fig3){ref-type="fig"}). We used Monocle to perform pseudotemporal ordering of our Cx30-CreER dataset together with the SVZ cells, using genes involved in the GO term Neurogenesis (GO:0022008), and projected the cells onto the pseudotime axis ([Figure 3d](#fig3){ref-type="fig"}). Interestingly, on this neurogenic trajectory, ground state astrocytes were located upstream of the SVZ stem cells, as if representing highly quiescent cells that pass through an initial activation phase before joining the SVZ stem cells ([Figure 3d](#fig3){ref-type="fig"}). We next compared the gene expression changes that occur in SVZ cells with those in our Cx30-CreER dataset. We used Monocle's gene clustering analysis of only the SVZ cells, without the striatal cells. We first confirmed the previously published finding that SVZ neurogenesis is accompanied by large-scale changes in genes associated with metabolism ([Figure 3---figure supplement 1a--c](#fig3s1){ref-type="fig"}; [@bib14]). Intriguingly, however, whereas SVZ neural stem cells appear to be maintained at a high baseline level of metabolic gene expression ([Figure 3---figure supplement 1b--c](#fig3s1){ref-type="fig"}), striatal astrocytes first passed through a phase of metabolic gene upregulation to reach this level, seen by superimposing the striatum-only ([Figure 2e](#fig2){ref-type="fig"}) and SVZ-only ([Figure 3---figure supplement 1b](#fig3s1){ref-type="fig"}) metabolic gene curves ([Figure 3e](#fig3){ref-type="fig"}). This suggested that the neurogenic program in striatal astrocytes starts with an activation phase during which these astrocytes begin to resemble SVZ stem cells with regard to metabolism-associated genes. Similarly, evidence for an initial activation phase was found also in gene expression activity: As described above, we detected a 1.4-fold difference in the number of genes detected in *Rbpj-*deficient astrocytes compared to ground-state astrocytes. This difference is similar in magnitude to a previously detected 1.7-times difference between adult SVZ stem cells and striatal astrocytes ([@bib7]). This suggested that the gene expression activity of *Rbpj-*deficient astrocytes began to quantitatively resemble that of neural stem cells. We asked if we could use our RNA sequencing data to address whether the differentiation potency of striatal astrocytes begins to resemble that of SVZ stem cells. 'Signaling entropy' is a measure of the interconnectedness of a cell's proteome. It represents the average number of possible protein-protein interactions by all proteins expressed by a cell. It is a reliable proxy for a cell's differentiation potency ([@bib35]; [@bib6]), the underlying rationale being that a highly interacting proteome enables promiscuous signaling, which in turn facilitates responding to a variety of differentiation signals. As a validation of the signaling entropy concept, we plotted signaling entropy versus pseudotime in the SVZ dataset and saw that SVZ cells exhibit their maximum signaling entropy as activated stem cells or transit-amplifying cells ([Figure 3---figure supplement 1d](#fig3s1){ref-type="fig"}). We found that the signaling entropy of striatal astrocytes increased after *Rbpj* deletion ([Figure 3f](#fig3){ref-type="fig"}), to the levels seen in SVZ stem cells ([Figure 3g](#fig3){ref-type="fig"}) (One-way ANOVA: F = 35.62, p\<0.0001; Ground-state \[0.8467 ± 0.0214\] vs. pre-division astrocytes \[0.8771 ± 0.0171, mean ±S.D\], p\<0.0001 \[unpaired t-test\]; pre-division astrocytes vs. pre-division SVZ \[0.8848 ± 0.0232\], p=0.0721). This supported the conclusion that striatal astrocytes achieve the same level of differentiation potency as SVZ neural stem cells. Right before entering transit-amplifying divisions, astrocytes were in their most neural stem cell-like state. In addition to the similarities described above, striatal astrocytes in this pre-division state had upregulated some marker genes of neural stem cells (e.g. *Fabp7 \[Blbp\], Egfr, Ascl1, Cd9, Cd81, Slc1a3 \[Glast\]*; [Figure 3h](#fig3){ref-type="fig"} and Figure 6). Other such markers were already expressed by ground-state astrocytes and their RNA levels did not change after *Rbpj* deletion (e.g. *Tnfrsf19 (Troy)*, *Sox2, Nr2e1 (Tlx)*, *Msi1 \[Musashi-1\], Rarres2;* [Figure 3---figure supplement 1e](#fig3s1){ref-type="fig"}). Interestingly, some classical neural stem cell markers were never upregulated by *Rbpj*-deficient astrocytes. For example, *Gfap*, *Prom1*, *Thbs4* and *Vim* remained at low levels throughout the neurogenic process ([Figure 3i](#fig3){ref-type="fig"}), showing that neurogenic astrocytes do not become transcriptionally identical to SVZ stem cells. [Supplementary file 1](#supp1){ref-type="supplementary-material"} includes a full list of genes differentially expressed between ground-state astrocytes and those in their stem cell-like pre-division state. The neurogenic program of striatal astrocytes is more similar to that of SVZ stem cells than to that of DG stem cells {#s2-5} --------------------------------------------------------------------------------------------------------------------- In the adult brain, active neural stem cells exist in two regions, the SVZ and the DG, and produce distinct neuronal subtypes. We asked whether the neurogenic program of striatal astrocytes is more similar to that of stem cells in the SVZ or the DG. For this, we integrated our AAV-Cre dataset with the aforementioned SVZ dataset from [@bib41]. and another previously published 10X Chromium dataset of DG neurogenesis ([@bib9]; [Figure 4a](#fig4){ref-type="fig"}). We used our AAV-Cre dataset rather than the Cx30-CreER dataset for this comparison because previously published 10X Chromium datasets exist for the SVZ and DG that contain both stem cells, transit-amplifying cells and neuroblasts. A clustering analysis revealed that cells clustered together with other cells of the same maturational stage, regardless of which brain region they came from ([Figure 4a](#fig4){ref-type="fig"}). This indicates that neurogenesis proceeds along the same general steps in all three regions. To perform a more focused comparison of the neurogenic transcriptional programs in the striatum, SVZ and DG, we next performed pairwise correlation between striatal cells and the corresponding maturational stages in the SVZ and DG ([Figure 4b--c](#fig4){ref-type="fig"}). We found that the transcriptomes of the striatal cells were more similar to those of SVZ stem cells than to those of DG stem cells in every maturational stage, in particular at the transit-amplifying cell and neuroblast stages ([Figure 4b--c](#fig4){ref-type="fig"}). {#fig4} We next took a more detailed look at neuroblasts, and only included transcription factors in our analysis ([@bib10]), reasoning that the neuroblast transcription factor profile is indicative of commitment to neuronal subtypes. We performed three pairwise differential expression analyses between the neuroblasts in the striatum, SVZ and DG and plotted the most differentially expressed transcription factors in a heatmap ([Figure 4d](#fig4){ref-type="fig"}). This revealed the close transcriptional similarity between striatal and SVZ neuroblasts, suggesting that striatal astrocytes and SVZ stem cells are predisposed to generate very similar neuronal subtypes (GABAergic interneurons), different from those in the DG (excitatory granule neurons). In summary, the transcriptional program governing neurogenesis by striatal astrocytes is highly similar, but not identical, to that of SVZ cells, and less similar to that of DG stem cells. We speculate that this similarity likely reflects a shared developmental history. It has, for example, been shown that the region-specific transcriptional signature among astrocytes is conserved when astrocytes are reprogrammed directly into neurons ([@bib8]). Astrocytes outside the striatum initiate an unsuccessful neurogenic program in response to *Rbpj* deletion {#s2-6} ---------------------------------------------------------------------------------------------------------- We previously found that, in addition to the striatum, *Rbpj* deletion triggers astrocyte neurogenesis in layer 1 of the medial cortex ([@bib16]). Now, we asked whether astrocytes in other parts of the brain also show signs of activating a neurogenic program, even though they do not complete neurogenesis. To detect faint signs of an initiated neurogenic program, we first performed an immunohistochemical staining against the early neurogenesis-associated transcription factor Ascl1 in Cx30-CreER; *Rbpj*^fl/fl^ mice, 4 weeks after tamoxifen administration. Importantly, we used tyramide-based signal amplification to boost the fluorescent signal in order to be able to detect low levels of Ascl1 protein. Intriguingly, this showed that many astrocytes throughout the brain had upregulated low levels of Ascl1 in response to *Rbpj* deletion ([Figure 5a--c](#fig5){ref-type="fig"}). This suggested that astrocytes in all brain regions initiate at least one early step in a neurogenic program in response to *Rbpj* deletion. To learn more, we next performed single-cell RNA sequencing on astrocytes isolated from the non-neurogenic somatosensory cortex of the same Cx30-CreER mice that we had used for the striatum analysis ([Figure 5d](#fig5){ref-type="fig"}). We chose the Cx30-CreER model for this analysis because it induces *Rbpj* deletion simultaneously throughout the brain, does not lead to any potentially confounding tissue damage, and does not suffer from viral tropism-induced differences in recombination efficiency between the striatum and cortex. We used Monocle to arrange the cortical cells in pseudotime together with the striatal cells and found that, regardless of brain region, cells from the different time points scored similarly along the initial stages of this pseudotime axis. However, all the cortical astrocytes halted their development prior to entering transit-amplifying divisions ([Figure 5e](#fig5){ref-type="fig"}). A density plot of cortical astrocytes from the different time points helped better illustrate the gradual progression along this neurogenic axis ([Figure 5f](#fig5){ref-type="fig"}). Two weeks after *Rbpj* deletion, cortical astrocytes had upregulated genes mainly associated with metabolism and gene expression, just like striatal astrocytes ([Figure 5g](#fig5){ref-type="fig"}, [Supplementary file 1](#supp1){ref-type="supplementary-material"}). They also steadily increased gene expression activity ([Figure 5h](#fig5){ref-type="fig"}), again similar to striatal cells. In addition, signaling entropy continuously increased after *Rbpj* deletion (0.85 ± 0.018 vs. 0.87 ± 0.018 \[mean ± S.D.\] in ground-state vs. pre-division astrocytes, respectively \[p\<0.0001, unpaired t test\]; [Figure 5i--j](#fig5){ref-type="fig"}) to almost the same level as in the striatal *Rbpj*-deficient astrocytes ([Figure 5j](#fig5){ref-type="fig"}; pre-division striatal vs. cortical astrocytes: p=0.0091), suggesting that, like the striatal astrocytes, the cortical ones were shifting toward a more stem cell-like state. At their highest pseudotime score, cortical astrocytes were at their most stem cell-like state, characterized by upregulation of neural stem cell genes such as *Ascl1*, *Egfr*, *Fabp7, Pou3f4, Msi1, Slc1a3, Cd81* to the same RNA levels as in striatal astrocytes or SVZ stem cells ([Figure 5k](#fig5){ref-type="fig"} and [Figure 6](#fig6){ref-type="fig"}). One neural stem cell marker, *Cd9* ([@bib14]), was conspicuously higher in striatal and SVZ cells than cortical cells ([Figure 5---figure supplement 1](#fig5s1){ref-type="fig"}). Another, *Neurog1,* was upregulated by both striatal and cortical astrocytes but was not expressed in the SVZ ([Figure 5---figure supplement 1](#fig5s1){ref-type="fig"}). Taken together, it seemed as if cortical astrocytes were preparing to activate the full neurogenic program but that they were unable to enter transit-amplifying divisions. {#fig5} {ref-type="fig"}). EGF injection does not lead to any influx of SVZ-derived S100β-negative transit-amplifying cells (each dot is one cluster; plot shows sum of three brain sections \[n = 3 mice\]). Error bars in (**d--f, h--i**) represent maximum and minimum values. Scale bar (**c**): 500 μm; LV: lateral ventricle.](elife-59733-fig6){#fig6} Cortical astrocytes can be isolated from an injury site and generate neurospheres in vitro ([@bib26]; [@bib4]; [@bib29]). Given this intrinsic capacity to activate neurogenic properties, we therefore wondered whether it might instead be the environment of the cortex that prevents these astrocytes from completing their neurogenic program in vivo. To gauge the neurogenic permissiveness of the striatal and cortical environments, we isolated neural progenitor cells by sorting tdTomato^+^ cells from the SVZ and DG of Cx30-CreER; tdTomato mice (with or without *Rbpj* deletion) 3--6 days after tamoxifen administration ([Supplementary file 3](#supp3){ref-type="supplementary-material"}). These cells were then immediately grafted into the striatum or cortex of littermate mice ([Figure 5l](#fig5){ref-type="fig"}), to see how many of the grafted cells would form neuroblasts and neurons. When the recipient mice were sacrificed and analyzed 4 weeks later, we found that more of the transplanted cells had developed into Dcx^+^ neuroblasts ([Figure 5m](#fig5){ref-type="fig"}) and NeuN^+^ neurons ([Figure 5n](#fig5){ref-type="fig"}) in the striatum than in the cortex (Dcx: striatum 52 ± 21%, cortex 20 ± 22%, mean ± S.D.; NeuN: striatum 10 ± 9%, cortex 2 ± 3%). This suggested that the cortex has an environment less permissive to neurogenesis than the striatum. Such a hostile environment may help explain why *Rbpj*-deficient astrocytes in the cortex fail to complete the neurogenic program that they initiate. Although we focused our analysis on the somatosensory cortex, our immunohistochemical staining of Ascl1 ([Figure 5b](#fig5){ref-type="fig"}) suggests that an aborted neurogenic program may occur throughout the entire brain in response to *Rbpj* deletion. Stalled neurogenic astrocytes in the striatum can resume neurogenesis if exposed to EGF {#s2-7} --------------------------------------------------------------------------------------- Although *Rbpj* deletion does trigger neurogenesis by astrocytes in the striatum, this process is most active in the medial striatum ([Figure 1a](#fig1){ref-type="fig"}). This uneven distribution suggests that in addition to Notch signaling, other mechanisms regulate astrocyte neurogenesis. We wanted to know if our RNA sequencing datasets could help us learn why many striatal astrocytes fail to complete neurogenesis. We noted that, after *Rbpj* deletion, it takes approximately 3--4 weeks until the first striatal astrocytes enter transit-amplifying divisions ([Figure 2c](#fig2){ref-type="fig"}). Yet, many cells isolated even 8 weeks after *Rbpj* deletion remained as astrocytes that seemed to have halted their development immediately prior to the transit-amplifying cell stage ([Figure 2c](#fig2){ref-type="fig"}). We asked whether stalled striatal astrocytes could resume their neurogenic program if they were stimulated to enter transit-amplifying divisions. Striatal astrocytes upregulate *Egfr* in response to *Rbpj* deletion ([Figure 3h](#fig3){ref-type="fig"}). We performed a single injection of the mitogen EGF directly into the lateral striatum of Cx30-CreER; *Rbpj*^fl/fl^ mice 7 weeks after tamoxifen administration ([Figure 6a](#fig6){ref-type="fig"}). In *Rbpj*^wt/fl^ control mice, EGF injection on its own was not enough to induce striatal neurogenesis; neither did it induce any neuroblast migration from the SVZ ([Figure 6b,d](#fig6){ref-type="fig"}) or any detectable increase in the amount of SVZ neuroblasts ([Figure 6---figure supplement 1a--c](#fig6s1){ref-type="fig"}). In wild-type mice, EGF did not trigger cell divisions in striatal astrocytes or non-astrocytes ([Figure 6---figure supplement 1d](#fig6s1){ref-type="fig"}). We concluded that EGF injection into the lateral striatum did not perturb SVZ neurogenesis or trigger confounding striatal proliferation. Interestingly, however, EGF injection into the striatum of *Rbpj*^fl/fl^ mice did lead to a doubling in the number of reporter-positive neuroblasts compared to the vehicle-injected contralateral striatum (216 ± 90 \[EGF hemisphere, mean ± S.D.\], 110 ± 61 \[vehicle hemisphere\]; p=0.023 \[paired t-test\]; [Figure 6c--d](#fig6){ref-type="fig"}). This increase was the result of an increased number of astrocytes entering transit-amplifying divisions rather than increased proliferation by the same number of astrocytes: EGF-injected striata contained on average twice as many neuroblast clusters as vehicle-injected striata (21 ± 10 \[EGF hemisphere, mean ±S.D.\], 8 ± 5 \[vehicle hemisphere\]; p=0.049 \[paired t-test\]; [Figure 6e](#fig6){ref-type="fig"}), but cluster size did not differ (p=0.59 \[Mann-Whitney test\]; [Figure 6f](#fig6){ref-type="fig"}). Some animals also showed a dramatic increase in the number of Ascl1^+^ transit-amplifying cell clusters in the EGF-injected striatum ([Figure 6g--h](#fig6){ref-type="fig"}). This increase, however, was less pronounced (p=0.132 \[paired t-test\]) than that of Dcx^+^ cells, possibly because most of the EGF-stimulated astrocytes had already passed the transit-amplifying stage and developed into neuroblasts 2 weeks after the EGF injection. To investigate the local astrocyte origin of these Ascl1^+^ clusters, we used residual S100β protein as a short-term lineage-tracing marker of striatum-generated transit-amplifying cells (see [Figure 2---figure supplement 3d--g](#fig2s3){ref-type="fig"}). We found that S100β protein levels were the same in Ascl1^+^ clusters in the EGF- and vehicle-injected striata ([Figure 6i](#fig6){ref-type="fig"}; p=0.159 \[unpaired t-test\], with a trend toward more S100β^high^ clusters in the EGF-injected striatum). This showed that EGF had caused no influx of S100β-negative cells from the SVZ into the striatum. Our results demonstrate that EGF administration can enable stalled neurogenic astrocytes in the striatum to initiate transit-amplifying divisions and resume neurogenesis. This effect was easily measurable even after a single, localized EGF injection. Yet, striatal neurogenesis was still primarily localized to the medial striatum, suggesting that many stalled astrocytes may require a stronger stimulus than a single injection to re-initiate neurogenesis. Further studies would be needed to tell whether longer and more broadly localized EGF exposure could recruit an even larger proportion of stalled striatal astrocytes. EGF exposure in the somatosensory cortex was not sufficient to make stalled *Rbpj*-deficient astrocytes enter transit-amplifying divisions there ([Figure 6---figure supplement 1e](#fig6s1){ref-type="fig"}). Interestingly, however, the mere act of inserting a thin syringe needle was enough of a stimulus to do so in some stalled cortical astrocytes ([Figure 6---figure supplement 1e](#fig6s1){ref-type="fig"}). We have thoroughly explored the effect of injuries on recruiting halted astrocytes in two separate studies (stab wound in the cortex [@bib39] and stroke in the striatum [@bib24]). Taken together, these results show that it is possible to enhance and modulate the astrocyte neurogenic program through targeted interventions, an observation that should be useful when attempting to recruit astrocytes as a reservoir for new neurons throughout the central nervous system. Discussion {#s3} ========== The brain has almost no capacity to replace lost neurons on its own. Although the SVZ and DG do contain neural stem cells, it is not feasible to use these regions as sources of replacement neurons for the rest of the brain. That is mainly because neurons generated in the SVZ or DG would need to migrate unfeasibly far to reach distant injury sites in the human brain. However, a therapeutic workaround could be to artificially stimulate neurogenesis by cells close to an injury. Astrocytes could be such a reservoir for new neurons because they have an intrinsic neurogenic potential and are very abundant. However, it will be necessary to understand the mechanisms governing astrocyte neurogenesis before the process can be harnessed and tailored to generate specific neuronal subtypes of significant amounts. Here, we used single-cell RNA sequencing to study the transcriptional program of parenchymal astrocytes as they initiate neurogenesis in response to deletion of the Notch-mediating transcription factor *Rbpj*. We find that the neurogenic program of parenchymal astrocytes is almost identical to that of SVZ neural stem cells. Based on the analyses in this study, we propose a model where parenchymal astrocytes are regarded as latent neural stem cells ([Figure 7](#fig7){ref-type="fig"}). {ref-type="fig"} and [Video 1](#video1){ref-type="video"}). Furthermore, S100β protein is found in many parenchymal astrocytes, but not in SVZ stem cells, and lingers at low levels in astrocyte-derived transit-amplifying cells even when the *S100b* gene is no longer expressed (dashed line), acting as a short-term lineage tracing marker. Other features are instead unique to the SVZ stem cells, such as expression of *Gfap, Thbs4, Vim* and *Prom1*, although markers of reactive astrogliosis, such as *Gfap*, are upregulated in neurogenic striatal astrocytes after stroke ([@bib16]). Astrocytes all over the brain initiate the neurogenic program in response to *Rbpj* deletion, but all astrocytes in the somatosensory cortex, and many in the striatum, halt their development prior to entering transit-amplifying divisions. In the striatum, stalled astrocytes can resume neurogenesis if exposed to EGF.](elife-59733-fig7){#fig7} Specifically, we find that initiation of the neurogenic program in astrocytes is dominated by a steady upregulation of genes associated with transcription and translation, as well as a transient wave of metabolism-associated genes. These findings fit well with what is known about neural stem cell activation in the DG and SVZ, where expression levels of genes associated with transcription and translation steadily increase throughout the neurogenic program ([@bib14]; [@bib27]). Our data suggest that parenchymal astrocytes start off at an even lower baseline level of gene expression than neural stem cells, and that they have increased the number of expressed genes \~ 1.4 fold by the time they reach their most stem cell-like state, prior to transit-amplifying divisions. Metabolic gene expression peaked right before striatal astrocytes entered transit-amplifying divisions, suggesting that the rapid burst of cell divisions is the most metabolically demanding step of the neurogenic program. In the DG, exit from quiescence requires increased lipid metabolism ([@bib13]), and once activated stem cells enter transit-amplifying divisions, metabolic genes are downregulated, both in the DG and SVZ ([@bib14]; [@bib27]). This similarity suggests that, like parenchymal astrocytes, neural stem cells in the DG and SVZ experience a metabolic peak prior to entering transit-amplifying divisions. We find that it takes 2--4 weeks for astrocytes to reach this pre-division state. One possible interpretation of this is that the most time-consuming portion of the astrocyte neurogenic program is the initial exit from deep quiescence, as is the case in quiescent muscle stem cells ([@bib28]). Another (and compatible) interpretation is that *Rbpj* protein may remain bound at its target promoters long after the *Rbpj* gene has been deleted, and that the neurogenic program is initiated only when the protein level has fallen below a certain threshold. Such stable transcription factor-DNA interaction is a mechanism by which some transcription factors buffer against fluctuating transcription levels ([@bib36]). One of our main findings is that all astrocytes in the striatum and somatosensory cortex initiate a neurogenic program in response to *Rbpj* deletion, even though only some astrocytes in the striatum and medial cortex manage to enter transit-amplifying divisions. This suggests that *all* astrocytes in the striatum and somatosensory cortex, and perhaps in other regions as well, are latent neural stem cells. We hypothesize that the inability of most astrocytes to enter transit-amplifying divisions is due to a lack of proper environmental signals rather than an intrinsic inability. This hypothesis is based on four observations: 1) A large body of literature has demonstrated that parenchymal astrocytes isolated from the injured mouse cortex can generate neurospheres in vitro ([@bib26]; [@bib4]; [@bib29]), proving that astrocytes have intrinsic neural stem cell potential but lack the proper in vivo environment to realize this potential. 2) We here transplanted neural stem cells to the cortex and striatum and found that fewer developed into neuroblasts and neurons in the cortex ([Figure 5l--n](#fig5){ref-type="fig"}), showing that the cortex has a non-permissive environment. 3) A single injection of EGF into the striatum was enough to make some astrocytes, which had stalled in a pre-division state, enter transit-amplifying divisions ([Figure 6](#fig6){ref-type="fig"}), showing that extracellular signals can bolster and improve the astrocyte neurogenic program. 4) In Cx30-CreER; *Rbpj*^fl/fl^ mice, most astrocyte-derived transit-amplifying cells and neuroblasts appear in the medial striatum, close to the SVZ. It is possible that the nearby SVZ provides a gradient of neurogenic factors into the medial striatum and establishes a more permissive environment there. Such a gradient has indeed been shown to appear if growth factors are infused into the lateral ventricle ([@bib38]; [@bib1]). In this study, we use *Rbpj* deletion as our trigger to induce neurogenesis by astrocytes. We propose that our results apply also to injury-induced astrocyte neurogenesis even in the absence of *Rbpj* deletion, such as that observed in the stroke-injured striatum. Decreased Notch signaling is the mechanism that triggers neurogenesis by striatal astrocytes in stroke-injured mice ([@bib16]). Therefore, the *Rbpj* deletion model is a biologically relevant way to activate the astrocyte neurogenic program without triggering confounding tissue processes that occur in response to injury, such as inflammation and reactive astrogliosis. Indeed, the precision afforded by our *Rbpj* deletion model allowed us to observe here that the astrocyte neurogenic program is not dependent on simultaneous reactive gliosis. Instead, neurogenesis and reactive astrogliosis are likely controlled by two independent, but compatible, transcriptional programs. Is there practical usefulness in designating parenchymal astrocytes as latent neural stem cells? We argue that there is. This nomenclature highlights an aspect of astrocyte biology that exists in parallel to the normal important functions of astrocytes in the healthy brain. Labeling parenchymal astrocytes as latent neural stem cells can help focus research efforts toward activating and fine-tuning the inherent neurogenic capacity of these cells to generate therapeutically useful neuronal subtypes. It is likely that astrocytes in different brain regions use different mechanisms to lock their astrocyte identity in place. Our study demonstrates that it is feasible to identify such mechanisms and seek to target them for enhancing neurogenesis by astrocytes throughout the central nervous system. Materials and methods {#s4} ===================== ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Reagent type\ Designation Source or\ Identifiers Additional\ (species) or\ reference information resource ----------------------------------------------------------- ------------------------------------------------------- --------------------------------------------------------------- --------------------------------------------------------------------------------------------- --------------------------------------------- Strain, strain background (*Mus musculus,* C57BL/6; M, F) Cx30-CreER PMID:[17823970](https://www.ncbi.nlm.nih.gov/pubmed/17823970) Strain, strain background (*Mus musculus,* C57BL/6; M, F) R26-tdTomato (Ai14) PMID:[25741722](https://www.ncbi.nlm.nih.gov/pubmed/25741722) Strain, strain background (*Mus musculus,* C57BL/6; M, F) R26-YFP PMID:[11299042](https://www.ncbi.nlm.nih.gov/pubmed/11299042) Strain, strain background (*Mus musculus,* C57BL/6; M, F) *Rbpj*(fl/fl) PMID:[11967543](https://www.ncbi.nlm.nih.gov/pubmed/11967543) Antibody anti-Ascl1 (Rabbit polyclonal) Cosmo Bio Product No: CAC-SK-T01-003 (RRID:[AB_10709354](https://scicrunch.org/resolver/AB_10709354)) Used at 1:2000 Antibody anti-Dcx (Goat polyclonal) Santa Cruz Biotechnology Product No: sc-8066 (RRID:[AB_2088494](https://scicrunch.org/resolver/AB_2088494)) Used at 1:500 Antibody anti-GFP (Chicken polyclonal) Aves Labs RRID:[AB_2307313](https://scicrunch.org/resolver/AB_2307313) Used at 1:2000 Antibody anti-Ki67 (Rat monoclonal) eBioscience Catalog No: SolA15 (RRID:[AB_10853185](https://scicrunch.org/resolver/AB_10853185)) Used at 1:2000 Antibody anti-S100 (Rabbit polyclonal) DAKO Catalog No: GA50461-2 (RRID:[AB_2811056](https://scicrunch.org/resolver/AB_2811056)) Used at 1:200 (Directly conjugated to A647) Peptide, recombinant protein Epidermal growth factor Sigma-Aldrich Catalog No: E4127 Recombinant DNA reagent AAV8-GFAP(0.7)-iCre-WPRE Vector Biolabs Catalog No: VB4887 Commercial assay or kit Papain Dissociation System Worthington Catalog No: LK003160 Commercial assay or kit Adult Brain Dissociation Kit Miltenyi Biotec Catalog No: 130-107-677 Commercial assay or kit Magnetic MACS Multistand Miltenyi Biotec Catalog No: 130-042-303 Commercial assay or kit MACS Large Cell Column Miltenyi Biotec Catalog No: 130-042-202 Commercial assay or kit Myelin Removal Beads II Miltenyi Biotec Catalog No: 130-096-731 Commercial assay or kit AMPure XT beads Beckman Coulter Catalog No: A63881 Commercial assay or kit Nextera XT dual indexes Illumina Commercial assay or kit Chromium Single Cell 3' Library and Gel Bead Kit (v3) 10X Genomics Catalog No: CG000183 Chemical compound, drug Percoll GE Healthcare Catalog No: 17-0891-01 Chemical compound, drug EdU Thermo Fisher Catalog No: C10424 Chemical compound, drug LIVE/DEAD Blue Dead Cell Stain Kit Thermo Fisher Catalog No: L23105 Software, algorithm R R Foundation For Statistical Computing Other Agilent Bioanalyzer Agilent Other BD Influx FACS machine BD Other 36-gauge beveled needle World Precision Instruments Catalog No: NF36BV-2 Other NovaSeq 6000 Illumina Other Illumina HiSeq 2500 Illumina ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Animals {#s4-1} ------- Cx30-CreER ([@bib30]), R26-tdTomato (Ai14) ([@bib15]), R26-YFP ([@bib31]), *Rbpj*^fl/fl^[@bib34] and wild-type mice were of the C57BL/6 strain and were \>2 months old. Genetic recombination was induced by intraperitoneal tamoxifen injections for five consecutive days (Sigma-Aldrich, St. Louis, MO; 20 mg/ml in 1:9 ethanol:corn oil; 2 mg/injection). Time points were counted from the last day of injection. Mice with no *Rbpj* deletion (for isolation of ground state astrocytes) were sacrificed one day after a three-day tamoxifen regimen. For EdU administration ([Figure 2---figure supplement 3c](#fig2s3){ref-type="fig"}), EdU (Thermo Fisher, Waltham, MA) was administered through the drinking water (0.75 g/l EdU in water containing 1% sucrose) for two weeks leading up to the animals' death. Mice were housed in standard conditions with 12/12 hr light/dark cycles and free access to food and water. Experimental procedures were approved by the Stockholms Norra Djurförsöksetiska Nämnd (Permit reference numbers N571-11 and N155-16). Immunohistochemistry {#s4-2} -------------------- Immunohistochemical staining was performed as described previously ([@bib16]). We used antibodies against Ascl1 (Cosmo Bio, Tokyo, Japan; rabbit, 1:2000), detected with or without ABC kit \[Vector Laboratories, Burlingame, CA\] and TSA \[PerkinElmer, Waltham, MA\]), Dcx (Santa Cruz Biotechnology, Dallas, TX; goat, 1:500), GFP/YFP (Aves Labs, Davis, CA, USA; chicken, 1:2000), Ki67 (eBioscience, San Diego, CA, USA; rat, 1:2000), S100 (DAKO, Glostrup, Denmark; rabbit, 1:200, directly conjugated to A647 using Alexa Fluor Antibody Labeling Kit \[Thermo Fisher\]). EdU was detected using Click-iT EdU Alexa Fluor 647 Imaging Kit (Thermo Fisher). Library preparation and sequencing for the Cx30-CreER dataset {#s4-3} ------------------------------------------------------------- One mouse brain was used for each time point, for a total of 4 brains. From each brain, a \~ 1 mm thick coronal slice was isolated, spanning rostrocaudal levels Bregma −0.2 to +1.0 ([Figure 2---figure supplement 1a--c](#fig2s1){ref-type="fig"}). From this section, the SVZ was isolated and discarded. The striatum and cortex were then isolated from both hemispheres. Tissue was cut into fine pieces and incubated with papain solution (20 units/ml) containing L-cysteine (1 mM), EDTA (0.5 mM) and DNase (2000 units/ml) (Papain Dissociation System \[LK003160\], Worthington, Lakewood, NJ), dissolved in EBSS (Thermo Fisher), at 37°C for 30 min, with occasional agitation. Then, the tissue was triturated with smaller and smaller pipet tips and filtered through a 70 μm cell strainer (BD, Franklin Lakes, NJ). After a 10 min centrifugation at 200\*g in a swing-bucket rotor at 4°C, supernatant was removed and cells were resuspended in 3 ml sterile-filtered washing buffer (Dulbecco's PBS containing sodium pyruvate, streptomycin sulfate, kanamycin monosulfate, glucose and calcium chloride; Sigma-Aldrich, D4031) containing 0.5% bovine serum albumin (BSA; Sigma-Aldrich, A9418). To remove debris, we then used gradient centrifugation and myelin removal beads in the following way. The cell suspension was carefully layered on top of 4 ml of 90% Percoll (GE Healthcare, Chicago, IL; 17-0891-01, diluted in 1.5 M sterile-filtered NaCl) in a 15 ml Falcon tube and centrifuged at 200\*g for 15 min in a swing-bucket rotor at 4°C. After removing the small top phase, the large bottom phase (including the white interphase) was resuspended in 17.5 ml washing buffer in a 50 ml Falcon tube and repeatedly aspirated with a Pipette Boy. This cell suspension was then centrifuged at 200\*g for 10 min at 4°C. The pellet was set aside, and to maximize cell yield the supernatant was again repeatedly aspirated and centrifuged. Then, the two pooled cell pellets were resuspended in 1 ml sterile-filtered MACS buffer (5% BSA and 2 mM EDTA in PBS). The cell suspension was incubated with 80 μl myelin removal beads II (Miltenyi Biotec, 130-096-731) for 15 min. Meanwhile, a MACS Large Cell Column (Miltenyi Biotec, Bergisch Gladbach, Germany; 130-042-202) was placed in a Magnetic MACS Multistand (Miltenyi Biotec) and activated by allowing 500 μl of MACS buffer to drop through. The cell suspension was passed through the MACS column and the flow-through was collected in a FACS tube pre-coated with 1% sterile-filtered BSA. MACS buffer (500 μl) was then passed through the column twice to increase cell yield. The cell suspension was then incubated with LIVE/DEAD Blue Dead Cell Stain Kit (Thermo Fisher, L23105) for 30 min. Immediately afterwards, an a BD Influx FACS machine (86 μm nozzle) was used to sort live tdTomato^+^ single cells into 96-well skirted PCR plates (Thermo Fisher) containing lysis buffer (containing dNTP \[2.5 mM\], oligo-dT \[2.5 mM\], RNAse Inhibitor \[Takara Bio, Kusatsu, Japan; 1:40\] and ERCC \[Ambion, TX; 1:4,000,000\]) with the machine set on \'Index Sort\' mode to record cell size information and fluorescence parameters used. Plates were immediately frozen on dry ice and stored at −80°C until processing. For preparation of single-cell cDNA libraries, the plates were thawed at 72°C for 4 min and immediately placed on ice. A reverse transcription of mRNA was performed and the resulting cDNA libraries were immediately subject to amplification for 19 cycles according to the Smart-Seq2 protocol ([@bib22]). The final libraries were subjected to bead purification (AMPure, Beckman Coulter, Brea, CA; 0.6:1 bead-to-sample ratio) to remove excess primers and primer dimers. Library quality was checked using an Agilent Bioanalyzer and DNA High Sensitivity microfluidics chips. After determining that libraries were of sufficiently high quality for downstream sequencing, 0.5--1.5 ng of cDNA from each single-cell library was used for tagmentation reactions with a custom Tn5 enzyme/oligo (comparable to the Nextera XT protocol) ([@bib23]). Nextera XT dual indexes were used (96 index kit) and each library was subjected to an additional 10 cycles of amplification. The final products were again subjected to bead cleaning to remove excess primers and monitored for successful amplification by random sampling of different wells and visualization of library size and quality on the Bioanalyzer. Successful tagmentation reactions were pooled as individual 96-well plates and sequenced using an Illumina HiSeq 2500 machine with 2\*125 bp sequencing on High Output mode. Read mapping, quality control and computational analyses for the Cx30-CreER dataset {#s4-4} ----------------------------------------------------------------------------------- ### Read mapping and quality control for striatal cells (Cx30-CreER dataset) {#s4-4-1} Raw reads were processed with Nesoni clip v. 0.132, removing sequencing adapters and bases with a per-base quality value lower than 20 ('-quality 20') and reads shorter than 64 nucleotides ('-length 64'). Transcript abundance was quantified using Salmon v. 0.8.2 ([@bib20]) by pseudo-aligning the filtered reads against the mouse transcriptome (Ensemble release E90; tdTomato sequence was added to the genome) using the cDNA labels combined with the 96 ERCC spike-in controls (Ambion). Median assignment rate was 61% (±10% S.D.). Gene-level summarization was calculated using tximport v. 1.4.0. Cells were sequenced to a median depth of 9\*10^5^ (±4\*10^5^ s.D.) reads per cell. Samples were excluded if they had \<1500 unique transcripts detected or had a low mapping rate (\<20%) or had shown poor library quality when a few samples were analyzed on the BioAnalyzer. Among the remaining cells, we detected a median of 2280 (±883 S.D.) unique transcripts per cell, consistent with previous studies ([@bib7]; [@bib40]). ### Pseudotime estimation using monocle (Cx30-CreER dataset) {#s4-4-2} Monocle (v. 1.4.0) was used to generate a pseudotime axis ([Figure 2c](#fig2){ref-type="fig"}, S5a): Briefly, we first used SCDE (v. 1.99.1) ([@bib12]) to generate a list of differentially expressed genes between ground-state and 8 week *Rbpj* deletion astrocytes (genes detected in \>10% of cells). Differentially expressed genes present in the GO term Neurogenesis (GO:0022008) were used as input to Monocle. To generate more robust pseudotime values for the cells, we performed the Monocle analysis three times, each time including differentially expressed genes of a different significance level (Z \> 1.96, 2.57 or 3.29). Each cell's average pseudotime value was used as the final pseudotime value for making the 'beeswarm plots' ([Figure 2c](#fig2){ref-type="fig"}). Beeswarm plots were generated using the Beeswarm package (v. 0.2.3). ### Monocle's gene clustering algorithm (Cx30-CreER dataset) {#s4-4-3} For investigating how groups of genes change as neurogenesis by astrocytes progresses ([Figure 2e--f](#fig2){ref-type="fig"}, S5b-c), Monocle's gene clustering algorithm was used to group genes with similar expression pattern along pseudotime. First, hierarchical clustering (using hclust \[method = ward.d2\]) and correlation heatmap plotting of striatal cells (using genes present in the GO term Neurogenesis, and differentially expressed between astrocytes at ground state and 8 weeks after *Rbpj* deletion) revealed five distinct cell groups ([Figure 2---figure supplement 2a](#fig2s2){ref-type="fig"}). These groups were sequentially distributed along the neurogenic trajectory in pseudotime ([Figure 2---figure supplement 2b](#fig2s2){ref-type="fig"}). We performed differential expression analysis (SCDE) for each of the five groups versus the other four groups to generate five lists of genes particularly highly expressed by each group. The combined gene list was used as input to the gene clustering algorithm. ### Gene ontology analysis (Cx30-CreER dataset) {#s4-4-4} For gene ontology (GO) analysis, we used DAVID v. 6.8 ([@bib11]) and GSAn ([@bib2]). To analyze which subcellular compartments genes belonged to ([Figure 2e](#fig2){ref-type="fig"}, S4a), DAVID's GOTERM_CC_FAT option was used. For all other analyses of gene function, the GOTERM_BP_FAT option was used. ### Analysis of SVZ cells from Llorens-Bobadilla et al. (Cx30-CreER dataset) {#s4-4-5} To compare our Cx30-CreER dataset with that from Llorens-Bobadilla et al., all samples were first mapped together against the mm10 reference transcriptome including the ERCCs using Salmon version 0.8.2. Gene-level TPMs were summarized from the Salmon output files with tximport R package version 1.4.0. ### Assessment of number of genes detected in ground-state astrocytes versus *Rbpj*-deficient astrocytes (Cx30-CreER dataset) {#s4-4-6} Ground-state astrocytes from the striatum were compared with those from the pre-division stage. Genes with TPM values \> 10 were defined as being expressed; the mean expression values from each group's cells were compared using an unpaired t-test. Use of cell sorter forward scatter values as a proxy for cell size (Cx30-CreER dataset) {#s4-5} --------------------------------------------------------------------------------------- For each sorted cell, a ratio was made between its forward-scatter value and the average forward-scatter value of that sort's tdTomato-negative cell population. Sample preparation for the AAV-Cre dataset {#s4-6} ------------------------------------------ Thirteen *Rbpj*^fl/fl^ mice were subjected to intrastriatal injection of AAV8-GFAP(0.7)-iCre-WPRE virus (VB4887; Vector Biolabs, Malvern, PA, USA) using coordinates in relation to bregma: 1.2 mm anterior, 2.5 mm lateral, 3 mm deep). Five weeks later, mice were sacrificed and the brain collected for isolation of single cells. We used a brain slicer to produce 1.5 mm thick sections spanning the rostrocaudal region transduced by the virus. Prior to isolating striata for tissue dissociation, we inspected fluorescent labeling at the microscope to ensure that only striatal cells (and not SVZ cells) had been transduced. At this stage, two mice were excluded because they had recombined cells in the SVZ. For the remaining 11 mice, striata were microdissected from each slice following the same approach outlined above (sample preparation for the Cx30-CreER experiment), pooled as one sample, and digested using Miltenyi's Adult Brain Dissociation kit. Single cells were finally FAC-sorted based on tdTomato signal as described above (i.e. for the Cx30-CreER dataset). Library preparation was performed using Chromium Single Cell 3' Library and Gel Bead Kit (v3, 10X Genomics, Pleasanton, CA) according to the manufacturer's instructions. Libraries were sequenced on a NovaSeq6000 S1 flowcell using a custom read setup: 28 nt (read 1), eight nt (i7 index), 166 nt (read 2). Pre-processing of the AAV-Cre dataset {#s4-7} ------------------------------------- Raw reads were obtained from the sequencer and aligned to the mouse genome (mm10) supplemented with tdTomato DNA sequence. We used cellranger v2.0.1 for pre-processing of raw reads followed by Seurat R package (v2.3.4) ([@bib32]) for downstream analysis of mapped data. Aligned transcripts were normalized for sequencing depth, log-transformed, and scaled using Seurat's default parameters. We excluded genes expressed in less than 3 cells, and cells with mitochondrial content exceeding 25% (n = 418). Next, we ran principal component analysis (PCA) on 2359 highly variable genes and selected the first 10 dimensions for non-linear dimensionality reduction (UMAP) and clustering. The analysis allowed us to identify distinct cell types composing the dataset ([Figure 1---figure supplement 1](#fig1s1){ref-type="fig"}). We removed contaminating cells lacking expression of tdTomato (e.g. microglia, n = 87), and cells expressing tdTomato transcripts but not involved in the astroglial neurogenic program (i.e. cells belonging to the oligodendrocyte lineage, n = 1,438). After filtering, we retained 1380 cells for further processing. Clustering of astrocytes and their progeny using the AAV-Cre dataset {#s4-8} -------------------------------------------------------------------- We included the top 3249 highly variable genes for running PCA and UMAP (using the first 20 PCs) on the filtered dataset. We next performed clustering based on the shared nearest neighbour algorithm (Seurat, v2.3.4) to identify distinct subpopulations within the sample ([Figure 1](#fig1){ref-type="fig"}). We next, ran pairwise comparisons using Wilcoxon's test to determine cluster-specific transcriptional profiles. Clustering and differential expression analyses allowed us to record the presence of two astrocyte clusters characterized by expression of *Gjb6* (Astrocyte Cluster 1) and upregulation of *Ascl1* (Astrocyte Cluster 2); a cluster encompassing transit-amplifying cells enriched in *Mki67* transcripts; and two clusters of neuroblasts expressing *Dcx* and *Robo2*, as well as *Foxp2* and *Nav3*. For analyzing differential expression along pseudotime of the AAV-Cre dataset ([Figure 2i](#fig2){ref-type="fig"}), Monocle (v. 2.12.0) was used. Integration with published datasets from SVZ and DG (AAV-Cre dataset) {#s4-9} --------------------------------------------------------------------- We aimed at comparing the neurogenic program initiated by striatal astrocytes with that recorded in the neurogenic niches of the SVZ and DG. For this purpose, we compared the transcriptional profiles of cells contained in the current AAV-Cre dataset to that of SVZ ([@bib41]) (accession code: GSE111527) and DG ([@bib9]) (accession code: GSE95315) neurogenesis. From the complete SVZ dataset, we only considered samples collected from wild-type female animals (an002, an003_F, and an003_L). Both SVZ and DG datasets were processed separately, in order to identify distinct cell types and retain only clusters implicated in the neurogenic program. Specifically, we ran PCA on highly variable genes (n = 6497 for SVZ and n = 2224 for DG), followed by tSNE and clustering performed on the top 15 PCs, and selected clusters of cells based on expression of classic neurogenesis-related markers (e.g. *Aqp4, Thbs4, Sox4, Top2a, Dcx*) for downstream analysis. Filtered datasets were integrated with striatal data by means of canonical correlation analysis (CCA, Seurat) considering the top 2000 HVGs merged across samples. Datasets were aligned using the first 13 dimensions of CCA and visualized in UMAP space. To investigate the relative distance of cell types across samples we ran hierarchical clustering based on a distance matrix constructed in the aligned space (i.e. using CCA dimensions), followed by differential expression analysis that allowed insight into shared and unique transcriptional programs active in the different neurogenic niches. Finally, we ran correlation analysis on the average expression of each gene to determine similarities in cell-specific transcriptional profiles across brain regions (data were visualized as scatterplots using ggplot 3.3.0). Cell transplantation {#s4-10} -------------------- Donor mice (Cx30-CreER; R26-tdTomato, either with or without inducible *Rbpj* deletion, see [Supplementary file 3](#supp3){ref-type="supplementary-material"}), were sacrificed 3--6 days after intraperitoneal tamoxifen administration. The SVZ and DG were dissected and cells isolated using the same protocol used to isolate cells for the Cx30-CreER dataset. Live tdTomato^+^ cells were sorted using an 86 µm nozzle into a FACS tube pre-coated with 1% BSA, containing 250 µl wash buffer (see cell isolation protocol for the Cx30-CreER dataset). Cell suspensions were kept on ice at all times and chilled during cell sorting. After sorting, cell suspensions were transferred to pre-coated microcentrifuge tubes and centrifuged at 200\*g for 10 min in a swing-bucket rotor at 4°C. The swing-bucket rotor was important as it enabled the small cell pellet to collect at the bottom of the tube. Supernatant was removed carefully. Tubes were then briefly centrifuged in a tabletop centrifuge to bring down a few extra microliters of fluid from the walls of the tube. This amount of liquid was enough to resuspend the cell solutions, which was done by carefully flicking the tubes. If more volume needed to be added, wash buffer was used. Cell suspension was transferred to 0.2 ml tubes, placed on ice and immediately transplanted to the brains of littermate mice. One microliter of this solution was injected into each of the following coordinates (relation to bregma): Striatum: 0.5 mm anterior, 2.0 mm lateral, 3.0 mm deep. Cortex: 0.5 mm anterior, 2.5 mm lateral, 1.0 mm deep. The entire protocol took \~16--18 hr to perform from beginning to end. During the analysis of transplantation-recipient mice, mice were excluded if \<20 transplanted cells were found. EGF injection {#s4-11} ------------- In Cx30-CreER; *Rbpj*^fl/fl^ and *Rbpj*^+/fl^ mice, intrastriatal EGF injection was performed seven weeks after tamoxifen administration. EGF (Sigma-Aldrich E4127, 200 ng/μl) was dissolved in PBS containing 0.1% bovine serum albumin (BSA). Four Cx30-CreER; *Rbpj*^fl/fl^ mice and four Cx30-CreER; *Rbpj*^fl/wt^ control mice were anesthetized with isoflurane (4% at 400 ml/min flow rate to induce anesthesia, followed by \~2% at 200 ml/min). Then, 2 μl of EGF solution was delivered into the lateral striatum through a single injection (0.7 mm anterior, 2.4 mm lateral of bregma; 3 mm deep of dura mater) using a 36-gauge beveled needle (World Precision Instruments, Sarasota, FL, USA). A vehicle solution consisting of 0.1% BSA in PBS was injected into the contralateral striatum of the same mice. Mice were sacrificed and analyzed 2 weeks after EGF injection. For estimating whether EGF induces proliferation in wild-type mice ([Figure 6---figure supplement 1d](#fig6s1){ref-type="fig"}), mice were sacrificed 48 hr after EGF injection. Evaluation of EGF's effect on cortical astrocytes was evaluated as follows. Animals were first injected with 0.3 μl of AAV-GFAP-Cre into the somatosensory cortex to delete *Rbpj* locally (1.0 mm anterior, 1.5 mm lateral of bregma. Liquid was injected at both 1.0 and 0.5 mm deep of dura mater). Both left and right hemispheres were injected with the virus. Four weeks later, 2\*0.3 μl of EGF solution was delivered into one hemisphere using the same injection coordinates. A vehicle solution consisting of 0.1% BSA in PBS was injected into the other hemisphere of the same mouse. Mice were sacrificed and analyzed 2, 3 and 4 weeks after EGF injection. Evaluation of the effect of EGF on the number of SVZ neuroblasts {#s4-12} ---------------------------------------------------------------- To estimate the number of neuroblasts in the SVZ ([Figure 6---figure supplement 1](#fig6s1){ref-type="fig"}), we performed an immunohistochemical staining against Dcx and used Dcx signal intensity as a proxy for cell numbers. We took tiled images of the SVZ in 3--5 brain sections per mouse using a Zeiss LSM 700 confocal microscope, using the same microscope settings for the left and right SVZ. CellProfiler v. 3.0.0 ([@bib5]) was used to identify Dcx^+^ cells or cell clusters and calculate total signal intensity (cell area\*mean intensity) on the EGF- and vehicle-injected hemispheres in all images. Assessment of S100β protein levels in striatal Ascl1^+^ cells for use as a short-term lineage tracing marker {#s4-13} ------------------------------------------------------------------------------------------------------------ To detect residual S100β protein levels in striatal Ascl1^+^ cells, we took images of all Ascl1^+^ cells found in the striatum and SVZ of five brain sections of one mouse, adjusting imaging depth for each cell and using the same microscope settings for every cell. Then, we measured Ascl1 and S100β signal intensity in each cell using ImageJ's Measure function ([@bib25]). Calculation of signaling entropy to estimate differentiation potency {#s4-14} -------------------------------------------------------------------- We used LandSCENT v. 0.99.3 ([@bib6]) to calculate signaling entropy on the single-cell level. Because the LandSCENT package only contains a protein-protein interaction network for human genes, we first converted our dataset's mouse gene names into their human orthologous counterparts using biomaRt. Only genes that were expressed (TPM ≥10) in ≥10% of cells were included in the analysis. Funding Information =================== This paper was supported by the following grants: - http://dx.doi.org/10.13039/501100001862Svenska Forskningsrådet Formas to Jonas Frisén. - http://dx.doi.org/10.13039/501100002794Cancerfonden to Jonas Frisén. - http://dx.doi.org/10.13039/501100001729Stiftelsen förStrategisk Forskning to Jonas Frisén. - http://dx.doi.org/10.13039/100010663H2020 European Research Council ERC-2015-AdG - 695096 to Jonas Frisén. - http://dx.doi.org/10.13039/501100004063Knut och Alice Wallenbergs Stiftelse to Jonas Frisén. - http://dx.doi.org/10.13039/100007464Torsten Söderbergs Stiftelse to Jonas Frisén. We want to thank Nigel Kee and Joanna Hård for valuable discussions, and Michael Ratz for help with preparing libraries for the AAV-Cre dataset. We thank Sarantis Giatrellis and Marcelo Toro for flow cytometry. This study was supported by the Swedish Research Council, the Swedish Cancer Society, SSF, the ERC, the Knut and Alice Wallenberg Foundation and Torsten Söderberg Foundation. Additional information {#s5} ====================== No competing interests declared. Conceptualization, Data curation, Software, Formal analysis, Supervision, Validation, Investigation, Visualization, Methodology, Writing - original draft, Project administration, Writing - review and editing, Designed the study, performed experiments, analyzed results, performed computational analyses of the Cx30-CreER dataset and prepared the manuscript. Data curation, Software, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review and editing, Performed experiments, analyzed results, interpreted data, took part in experimental design and contributed to editing the manuscript. Performed the computational analyses of the AAV-Cre dataset. Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - review and editing, Performed experiments, analyzed results, interpreted data, took part in experimental design and contributed to editing the manuscript. Data curation, Formal analysis, Investigation, Methodology, Prepared sequencing libraries for the Cx30-CreER dataset. Software, Mapped sequencing reads. Software, Mapped sequencing reads. Supervision, Supervised CT-L and MB-S. Conceptualization, Resources, Supervision, Funding acquisition, Methodology, Writing - original draft, Project administration, Writing - review and editing, J.F. performed project design and coordination, interpreted data and prepared the manuscript. Animal experimentation: All animal experimental procedures were approved by the Stockholms Norra Djurförsöksetiska Nämnd (Permit reference numbers N571-11 and N155-16). Additional files {#s6} ================ ###### Raw data for plots. ###### Genes differentially expressed between ground-state and *Rbpj*-deficient astrocytes. Data is shown for both striatum and somatosensory cortex. Astrocytes at the pre-division stage are in their most stem cell-like state. Therefore, genes differentially expressed at this time point represent potential marker genes for the astrocyte stem cell state. ###### Lists of genes characteristic for the four gene clusters in [Figure 2e](#fig2){ref-type="fig"}. Results from a GO analysis (DAVID) is provided for each gene cluster. ###### Details about mice transplanted with neural stem cells ([Figure 6l--n](#fig6){ref-type="fig"}). This list provides information about the mice that were used as transplantation donors (see also Methods). Data availability {#s7} ================= The Cx30-CreER dataset (fastq files and processed expression matrix) has been deposited in ArrayExpress (accession E-MTAB-9268). The AAV-Cre dataset has been deposited in the Gene Expression Omnibus (GEO; accession GSE153916). The following datasets were generated: MagnussonJPFrisénJZamboniMSantopoloGMoldJEBarrientos-SomarribasMTalavera-LopezCAnderssonBr2020Activation of a neural stem cell transcriptional program in parenchymal astrocytesArrayExpressE-MTAB-9268 ZamboniMMagnussonJPFrisénJ2020Transcriptomics analysis of neurogenesis by striatal astrocytes upon Rbpj-K deletionNCBI Gene Expression OmnibusGSE153916 The following previously published datasets were used: Llorens-BobadillaEZhaoSBaserASaiz-CastroGZwadloKMartin-VillalbaA2015Single-Cell Transcriptomics Reveals a Population of Dormant Neural Stem Cells that Become Activated upon Brain InjuryNCBI Gene Expression OmnibusGEO:GSE67833 ZywitzaVMisiosABunatyanLWillnowTERajewskyN2018Single-cell transcriptomics characterizes cell types in the subventricular zone and uncovers molecular defects impairing adult neurogenesis.NCBI Gene Expression OmnibusGEO:GSE111527 HochgernerHZeiselALönnerbergPLinnarssonS2018Conserved properties of dentate gyrus neurogenesis across postnatal development revealed by single-cell RNA sequencingNCBI Gene Expression OmnibusGEO:GSE95753 10.7554/eLife.59733.sa1 Decision letter Gleeson Joseph G Reviewing Editor Howard Hughes Medical Institute, The Rockefeller University United States Jiao Jianwei Reviewer Chinese Academy of Sciences China Jessberger Sebastian Reviewer University of Zurich Switzerland In the interests of transparency, eLife publishes the most substantive revision requests and the accompanying author responses. **Acceptance summary:** The manuscript studies the mechanisms by which specialized astrocytes in distinct anatomic regions, triggered by stoke and decreased notch signaling, initiate a neurogenic program. The two main findings are that: 1.as astrocytes initiate neurogenesis they first become transcriptionally similar to SVZ progenitors; 2. astrocytes that do not progress to a progenitor state can be induced to do so by administration of EGF in vivo. **Decision letter after peer review:** Thank you for submitting your article \"Activation of a neural stem cell transcriptional program in parenchymal astrocytes\" for consideration by *eLife*. Your article has been reviewed by three peer reviewers, and the evaluation has been overseen by Joseph Gleeson as the Reviewing Editor and Marianne Bronner as the Senior Editor. The following individuals involved in review of your submission have agreed to reveal their identity: Jianwei Jiao (Reviewer \#2); Sebastian Jessberger (Reviewer \#3). The reviewers have been given the opportunity to discuss the reviews with one another and the Reviewing Editor has drafted this decision to help you prepare a revised submission. We would like to draw your attention to changes in our revision policy that we have made in response to COVID-19 (https://elifesciences.org/articles/57162). Specifically, we are asking editors to accept without delay manuscripts, like yours, that they judge can stand as *eLife* papers without additional data, even if they feel that they would make the manuscript stronger. Thus the revisions requested below only address clarity and presentation. Summary: The manuscript studies the mechanisms by which specialized astrocytes in distinct anatomic regions, triggered by stoke and decreased notch signaling, initiate a neurogenic program. *Rbpj*, a Notch-mediating transcription factor, is used to modulate Notch signaling with temporal and spatial control. This is a very well executed study that looks at understanding the neurogenic potential of astrocytes in vivo. The authors use scRNAseq to profile genetically traceable astrocytes that have been \"induced\" to reprogram into neurons. The authors show that deletion of *Rbpj* induces molecular programs that resemble expression profiles of endogenous, neurogenic NSCs (from the SVZ) when *Rbpj* is deleted in striatal areas (more so in the medial parts of the striatum) that are permissive for neurogenesis. In contrast, they find that cortical astrocytes upon *Rbpj* deletion initially enter a NSC-like program but become stalled before differentiating into a transit-amplifying state. Two distinct labeling methods are used and the work is very extensive in its characterization. There are two main findings: 1. That as astrocytes initiate neurogenesis they first become transcriptionally similar to SVZ progenitors; 2. That astrocytes that do not progress to a progenitor state can be induced to do so by administration of EGF (in vivo). Essential revisions: -- Can the authors provide a better molecular definition of the astrocyte-derived progenitors. It is clear that they cluster closer to SVZ progenitors, but what are their core genetic signatures (I imagine they will be 30-40 genes)? -- In the induction (by EGF) experiment, how many astrocytes can now enter the trans-amplifying progenitor stage? Is this a tissue-level effect? What happens to other cells around the astrocytes in response to EGF. -- The serial numbers in some figure legends are confused and misleading. The authors should consider to put the numbers in front of each sentence rather than at the end of sentence and keep them in series. -- The description of these figures should be short and clear, which will be easier to read. I suggest that some legend details are better to write in the main text. -- Figure 5C seems not the regions labeled in B. The signal pattern is different. -- For Figure 1A, authors need to provide some details about how they analyze DCX+ signal and the standard they used to represent DCX+ with red dots in the Materials and methods. -- Of course, it would be interesting to see if also cortical astrocytes can be induced to overcome a pre-TAP roadblock by infusion of EGF. This somewhat obvious experiment is missing -- at the same time it is not absolutely critical to support the main conclusions of the data. 10.7554/eLife.59733.sa2 Author response > Essential revisions: > > -- Can the authors provide a better molecular definition of the astrocyte-derived progenitors. It is clear that they cluster closer to SVZ progenitors, but what are their core genetic signatures (I imagine they will be 30-40 genes)? We thank the reviewers for the great suggestion of providing a more detailed molecular definition of striatal astrocytes in their stem cell-like state. We now include a list of all genes differentially expressed between striatal astrocytes at ground state versus their stem cell-like pre-division state. This list is included as a tab in Supplementary file 1 and is referred to in the main text (subsection "Parenchymal astrocytes are located upstream of a neural stem cell state and acquire a transcriptional profile of neural stem cells upon their activation"). This gene list provides a detailed view of which genes have been both up- and downregulated compared to ground state astrocytes, which may provide both a better understanding for the astrocyte neurogenic program as well as putative marker genes for the astrocyte stem cell state. For example, one conspicuous group of genes that emerge as highly specific to the astrocytes' stem cell state are multiple paralogs of the serine-protease inhibitor Serpina3 (Serpina3c, Serpina3f, Serpina3k, Serpina3m, Serpina3n). > -- In the induction (by EGF) experiment, how many astrocytes can now enter the trans-amplifying progenitor stage? The reviewers ask a very interesting question: How many astrocytes can now enter the transit-amplifying stage, i.e. *are now capable* of doing so? Our scRNA-seq data suggest that all astrocytes are *capable* of entering transit-amplifying divisions. Our EGF experiment shows that even a single injection of EGF is enough to double the number of astrocytes that do so. That number is still relatively small: In each brain section analyzed, we find evidence that on the order of tens of striatal astrocytes per brain section have entered transit-amplifying divisions at the time point of our analysis (Ascl1+ clusters plus Dcx+ clusters). There are on the order of 500-1000 striatal tdTomato+ astrocytes per brain section and hemisphere (data not shown). Thus, most *Rbpj*-KO astrocytes had not entered transit-amplifying divisions at the time point of our analysis. However, our EGF administration was highly localized and of very short duration. The reviewers' question can also be interpreted to mean: "If EGF could be administered with optimal concentration, duration and distribution within the striatum, would EGF be capable of recruiting every single stalled *Rbpj*-KO astrocyte into transit-amplifying divisions, or would some astrocytes still be stuck in their stalled state?" Unfortunately, the results from our experiment cannot address this highly interesting question. We have now added a sentence in the manuscript (subsection "Stalled neurogenic astrocytes in the striatum can resume neurogenesis if exposed to EGF") to mention this point. > Is this a tissue-level effect? Our experiment does not provide evidence that EGF induces a tissue-wide re-initiation of astrocyte neurogenesis. We administered EGF very locally using stereotaxic surgery. Even so, the distribution of neurogenic astrocytes remained quite similar as before, with more neurogenic cells in the medial striatum. This suggests that, although EGF manages to push many striatal astrocytes into transit-amplifying divisions, additional mechanisms are likely to regulate this step, and may be identified in the future. We have included a sentence in the manuscript (subsection "Stalled neurogenic astrocytes in the striatum can resume neurogenesis if exposed to EGF") to clarify this point. > What happens to other cells around the astrocytes in response to EGF. We now include a panel in Figure 6---figure supplement 1, and a sentence in the main text (subsection "Stalled neurogenic astrocytes in the striatum can resume neurogenesis if exposed to EGF") to show what happens to both astrocytes and non-astrocytes 48 hours after a striatal EGF injection in wild-type mice. Neither astrocytes nor non-astrocytes show any increased cell division after EGF injection. Figure legends and the Materials and methods have been updated to reflect these additions. > -- The serial numbers in some figure legends are confused and misleading. The authors should consider to put the numbers in front of each sentence rather than at the end of sentence and keep them in series. This has now been done. > -- The description of these figures should be short and clear, which will be easier to read. I suggest that some legend details are better to write in the main text. We have now shortened the figure legends. > -- Figure 5C seems not the regions labeled in B. The signal pattern is different. Thank you for pointing this out. The square in Figure 5B has now been adjusted. > -- For Figure 1A, authors need to provide some details about how they analyze DCX+ signal and the standard they used to represent DCX+ with red dots in the Materials and methods. This is a relevant point. Because Dcx is a microtubule-binding protein, it shows a filamentous staining pattern that can stretch quite far from the cell nucleus. However, the red dots in Figure 1A represent only the nuclei of Dcx+ cells. (By the way, the same is true for all other Dcx quantifications in the study) Dcx+ cells always show a very bright Dcx signal, so there was no need to define signal-to-noise cutoff levels. We have now specified in the figure legend of Figure 1A that red dots represent nuclei of Dcx+ cells. > -- Of course, it would be interesting to see if also cortical astrocytes can be induced to overcome a pre-TAP roadblock by infusion of EGF. This somewhat obvious experiment is missing -- at the same time it is not absolutely critical to support the main conclusions of the data. EGF injection did not show the same effect in the somatosensory cortex as in the striatum. We now include these data as a panel in Figure 6---figure supplement 1 and an explanatory sentence in the main text (subsection "Stalled neurogenic astrocytes in the striatum can resume neurogenesis if exposed to EGF"). Interestingly, however, just inserting a thin syringe needle into the cortex was sufficient to push some cortical *Rbpj*-KO astrocytes into transit-amplifying divisions. We have thoroughly explored the effect of injury in recruiting astrocytes to neurogenesis in two separate studies and found that a stab wound injury in the cortex as well as a striatal stroke promotes this process when Notch signaling is blocked. We now include references to these studies in the aforementioned subsection (Zamboni et al., in press; Santopolo et al., 2020). [^1]: Department of Bioengineering, Stanford University, Stanford, United States. [^2]: The Francis Crick Institute, London, United Kingdom. [^3]: These authors contributed equally to this work. | Mid | [
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Introduction {#s1} ============ CXCR4 is a seven-transmembrane GPCR for the chemokine, CXCL12. Both CXCR4 and CXCL12 are broadly expressed by cells of multiple tissues and play an indispensable role in embryogenesis [@pone.0015397-Murdoch1]. Genetic ablation of CXCR4 or CXCL12 leads to embryonic lethality, as a result of defects in cardiogenesis, vascular development, hematopoiesis, and the CNS [@pone.0015397-Nagasawa1]--[@pone.0015397-Lieberam1]. In adulthood, CXCR4 and CXCL12 have been implicated in pathogenesis of autoimmune diseases and tumor metastasis [@pone.0015397-Nanki1]--[@pone.0015397-Burger1]. However, the precise molecular mechanisms that underlie these diverse physiological and pathological functions remain obscure. Like the majority of GPCRs, CXCR4 contains a highly conserved DRY motif (Asp-Arg-Tyr) located in the second intracellular loop. Extensive studies using rhodopsin and adrenergic receptors as models have established a general paradigm for GPCR activation. It proposes that ligation of GPCR triggers protonation of the Asp residue in the DRY motif, inducing conformational changes of the GPCR and activation of the interacting G proteins [@pone.0015397-Gether1], [@pone.0015397-Meng1]. Mutation of the DRY motif of chemokine receptors prevents ligand-induced activation of the pertussis toxin (PTX)-sensitive Gαi proteins and abolishes generation of second messengers and chemotaxis, indicating a pivotal role of the DRY motif in G-protein mediated signaling [@pone.0015397-Dohlman1]--[@pone.0015397-Gosling1]. Increasing evidence shows GPCRs may also exert biological effects independent of G-protein function. The C-terminal (CT) tail of GPCRs is rich in serines and threonines, and truncation of the tail of several chemokine receptors abrogates ligand-activated receptor phosphorylation, demonstrating that the tail of these receptors is the only phosphorylation target of GPCR kinases (GRKs) [@pone.0015397-Haribabu1], [@pone.0015397-Signoret1]. Phosphorylated GPCR tail binds to β-arrestins, leading to rapid internalization and desensitization of the ligand-activated receptor [@pone.0015397-Krupnick1], [@pone.0015397-Ferguson1]. In addition to mediating receptor internalization, β-arrestins also serve as scaffold proteins, recruiting Src family tyrosine kinases to the phosphorylated GPCRs and consequently activate MAP kinases [@pone.0015397-Lefkowitz1]. Given that GPCRs may deliver signals through the DRY motif and its cytoplasmic tail, it is important to determine whether the DRY motif and the tail of CXCR4 act as independent signaling transduction modules that carry out distinct cellular functions. The functional importance of the CT tail of CXCR4 has been underscored by identification of truncating mutations of CXCR4 in patients with WHIM ([w]{.ul}arts, [h]{.ul}ypogammaglobulinemia, [i]{.ul}mmunodeficiency, and [m]{.ul}yelokathexis) syndrome. WHIM patients carry autosomal dominant mutations in *Cxcr4* that eliminate a part of the serine-rich CT tail [@pone.0015397-Diaz1]. Considerable studies have been conducted using mutant cells from WHIM patients or a variety of cell lines transfected with truncational mutants of CXCR4 to investigate WHIM pathogenesis. While all these data show that deletion of the tail impairs ligand induced receptor internalization, the biochemical and cellular responses, however, seem to be highly variable in these *in vitro* systems, with variations in MAPK activation and chemotaxis [@pone.0015397-Kawai1]--[@pone.0015397-Roland1]. These discrepancies could be attributed to different expression levels of the transgenic CXCR4 as well as to different signaling machinery available in the utilized cell lines. To overcome these problems, we generated mutant mice that express tail-truncated CXCR4 by a "knock-in" approach and used these mice to investigate the developmental, cellular, and biochemical functions of the CXCR4 tail under physiological conditions. Results of the present study reveal that truncation of the CT tail of CXCR4 not only obliterates G-protein independent signaling pathways mediated by tail-associated factors, but also prevents signaling through Gαi, resulting in similar developmental defects as seen in CXCR4-null mice. Results {#s2} ======= Generation of CXCR4-ΔT mice {#s2a} --------------------------- The cytoplasmic tail of CXCR4 contains 16 serine residues which are the putative targets of GRKs. In order to evaluate the precise biological functions mediated by the CT tail of CXCR4 we removed the last 42 amino acids from CXCR4 (aa 318--359), thereby completely eliminating the sequences that confer GRK activity and β-arrestin recruitment ([Fig. 1*A*](#pone-0015397-g001){ref-type="fig"}, mutant CXCR4 is hereafter denoted as ΔT). To ensure a physiological expression of ΔT, we generated "knock-in" mice ([Fig. S1](#pone.0015397.s001){ref-type="supplementary-material"}). Our results showed that ΔT was expressed at an identical level to that of wildtype (WT) CXCR4 on myeloid cells in embryonic day (E) 18.5 fetal liver ([Fig. 1*B*](#pone-0015397-g001){ref-type="fig"}). Furthermore, ΔT bound CXCL12 with an affinity similar to that of WT CXCR4 ([Fig. 1*C*](#pone-0015397-g001){ref-type="fig"}). In this report, we refer to the mutant mice carrying the CXCR4 tail-truncated allele as "ΔT mice". {#pone-0015397-g001} ΔT mutants phenocopy the developmental defects of CXCR4-null mice {#s2b} ----------------------------------------------------------------- Previous reports have shown that CXCR4-null mice exhibit multiple developmental defects and die perinatally [@pone.0015397-Tachibana1], [@pone.0015397-Zou1], [@pone.0015397-Ma1]. Such an embryonic lethal phenotype was not rescued in ΔT mice, however, unlike CXCR4-null mice of which only 50% survived till E17.5 and all with reduced body sizes [@pone.0015397-Zou1], ΔT embryos were present at Mendelian ratios till E18.5 with grossly normal body sizes and morphology (data not shown). To determine to what extent the ΔT mutation affected organogenesis, we examined those organs of which formation was critically dependent on CXCR4. We found that, similar to that observed in CXCR4-null mice, ΔT mice lacked large vessels in the gastrointestinal area ([Fig. 2*A*](#pone-0015397-g002){ref-type="fig"}); had displaced cells of the external granule layer (EGL) in the cerebellum ([Fig. 2*B*](#pone-0015397-g002){ref-type="fig"}); defective B cell genesis ([Fig. 2*C*](#pone-0015397-g002){ref-type="fig"}) and severely impaired bone marrow (BM) myelopoiesis ([Fig. 2*D*](#pone-0015397-g002){ref-type="fig"}). These results together indicate that, although the overall impact on animal development is relatively milder, the ΔT mutation imposes almost identical effects as the CXCR4-null mutation on the development of neural, vascular and hematopoietic systems. {#pone-0015397-g002} Since ΔT mice were embryonic lethal, we generated CXCR4^f/ΔT^ mice and crossed them to transgenic CD19-Cre (B cell specific) and ROSA^ET2-CRE^ mice (tamoxifen induced) to delete the floxed *Cxcr4* allele and conditionally express ΔT in specific lineages of cells. We also established pro-B cell lines by Abelson virus transformation for *in vitro* studies to determine cellular and biochemical functions of the CXCR4 tail. The CXCR4 tail is critical for CXCL12-induced chemotaxis but dispensable for integrin-mediated adhesion {#s2c} ------------------------------------------------------------------------------------------------------- At the late gestation, the primary site of hematopoiesis shifts from the fetal liver (FL) to BM. This process is dependent on CXCR4-mediated migration of hematopoietic stem cells (HSCs) [@pone.0015397-Nagasawa1], [@pone.0015397-Zou1], [@pone.0015397-Ma1]. Since myelopoiesis was relatively normal in the FL but defective in BM of ΔT mice ([Fig. 2*D*](#pone-0015397-g002){ref-type="fig"}), it was conceivable that the ΔT mutation impaired BM homing of hematopoietic cells. To determine whether the CXCR4 tail was required for chemotaxis, we measured the chemotactic response of ΔT pro-B cells toward CXCL12 by a transwell assay. We found that while 15--20% of WT pro-B cells underwent chemotaxis toward CXCL12, less than 2% of ΔT cells migrated under the same condition ([Fig. 3*A*](#pone-0015397-g003){ref-type="fig"}). Abolishment of CXCL12-induced chemotaxis was also found for the FL hematopoietic cells ([Fig. 3*B*](#pone-0015397-g003){ref-type="fig"}), demonstrating that the CXCR4 tail is essential for CXCL12-mediated chemotaxis. {#pone-0015397-g003} We have shown previously that CXCR4 signaling promotes retention of B-cell precursors in the BM [@pone.0015397-Nie1], presumably through VCAM-1/VLA-4 mediated firm adhesion [@pone.0015397-Leuker1], [@pone.0015397-Koni1] and lack of CXCR4 leads to the release of these precursors into the periphery. To examine whether ΔT is still able to facilitate the retention of B-cell precursors in the BM, we analyzed B-cell subsets in peripheral blood and spleen of CD19-Cre- CXCR4^f/ΔT^ (WT), CD19-Cre+ CXCR4^f/ΔT^ (ΔT), and CD19-Cre+ CXCR4^f/f^ mice (CXCR4 null) by flow cytometry. In WT animals, B cell precursors (B220^lo^IgM^−^) were barely detectable in PB ([Fig. S2](#pone.0015397.s002){ref-type="supplementary-material"}). When *Cxcr4* was deleted, a substantial amount of B cell precursors were released from the BM to the periphery ([Fig. 4*A*](#pone-0015397-g004){ref-type="fig"}) and this population was significantly reduced in the in the blood and spleen of ΔT mice, suggesting that ΔT partially restored BM retention ([Fig. 4*A*](#pone-0015397-g004){ref-type="fig"} and [Fig. S2](#pone.0015397.s002){ref-type="supplementary-material"}). {#pone-0015397-g004} To directly examine whether the cytoplasmic tail of CXCR4 was required for triggering integrin-mediated cell adhesion, we decided to test *in vitro* the ability of ΔT to promote B cell adherence to VCAM-1. To exclude the possible interference from CXCR7, the other receptor for CXCL12, we used ΔT, CXCR4-null and WT pro-B cells in a static adhesion assay. These pro-B cells have an identical cell-surface level of VLA-4 (receptor for VCAM-1) but do not express CXCR7 ([Fig. S3](#pone.0015397.s003){ref-type="supplementary-material"}). As shown in [Fig. 4*B*](#pone-0015397-g004){ref-type="fig"}, WT pro-B cells exhibited a 4-fold increase in VCAM-1 adhesion after CXCL12 stimulation, whereas CXCR4-null cells exhibited only basal VCAM-1-binidng activity. Notably, CXCL12 induced adherence of ΔT cells to VCAM-1 was comparable to that of WT ([Fig. 4*B*](#pone-0015397-g004){ref-type="fig"}). These results indicate that tail-truncated CXCR4 is still able to mediate inside-out signaling that activates VLA-4. Interestingly, the adhesion of WT and ΔT mutant pro-B cells to VCAM-1 was not affected by PTX pretreatment ([Fig. S4](#pone.0015397.s004){ref-type="supplementary-material"}), suggesting that activation of VLA-4 was independent of Gαi signals. CT tail deletion abolishes β-arrestin binding and impairs CXCR4 internalization {#s2d} ------------------------------------------------------------------------------- Whether the tail of CXCR4 is the only cytoplasmic domain that recruits β-arrestins remains controversial. Whereas a number of studies have shown that CXCR4 is primarily associated with β-arrestins through its CT tail [@pone.0015397-Mccormick1], [@pone.0015397-Busillo1], others can co-IP tail-truncated CXCR4 with β-arrestins [@pone.0015397-Lagane1], [@pone.0015397-Cheng1] or detect it co-localized with β-arrestins by microscopy [@pone.0015397-Ueda1]. To detect the interaction between β-arrestins and ΔT, we performed a Tango assay [@pone.0015397-Barnea1] in which ligand-induced rapid and transient interaction between CXCR4 and β-arrestins is converted into an accumulative transcriptional response ([Fig. 5*A*](#pone-0015397-g005){ref-type="fig"}). We found that reporter cells expressing WTCXCR4-tTA exhibited an increased luciferase activity after CXCL12 stimulation. In contrast, such CXCL12-induced luciferase gene activation was not detected in ΔTCXCR4-tTA-expressing reporter cells ([Fig. 5*B*](#pone-0015397-g005){ref-type="fig"}). This provides strong evidence that association between CXCR4 and β-arrestin2 absolutely depends on its cytoplasmic tail. {#pone-0015397-g005} Interaction of β-arrestins and the phosphorylated CT tail of GPCRs has been shown to cause agonist-induced receptor internalization, a process considered as an important step in signal desensitization [@pone.0015397-Pierce1]. As shown in [Fig. 5*C*](#pone-0015397-g005){ref-type="fig"}, for pro-B cells, CXCL12 treatment induced internalization of 35--40% of cell surface WT CXCR4 within 5 min, and maximal internalization of 50% was achieved at 60 min. On the contrary, CXCL12 binding to ΔT did not trigger endocytosis at all. Interestingly, FL cells downmodulated surface WT CXCR4 in response to CXCL12 with slower kinetics but stronger magnitude compared to that in pro-B cells. Similar to that seen in mutant pro-B cells, there was no obvious internalization of ΔT in FL cells 30 min after CXCL12 stimulation. However, after 2 h of CXCL12 incubation ∼50% of ΔT had been internalized in FL cells compared to 80% for WT ([Fig. 5*D*](#pone-0015397-g005){ref-type="fig"}). Heterozygous ΔT mutant cells displayed an intermediate level of receptor internalization ([Fig. 5*E*](#pone-0015397-g005){ref-type="fig"}), a phenotype previously seen in cells from some patients with WHIM syndrome [@pone.0015397-Kawai1]. Taken together, our data indicate that the truncation of the CXCR4 tail severely compromises CXCL12-induced receptor internalization in primary cells. The disparity in results observed between FL and pro-B cells could be explained by FL cells expressing CXCR7 that can form heterodimers with CXCR4 [@pone.0015397-Levoye1]. Therefore, internalization of ligand-bound CXCR7 could result in partial downmodulation of heterodimerized ΔT, a process that would not occur in pro-B cells which do not express CXCR7. The CT tail is critical for CXCR4 G-protein-dependent and -independent signaling {#s2e} -------------------------------------------------------------------------------- It remains to be determined whether signals initiated from G proteins and the cytoplasmic tail-associated molecules may act independently or must cross-talk to coordinately regulate proper cellular functions. Therefore, we decided to use our ΔT mutant cells to dissect the role of the CXCR4 tail in the CXCR4 signaling cascade. To obtain sufficient primary ΔT cells for biochemical studies, we generated ROSA^ET2-CRE^ CXCR4-ΔT/F mice in which the floxed *Cxcr4* gene (*Cxcr4^F^*) can be deleted by tamoxifen induced Cre, allowing only ΔT expression in adult tissues (referred to as conditional ΔT mice). Treatment of the conditional ΔT mice with tamoxifen led to nearly complete deletion of the *Cxcr4^F^* allele in splenocytes, and the overall lymphoid and myeloid compartments of the spleen in the mutant and WT mice were comparable (data not shown). To determine whether the ΔT mutation impaired CXCR4 signaling, we first examined activation of ERK and PKB, which have been shown to be downstream of both β-arrestin and G protein signaling pathways [@pone.0015397-Luttrell1]. We found that both ERK and PKB were rapidly and transiently phosphorylated in WT cells after CXCL12 stimulation ([Fig. 6*A*](#pone-0015397-g006){ref-type="fig"}). This signaling event was dependent on Gαi protein activation, as PTX treatment blocked their phosphorylation completely ([Fig. 6*B*](#pone-0015397-g006){ref-type="fig"}). To our surprise, stimulation of ΔT splenocytes with CXCL12 failed to induce measurable levels of phosphorylation of either ERK or PKB, suggesting that the lack of the CXCR4 tail impairs G-protein activation ([Fig. 6*A*](#pone-0015397-g006){ref-type="fig"}). Similar results were also obtained using FL cells and Abelson transformed pro-B cells ([Fig. S5](#pone.0015397.s005){ref-type="supplementary-material"}), indicating that the observed defect in the activation of these signaling pathways is a ubiquitous rather than a cell-lineage specific phenomenon. {#pone-0015397-g006} To further evaluate whether the tail contributed to CXCR4 mediated G-protein signaling, we examined CXCL12 induced intracellular calcium mobilization, a key signaling event known to be activated only by Gβγ [@pone.0015397-CabreraVera1]. Surprisingly, we found that CXCL12 stimulation was not able to elicit calcium flux in ΔT cells ([Fig. 6*C*](#pone-0015397-g006){ref-type="fig"}). These results suggest that the CXCR4 tail may play an essential role in G-protein activation. CXCR4 mediated Gαi protein activation is dependent on the CXCR4 tail {#s2f} -------------------------------------------------------------------- Mutational studies showed that a cluster of amino acid residues located at the N-terminal of the cytoplasmic tail of GPCRs was critical for G-protein activation [@pone.0015397-Rosenbaum1]. However, it is not clear whether the CT tail was actually involved in G-protein coupling. Since our data showed that ΔT failed to activate multiple signaling pathways downstream of G proteins, we sought to determine whether the ΔT mutation altered the physical interaction between CXCR4 and heterotrimeric G proteins. We found that anti-CXCR4 immunoprecipitated an equivalent amount of Gαi in WT and ΔT cells ([Fig. 7*A*](#pone-0015397-g007){ref-type="fig"}), indicating that heterotrimeric G-proteins are still physically associated with ΔT. {#pone-0015397-g007} Although the CXCR4 tail was not required for G-protein association, it may control G-protein activity. To assess this possibility, we examined Gαi activity by measuring intracellular cAMP levels after CXCL12 stimulation. In WT cells, CXCL12-activated Gαi proteins inhibited forskolin-induced adenylyl cyclase activity, leading to the suppression in intracellular cAMP production. However, the forskolin elevated intracellular cAMP level was not attenuated in ΔT cells after CXCL12 stimulation ([Fig. 7*B*](#pone-0015397-g007){ref-type="fig"}). These data demonstrate that the CXCR4 tail, although dispensable for G-protein association, is required for heterotrimeric G-protein activation. Discussion {#s3} ========== Models regarding GPCR activation and signaling have been rapidly modified to accommodate new data derived from structural and mutational analysis of GPCRs. In a classical model, GPCRs mediate virtually all signaling events through their coupled G proteins, and the cytoplasmic tail of GPCRs plays only a negative regulatory role through the interacting β-arrestins to downmodulate ligand-activated receptors and desensitize cells from further ligand stimulation [@pone.0015397-Lefkowitz2]. This view has been changed after the finding of "ligand bias", namely, a GPCR engaged to different ligands can activate G proteins without inducing receptor internalization or can activate downstream MAPK pathways through β-arrestins in the absence of detectable G protein activities [@pone.0015397-Kohout1]--[@pone.0015397-Colvin1]. In a revised model, different agonists may induce the same GPCR to assume different active states, resulting in exposure of distinct cytoplasmic interfaces to different interacting molecules (the G proteins or β-arrestins) that contribute to various cellular outcomes [@pone.0015397-Violin1]. The physiological significance of these signaling mechanisms has not been delineated in vivo. Here, we used CXCR4 as a model molecule to elucidate the cellular effects mediated by individual signaling modules of GPCRs. For this reason, we generated ΔT mice. Our results demonstrate that the CXCR4 tail plays an essential function of CXCR4 in the developing brain, vascular and hematopoietic systems. However, the embryonic lethality of CXCR4-ΔT mice was unexpected, as patients with WHIM syndrome who also harbor truncating mutations at the CXCR4 C-terminus exhibited a dominant gain of function phenotype. We speculate that C-terminus truncated CXCR4 in WHIM patients might lose desensitization function but retain partial signaling properties through the remaining 8 to 12 serine residues in its tail. This postulation is supported by recent findings indicating that site-specific phosphorylation of serine residues at the CXCR4 tail is regulated by different GRKs which have either positive or negative impact on CXCR4 signaling [@pone.0015397-Busillo1]. Further studies are required to elucidate whether knock-in mice expressing the same mutant form of CXCR4 as WHIM patients recapitulate the human pathogenesis. A question that remains unanswered is how the CXCR4 tail facilitates G-protein activation. G proteins are presumably activated through a cascade of conformational changes upon ligand binding to GPCRs. Due to the high flexibility of the C-terminus of GPCRs, this portion has been deleted to promote crystallization of GPCRs for structural studies [@pone.0015397-Cherezov1], [@pone.0015397-Rasmussen1]. Therefore, no information can be inferred from the available structures on the interdependence between the C-terminus of GPCRs and GPCR-associated G proteins. Based on biochemical studies, the tail of GPCRs is known to interact with GRKs and β-arrestins. Although it is unclear whether such an interaction facilitates G-protein activation, experiments from β-arrestin2 and GRK6 knock-out mice seem to suggest otherwise [@pone.0015397-Fong1]. It is conceivable that the tail itself or other unknown associated molecules may help to facilitate the conformational change and activation of GPCR interacting heterotrimeric G proteins upon ligand stimulation [@pone.0015397-Ding1]. Further mutagenesis and proteomics studies may help to resolve this issue. It should be mentioned that ΔT embryos exhibited a relatively milder developmental retardation as compared to the CXCR4-null mice. Consistently, the ΔT mutation completely abolishes the chemotaxis function but still retained the adhesion ability of WT pro-B cells to VCAM-1 upon CXCL12 stimulation. These results thus reveal the existence of a CT tail and G-protein independent pathway responsible for CXCR4-induced inside-out signaling for integrin activation. In agreement with this notion, it has been shown that activation of CXCR7, results in integrin-mediated adhesion without evoking obvious G-protein signaling [@pone.0015397-Burns1]. In the case of CXCR4, we and others have found that PTX could completely block CXCL12 induced chemotaxis but not adhesion [@pone.0015397-Mazo1]. At present, the nature of this tail- and G protein-independent pathway remains unclear. In summary, we generated ΔT mice to directly determine the signaling properties of the CXCR4 tail and to assess the physiological relevance of this signaling module. Results from our studies have revealed an unexpected regulatory role of the tail in G-protein activation. This discovery is important not only for understanding the mechanisms of GPCR activation and function but is also pertinent for future drug development. Materials and Methods {#s4} ===================== Ethics Statement {#s4a} ---------------- All experiments were reviewed and approved by the Institutional Animal Care and Use Committee at the Feinstein Institute for Medical Research (IACUC Protocol \#2009-023). Mice {#s4b} ---- Strategies for gene targeting, ES cell screening and genotyping of ΔT mice are provided in *[Fig. S1](#pone.0015397.s001){ref-type="supplementary-material"}*. To generate mice that express ΔT in adult tissues, ΔT mice were bred to previously described ROSA^ET2-CRE^ Cxcr4^+/F^ mice [@pone.0015397-Nie2] to obtain conditional ΔT mice (ROSA^ET2-CRE^ CXCR4-ΔT/F) and littermate controls (CXCR4-ΔT/F). To express ΔT specifically in B-lineage cells, ΔT mice were bred to CD19-Cre Cxcr4^+/F^ mice to generate CD19-Cre+ CXCR4-ΔT/F mice. Previously reported CXCR4-null mice were used as negative controls. Abelson virus transformation of pro-B cells {#s4c} ------------------------------------------- FL cells were isolated from E15.5 WT and ΔT embryos and incubated with Abelson virus suspensions (gift from Dr. Hua Gu, Columbia University) for 2 h, 37°C. Cells were then cultured in OptiMEM + 10% FBS. 7 d later, cells underwent a second round of Abelson virus infection. CXCR4-null pro-B cell lines were generated by infecting splenocytes of CXCR4^f/f^CD19-Cre mice with Abelson virus. Primary transformants were analyzed by flow cytometry and confirmed to be a homogenous population of B220^+^CD43^+^ pro-B cells. Histology {#s4d} --------- Histology analysis was performed as described [@pone.0015397-Zou1]. Briefly, brains of E18.5 embryos were dissected, fixed in Bouin\'s solution and embedded in paraffin. 6 µm brain sections were stained with hematoxylin and eosin and analyzed under a Nikon Eclipse TE2000-E microscope equipped with a Nikon DS-Fi1 color camera. Flow cytometry and receptor internalization {#s4e} ------------------------------------------- Cells from the PB, spleen or FL were stained using following antibodies: anti-B220 APC, anti-CD43 FITC, anti-CD19 PE, anti-Gr-1 PE, anti-CD11b FITC and anti-IgM FITC (all from eBioscience). Data were attained on an LSR II (Becton Dickinson) and analyzed using FlowJo software (Tree Star). For receptor internalization analysis, cells were resuspended at 4×10^6^ cells/ml in DMEM and stimulated with 0.5 µg/ml CXCL12 at 37°C. Reactions were terminated by addition of 4% PFA. Cells were stained for surface CXCR4 with anti-CXCR4 biotin (BD) and streptavidin-conjugated PE-Cy7 (eBioscience). CXCR4 downmodulation was determined based on the mean fluorescent intensity (MFI) of CXCR4 expression with the following formula: % downmodulation = 100 x {(MFI of unstimulated cells (at time t) -- MFI of stimulated cells (at time t))/MFI of unstimulated cells (at time 0)}. Chemotaxis and adhesion assays {#s4f} ------------------------------ Chemotaxis was performed in transwells (5 µM pore size, Costar). The upper chambers containing 2×10^5^ cells were placed into lower wells with 0.5 µg/ml CXCL12 (Peprotech). After 3 h incubation at 37°C, migrated cells were collected and enumerated by flow cytometry. Adhesion assays were done as previously described [@pone.0015397-DeGorter1]. Briefly, 96-well plates (Greiner) were coated with 1 µg/ml rmVCAM-1-Fc (R&D Systems) and CXCL12 (0.5 µg/ml). Wells were blocked with PBS +2% BSA and 50 µg/ml heparin sulphate. Pro-B cells were seeded at 3×10^5^ cells/well and incubated at 37°C, 2 min. Non-adherent cells were removed by washing and adherent cells counted by flow cytometry. Calcium mobilization {#s4g} -------------------- 5×10^5^ FL cells from E18.5 embryos in 0.5 ml of assay buffer (25 mM HEPES, pH 7.4, 0.1% BSA, 2.5 mM probenecid in Hank\'s buffer) were loaded for 30 min at 37°C with 2 µM Fluo-4 and 0.84 µM Fura-red (Molecular Probes). Cells were then washed and resuspended in pre-warmed assay buffer. Samples were first analyzed by flow cytometry for 1 min to establish a baseline before stimulation with 0.5 µg/ml CXCL12 for 2 min and then 2 µM ionomycin (Sigma) for another 2 min. Immunoprecipitation and immunoblotting {#s4h} -------------------------------------- To detect interaction between CXCR4 and G-proteins, WT, CXCR4-null and ΔT pro-B cells were serum-starved for 2 h at 37°C and then cross-linked with 1 mM DSP (dithio-bis-succinimidyl propionate, Pierce) for 30 min, RT. Then cells were lysed by addition of lysis buffer (0.1 M NaCl, 50 mM Tris-HCl, pH 7.4, 15 mM EGTA, 1% SDS, 1% Triton X-100, 1% Cymal-5, 50 µg/ml DNase I, and protease inhibitors (Roche)). Lysates were centrifuged and cleared samples incubated with 10 µg/ml anti-CXCR4 (Abcam) overnight, 4°C, and then with 30 µl protein G agarose for an additional 3 h. Beads were washed, eluted in 2x SDS sample buffer, resolved by 4--12% gradient SDS-PAGE, and analyzed by immunoblotting with anti-Gαi (Santa Cruz Biotechnology). For detection of pERK and pPKB, splenocytes from conditional ΔT mice and littermate controls were stimulated with 0.5 µg/ml CXCL12 for indicated times and immunoblots prepared from lysates. Western blot analysis was carried out with antibodies against pPKB (S473, Cell Signaling), ERK and pERK (Thr202, Tyr204) (Santa Cruz Biotechnology). Radioligand binding assay {#s4i} ------------------------- HEK cells stably transfected with WT CXCR4 or ΔT were used in a standard competitive radioligand binding assay. Briefly, cells were incubated for 2 hr at 4°C with 187 pM ^125^I-CXCL12 (PerkinElmer) in the presence of increasing concentrations of cold CXCL12 (0--1000 nM). After washing 3 times in wash buffer (0.5 M NaCl, 1% BSA, 5 mM MgCl~2~, 1 mM CaCl~2~, 25 mM HEPES, pH 7.1), bound radioactivity was measured using a β counter (Beckman LS 6500SC). Data were averaged from three independent experiments, and calculated as: % of binding = 100 x {(cpm~non-comp.~ -- cpm~sample~)/cpm~non-comp.~} Intracellular cAMP assay {#s4j} ------------------------ Splenocytes isolated from conditional ΔT mice and controls were starved in serum-free medium for 1 h at 37°C. After incubation with 1 mM 3-isobutyl-1-methylxanthine (IBMX) at 37°C for 10 min, cells were stimulated with 1 µg/ml CXCL12 for 10 min, followed by 10 min incubation in the presence of 1 µM forskolin. Intracellular cAMP levels were determined using a competitive enzyme immunoassay (Amersham) following the manufacturer\'s instructions. Tango assay {#s4k} ----------- Plasmids β-arrestin-TEV and VTT (TEV cleavage site-tTA fusion construct) were kindly provided by the Richard Axel lab (Columbia University). Luciferase reporter vector (pBI-GI) was from Invitrogen. WT CXCR4 and ΔT were obtained by PCR using primers outlined in *[Text S1](#pone.0015397.s006){ref-type="supplementary-material"}*, and cloned into the VTT plasmid to generate WT or ΔT fused to the TEV cleavage site ENLYFQL followed by tTA (plasmids WTCXCR4-tTA or ΔTCXCR4-tTA). HEK cells were plated into a 96-well flat-bottomed plate at 50,000 cells/well and transfected with β-arrestin-TEV, WTCXCR4-tTA or ΔTCXCR4-tTA, and pBI-GI at a ratio of 1∶5∶1 and incubated overnight at 37°C. Supernatant was then replaced with fresh DMEM ±1 µg/ml CXCL12 and incubated for 6 hr, 37°C. Media was aspirated and BrightGlo luciferase substrate (Promega) added to each well and activity measured by a Berthold TriStar LB941 plate reader. Supporting Information {#s5} ====================== ###### **Generation of Mutant Mice.** (A) Structure of the wildtype *Cxcr4* locus, map of the targeting construct, the targeted *Cxcr4* allele before and after Cre/loxP-mediated *neo* gene deletion. The tail-truncation mutation was introduced into the second exon by PCR (Exon II). (B) Southern blot analysis of tail DNA from wildtype, heterozygous mice carrying both the mutated exon II and the *neo* gene (+/−), and heterozygous mice carrying mutant *Cxcr4* allele after *neo* gene deletion (+/mu). The allele detected by probe a: wildtype or mutant *Cxcr4* allele without the *neo* gene: 3.8 kb; the mutant *Cxcr4* allele with the *neo* gene: 5.0 kb. The allele detected by probe b: wildtype: 7.2 kb; the mutant *Cxcr4* allele with or without the *neo* gene: 4.9 kb. The following PCR primers are used for genotyping, which produces a 405-bp wildtype band and a 303-bp tail-truncated *Cxcr4* band: 005-Δ5′: 5′-CTTCTTCCACTGTTGCCTGAACC-3′ 005-Δ3-end: 5′- GCCACAGGTCCCTGCCTAGAC-3′ (TIF) ###### Click here for additional data file. ###### **B cell precursors in the spleen and peripheral blood.** Splenocytes and peripheral blood cells were isolated from 6-week-old wildtype (ΔT/F), CD19-Cre+ CXCR4^F/ΔT^ (ΔT/-) and CD19-Cre+ CXCR4^F/F^ (−/−) mice and stained with antibodies against CD19, B220 and IgM. CD19^+^-gated cells were plotted with IgM and B220. Numbers (mean ± SD) represent percentages of B220^lo^IgM^−^ B-cell precursors within the CD19^+^ B-cell population (n = 5--8). (TIF) ###### Click here for additional data file. ###### **Expression of CXCR4, CXCR7 and CD29 in pro-B cells.** (A) Cell surface expression of VLA-4 (α4β1) on Abelson-transformed pro-B cells derived from the wildtype (shaded) and CXCR4-ΔT mice (red line) were detected with anti-CD29 (integrin β1) and analyzed by flow cytometry. (B) Cell surface expression of CXCR4 on Abelson-transformed pro-B cells derived from wildtype, CXCR4-null and CXCR4-ΔT mice. (C) Expression of CXCR7 was determined by qRT-PCR. RNA was purified from fetal liver cells of E18.5 wildtype (WT) or CXCR7^−/−^ embryos, bone marrow cells of wildtype 8-week-old mice, or Abelson-transformed WT pro B cells using an RNeasy kit (Qiagen). cDNA was then prepared using SuperScriptIII First Strand Synthesis kit (Invitrogen). qRT-PCR was performed using primers specific for CXCR7. Each value was normalized to β-actin expression levels. (TIF) ###### Click here for additional data file. ###### **Pro-B cell adhesion to VCAM-1 is insensitive to pertussis toxin treatment.** Pro-B cells were treated with 100 ng/ml of pertussis toxin (PTX) for 3 h at 37°C. PTX-treated and untreated cells were respectively seeded in 96-well plates coated with 1 µg/ml of mouse VCAM-1-Fc with or without 0.5 µg/ml of CXCL12, and incubated at 37°C for an additional 2 min. Non-adherent cells were then removed by washing, adherent cells were collected and counted. Bar graphs represent the percentages of pro-B cells attached to VCAM-1 in the presence or absence of PTX. Wildtype and CXCR4-ΔT cells are indicated by open and gray bars, respectively. (TIF) ###### Click here for additional data file. ###### **Impaired signaling in CXCR4 CXCR4-ΔT pro-B cells.** Abelson-transformed pro-B cells were stimulated with 0.5 µg/ml CXCL12 for indicated times. Cell lysates were prepared and Western blot analysis for phosphorylated PKB at serine 473 (pPKB) or phosphorylated ERK (pERK) were performed. Equal loading of protein was confirmed by re-blotting with anti-ERK antibody. Results are representative of at least 3 independent experiments. (TIF) ###### Click here for additional data file. ###### Primers. (DOC) ###### Click here for additional data file. The authors thank all Zou lab members for discussions; J. Liao for genotyping mice; R. Clynes for help in ligand-binding assay; H. Gu for Abelson virus supernatant. **Competing Interests:**The authors have declared that no competing interests exist. **Funding:**This work was supported in part by the DANA Foundation (CU-51912001), the Sandler Program for Asthma Research (SPAR 04-0179), and the Irene Diamond Fund (SHRI 1703) to Y.-R. Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. [^1]: Conceived and designed the experiments: DC YZ. Performed the experiments: DC YN YZ. Analyzed the data: DC YZ. Contributed reagents/materials/analysis tools: JW YZ. Wrote the paper: DC YZ. [^2]: Current address: Department of Immunology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America [^3]: Current address: Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, New York, United States of America | Mid | [
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Seroepidemiology of human Toxocara and Ascaris infections in the Netherlands. Toxocara canis, Toxocara cati and Ascaris suum are worldwide-distributed zoonotic roundworms of dogs, cats and pigs, respectively. The epidemiology of these parasites in developed countries is largely unclear. Two countrywide cross-sectional serosurveys were therefore conducted in the Netherlands in 1995/1996 and 2006/2007 to investigate the prevalence, trends and risk factors for human Toxocara and Ascaris infections in the general population. The Netherlands is characterized by high pig production, freedom from stray dogs and virtual absence of autochthonous infections with the human-adapted roundworm Ascaris lumbricoides. Over the 10 years between the two serosurveys, Toxocara seroprevalence decreased significantly from 10.7 % (n = 1159) to 8.0 % (n = 3683), whereas Ascaris seroprevalence increased significantly from 30.4 % (n = 1159) to 41.6 % (n = 3675), possibly reflecting concomitant improvements in pet hygiene management and increased exposure to pig manure-contaminated soil. Increased anti-Toxocara IgGs were associated with increasing age, male gender, contact with soil, ownership of cats, cattle or pigs, hay fever, low education, high income and non-Western ethnic origin. Increased anti-Ascaris IgGs were associated with increasing age, owning pigs, low education, childhood geophagia and non-Dutch ethnic origin. Besides identifying specific groups at highest risk of Toxocara and Ascaris infections, our results suggest that these infections mainly occur through environmental, rather than foodborne, routes, with direct contact with soil or cat and pig ownership being potentially modifiable exposures. | High | [
0.69047619047619,
36.25,
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Hugh de Courtenay, 2nd/10th Earl of Devon Sir Hugh de Courtenay, 2nd/10th Earl of Devon (12 July 1303 – 2 May 1377), 2nd Baron Courtenay, feudal baron of Okehampton and feudal baron of Plympton, played an important role in the Hundred Years War in the service of King Edward III. His chief seats were Tiverton Castle and Okehampton Castle in Devon. The ordinal number given to the early Courtenay Earls of Devon depends on whether the earldom is deemed a new creation by the letters patent granted 22 February 1334/5 or whether it is deemed a restitution of the old dignity of the de Redvers family. Authorities differ in their opinions, and thus alternative ordinal numbers exist, given here. Origins Hugh de Courtenay was born on 12 July 1303, the second son of Hugh de Courtenay, 1st/9th Earl of Devon (1276–1340), by his wife Agnes de Saint John, a daughter of Sir John de Saint John of Basing, Hampshire. He succeeded to the earldom on the death of his father in 1340. His elder brother, John de Courtenay (c.1296-11 July 1349), Abbot of Tavistock, as a cleric was unmarried and although he succeeded his father as feudal baron of Okehampton, did not succeed to the earldom. Career By his marriage to Margaret de Bohun, Countess of Devon in 1325, Courtenay acquired the manor of Powderham; it was later granted by Margaret de Bohun to one of her younger sons, Sir Philip Courtenay (died 1406), whose family has occupied it until the present day, and who were recognised in 1831 as having been de jure Earls of Devon from 1556. On 20 January 1327 Courtenay was made a knight banneret. In 1333 both he and his father were at the Battle of Halidon Hill. He was summoned to Parliament on 23 April 1337 by writ directed to Hugoni de Courteney juniori, by which he is held to have become Baron Courtenay during the lifetime of his father. In 1339 he and his father were with the forces which repulsed a French invasion of Cornwall, driving the French back to their ships. The 9th Earl died 23 December 1340 at the age of 64. Courtenay succeeded to the earldom, and was granted livery of his lands on 11 January 1341. In 1342 the Earl was with King Edward III's expedition to Brittany. Richardson states that the Earl took part on 9 April 1347 in a tournament at Lichfield. However, in 1347 he was excused on grounds of infirmity from accompanying the King on an expedition beyond the seas, and about that time was also excused from attending Parliament, suggesting the possibility that it was the Earl's eldest son and heir, Hugh Courtenay, who had fought at the Battle of Crecy on 26 August 1346, who took part in the tournament at Lichfield. In 1350 the King granted the Earl permission to travel for a year, and during that year he built the monastery of the White Friars in London. In 1352 he was appointed Joint Warden of Devon and Cornwall, and returned to Devon. In 1361 he and his wife were legatees in the will of her brother, Humphrey de Bohun, 6th Earl of Hereford, which greatly increased his wealth and land holdings. Later years Courtenay made an important contribution to the result of the Battle of Poitiers in 1356. The Black Prince had sent the baggage train under Courtenay to the rear, which proved to be a wise manoeuvre as the long trail of wagons and carts blocked the narrow bridge and the escape route for the French. Courtenay played little part in the battle as a result of his defensive role. Courtenay retired with a full pension from the king. In 1373 he was appointed Chief Warden of the Royal Forests of Devon, the income of which in 1374 was assessed by Parliament at £1,500 per annum. He was one of the least wealthy of the English earls, and was surpassed in wealth by his fellow noble warriors the Earl of Arundel, Earl of Suffolk and Earl of Warwick. Nevertheless he had a retinue of 40 knights, esquires and lawyers in Devon. He also held property by entail, including five manors in Somerset, two in Cornwall, two in Hampshire, one in Dorset and one in Buckinghamshire. He had stood as patron in the career of John Grandisson, Bishop of Exeter. He supported the taking-on of debt to build churches in the diocese of Exeter. He died at Exeter on 2 May 1377 and was buried in Exeter Cathedral on the same day. His will was dated 28 Jan 13--. Marriage and issue On 11 August 1325, in accordance with a marriage settlement dated 27 September 1314, Courtenay married Margaret de Bohun (b. 3 April 1311 - d. 16 December 1391), eldest surviving daughter of Humphrey de Bohun, 4th Earl of Hereford (by his wife Princess Elizabeth, a daughter of King Edward I), by whom he had eight sons and nine daughters: Sir Hugh Courtenay (d.1348), KG, eldest son and heir apparent, who died shortly before Easter term, 1348, predeceasing his father. He married, before 3 September 1341, Elizabeth de Vere (d. 16 August 1375), a daughter of John de Vere, 7th Earl of Oxford by his wife Maud de Badlesmere (a daughter of Bartholomew de Badlesmere, 1st Baron Badlesmere), by whom he had an only son, Hugh Courtenay, 3rd Baron Courtenay, (d.20 February 1374) who died without issue. Elizabeth de Vere survived her husband and remarried successively to John de Mowbray, 3rd Baron Mowbray (d. 4 October 1361), and to Sir William de Cossington. Thomas Courtenay (born c.1329-31), a Canon of Crediton and Exeter. Sir Edward Courtenay (c.1331-1368/71) of Godlington, who was born at Haccombe in Devon, and died between 2 February 1368 and 1 April 1371, predeceasing his father. He married Emeline Dawney (c.1329 – 28 February 1371), daughter and heiress of Sir John Dawney (d.1346/7) of Mudford Terry in Somerset by whom he had issue as follows: Edward Courtenay, 3rd/11th Earl of Devon (d.1419), who married Maud Camoys. The earldom remained in their descendants until their great-grandson, Thomas Courtenay, 6th/14th Earl of Devon, was beheaded at York on 3 April 1461 after the Battle of Towton, without issue. All his honours were forfeited by attainder, and the earldom eventually passed, after a brief period of confusion during the Wars of the Roses (for which see Earl of Devon), by a new creation in 1485 to Edward Courtenay, 1st Earl of Devon (d.1509), the grandson of Sir Hugh Courtenay (1358-1425) of Boconnoc in Cornwall and of Haccombe in Devon, younger brother of the 3rd/11th Earl. Sir Hugh Courtenay (1358-1425) of Boconnoc in Cornwall and of Haccombe in Devon, whose grandson was Edward Courtenay, 1st Earl of Devon (d.1509). Robert Courtenay. William Courtenay (c.1342 – 31 July 1396), Archbishop of Canterbury. Sir Philip Courtenay (c.1355 – 29 July 1406) of Powderham in Devon, who married Ann Wake, a daughter of Sir Thomas Wake by his wife Alice Patteshull, a daughter of Sir John de Patteshull. Sir Peter Courtenay (d. 2 February 1405), KG, of Hardington Mandeville, Somerset, who married Margaret Clyvedon, widow of Sir John de Saint Loe (d. 8 November 1375), and daughter and heiress of John de Clyvedon. His monumental brass, much worn, but still showing the arms of Courtenay impaling Bohun, survives in the floor of the south aisle of Exeter Cathedral. Humphrey Courtenay, who died young without issue. Margaret Courtenay (the elder), (born c. 1328 - died 2 Aug 1395), who married John de Cobham, 3rd Baron Cobham. Elizabeth Courtenay (d. 7 August 1395), who married firstly, Sir John de Vere (d. before 23 June 1350) of Whitchurch, Buckinghamshire, eldest son and heir apparent of John de Vere, 7th Earl of Oxford, by his wife Maud de Badlesmere; and secondly to Sir Andrew Luttrell of Chilton, in Thorverton, Devon and had issue, including Sir Hugh Luttrell. Katherine Courtenay (d. 31 December 1399), who married, before 18 October 1353, Thomas Engaine, 2nd Baron Engaine (d. 29 June 1367), without progeny. Anne Courtenay. Joan Courtenay, who married, before 1367, Sir John de Cheverston (died c. 1375), by whom she had no issue. Margaret Courtenay (the younger), (born btw. 1342 and 1350 - died after July 1381), who married Sir Theobald Grenville II (died by July 1381). ______ Courtenay (7th daughter). ______ Courtenay (8th daughter). ______ Courtenay (9th daughter). References Bibliography Browning, Charles H., Americans of Royal Descent, 6th ed. 1905, p. 105-108 Holmes, G. Estates of Higher Nobility in Fourteenth Century England, Cambridge, 1957, p. 58 Mortimer, Ian Edward III (London 2007). Ormrod, W. M. The Reign of Edward III (Tempus Publishing 1999). Saul, Nigel, ed. The Oxford History of Medieval England (OUP 1997). Register of Edward, the Black Prince, (ed) A. E. Stamp & M. C. B. Dawes (London 1930-33). Sumption, Jonathan, The Hundred Years War, 2 vols, Vol.1: Trial by Battle, vol. 2: Trial by Fire (Faber 1999). Waugh, Scott L., England in the Reign of Edward III (CUP 1991) Tuck, Anthony, Crown and Nobility; England 1272-1461: political conflict in late medieval England, 2nd ed., (Blackwell 1999). Further reading External links For the entry for Hugh Courtenay, 10th Earl of Devon, in The Peerage.com, see For the tomb of Hugh Courtenay, 10th Earl of Devon, see findagrave.com entry Category:1303 births Category:1377 deaths Category:Burials at Exeter Cathedral Category:Courtenay family Hugh de Courtenay, 10th Earl of Devon Devon, Hugh de Courtenay, 10th Earl of Category:Knights banneret of England Category:People of the Hundred Years' War | High | [
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Marcie Thompson always told her son Johnathan Wilson to play with confidence. Whether it was when Wilson was a seven-year-old dominating the flag football league, or now a starting receiver at Kansas, Thompson was always ready with some advice. "We taught him to own the field," Thompson said, "When you step out there that is your field." | Mid | [
0.631578947368421,
36,
21
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--- title: "Hold up your iPhone in honor of iOS 7" excerpt: "PaperFaces portrait of @agebhard drawn with Paper for iOS on an iPad." image: path: &image /assets/images/paperfaces-agebhard-twitter.jpg feature: *image thumbnail: /assets/images/paperfaces-agebhard-twitter-150.jpg categories: [paperfaces] tags: [portrait, illustration, Paper for iOS, beard] --- PaperFaces portrait of <a href="https://twitter.com/agebhard">@agebhard</a>. {% include_cached boilerplate/paperfaces-2.md %} {% figure caption:"Working the background with watercolor." %} [](/assets/images/paperfaces-agebhard-process-1-lg.jpg) {% endfigure %} {% figure caption:"Work in progress screenshots (**Paper for iOS**)." class:"gallery-3-col" %} [](/assets/images/paperfaces-agebhard-process-2-lg.jpg) [](/assets/images/paperfaces-agebhard-process-3-lg.jpg) [](/assets/images/paperfaces-agebhard-process-4-lg.jpg) [](/assets/images/paperfaces-agebhard-process-5-lg.jpg) [](/assets/images/paperfaces-agebhard-process-6-lg.jpg) [](/assets/images/paperfaces-agebhard-process-7-lg.jpg) {% endfigure %} | Low | [
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30.25,
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Rick Santorum and the Sexual Counter-Revolution Almost a century ago this month, women's rights activist Emma Goldman was arrested in New York for distributing "obscene, lewd, or lascivious articles". What she was doing was handing out pamphlets about birth control, with the aim of freeing women sexually and socially from the burden of unwanted pregnancy, and she got a spell in a prison workhouse for her trouble. Walk around Lower Manhattan today, as I did this morning, and you'd think that history had vindicated Goldman's long campaign for sexual freedom. Pop songs promising a catalogue of horizontal delights pump out of the doorways of shops selling dildos and cheap knickers in the early mornings. Men hold hands with their husbands in SoHo. Wall Street workers in skirt suits jostle on the subway with excited teenagers in tiny shorts defying their parents and the winter chill. Everywhere, on billboards and bus-stops and hoardings a hundred feet high, images of female sexual availability bulge and shine and flutter their perfect airbrushed eyelashes. Thighs glisten, legs spread and giant red lips open wetly for the latest low-calorie yoghurt. Surely, you'd think, this is a sweaty shangri-la of erotic liberty. Surely this is one place where the sexual revolution of the 1960s was allowed to reach its logical conclusion. Step into any coffee shop or diner that carries the rolling news, however, and you'll find that in the land of the free not everything is as free as it seems. Over the past few weeks, right-wing politicians have launched an all-out assault on women's sexual and reproductive freedom and LGBT rights, attacking not just gay marriage and abortion but contraception, too. In 2012, the morality of hormonal birth control is now a serious hot-button issue in the Republican presidential race. Last week, not a single woman was allowed to testify before a Washington hearing on reproductive rights and "religious freedom" — which includes allowing bosses to deny their female employees contraceptive health coverage on moral grounds. Meanwhile, the state of Virginia debated whether or not to force every women seeking an abortion to submit to vaginal probing with an ultrasound device, a policy that campaigners called "state-sponsored rape" — one state representative commented that he couldn't see what the problem was, as these women had already consented to being penetrated when they got pregnant. As panels of terrifying old men gather on national television to debate whether and how far women should be punished for having sex outside marriage one could be forgiven for thinking that American politics had temporarily been scripted by Margaret Atwood. As the recession crunches down, the country is awash with anti-erotic, anti-queer, anti-woman rhetoric that goes beyond 'culture war' into the territory of sexual counter- revolution. The Republicans know that contraception in particular is a losing issue for them – a New York Times poll found that two thirds of voters, including 67 per cent of Catholics, support requiring employee health care plans to cover the cost of birth control, and Obama is up ten points with women from August – but they can't help themselves. One whiff of an uncontrolled pudenda and they start scrapping like housedogs who have been sprayed with pheromones, which makes for such classic TV moments as candidate Newt Gingrich, currently America's most famous serial adulterer, seriously participating in a debate about sexual continence. To call this backlash a culture war would be to imply that more than one side is fighting. This is far from the case. Compared to the pageant of homophobic and misogynist pants-wetting going on on the American right, all the Democrats need to do to make themselves look like a sane and useful political outfit is to sit back and watch the Republicans engage in auto-erotic asphyxiation. Americans have short memories, particularly in election years, and most seem to have forgotten that it is barely two months since President Obama stepped in to restrict the sale of the morning-after-pill — to girls under 17 — a move seemingly designed to reassure the increasingly suspicious, sexist American centre-right that he hates sexual freedom a little bit, too. Just not as much as those crazy Republicans. Curiously enough, precisely the same arguments seem to be at play when British conservatives attack abortion rights and sexual health – they might be gradually reintroducing fear of female sexuality into mainstream public life, but at least they're not as bad as those crazy Americans. Meanwhile, the public conversation about women's rights and sexual freedom is creeping back, inch by inch, towards conservative censoriousness. This new sexual counter-revolution is bigger than America. The rhetoric of god, marriage, morality and little girls learning to keep their legs closed has crossed the pond with all the tooth-aching tenacity of a Katy Perry song. Last week, we had Baroness Warsi going to the Vatican to announce that Europe needs to be more 'confident in its Christianity'. This week, it's a campaign by theTelegraphto remind women, their doctors and the government that abortions are not available 'on demand', a move that follows two years of attacks on sex education and the legal right to choose in parliament. Just like in the United States, the effect of this mission creep of legislative misogyny is to chip away at public support for women's right to control our bodies and our destinies. It's worth reminding ourselves what birth control and abortion actually mean in political terms. The hormonal birth control pill was the first step in a technological revolution that, within living memory, liberated one half of the human race from functional dependency on the other. With legal abortion as the other side of the equation should birth control fail, women can finally be the mistresses of our own reproductive systems, rather than the slaves of it. We can choose when, if and how many children we want, we can be sexually active without fear of pregnancy, and we can participate, at least in theory, in every area of public and professional life – we can have, in short, all the advantages that men have always enjoyed through accident of biology. Pro-choice campaigners speak of a woman's right to "control her own body", rather than have it controlled for her by her husband, the church or the state, as if that right were a social given rather than something that our mothers and grandmothers fought and went to prison to win. When conservative head-bangers like Rick Santorum complain that birth control encourages women and girls to have sex outside marriage, the appropriate response should be "yes, and?". Of course we want to have sex outside marriage without fear of social or economic punishment. Of course we want to control our fertility and, with it, our future. These are precisely the technological advances that make real equality a possibility, and they are precisely the advances that players in the big boys' throwback club of modern politics wish to curtail when they complain of "moral decline" in public life. The sexual counter-revolution is all about control. It's about control of women, control of desire, and control of political space at a time when elected representatives have nothing to offer voters beyond sops to our most fearful prejudices. As for those dirty billboards, they are part of the equation. A culture of objectification is part of managing and monetising the social fact of desire. Anglo-American culture has never had a problem with sex as long as it is carefully managed — as long as it is enjoyed only by straight men and endured by women, guiltily, in the dark. | Mid | [
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/* * DO NOT ALTER OR REMOVE COPYRIGHT NOTICES OR THIS HEADER. * * Copyright (c) 1997-2013 Oracle and/or its affiliates. All rights reserved. * * The contents of this file are subject to the terms of either the GNU * General Public License Version 2 only ("GPL") or the Common Development * and Distribution License("CDDL") (collectively, the "License"). You * may not use this file except in compliance with the License. You can * obtain a copy of the License at * https://glassfish.dev.java.net/public/CDDL+GPL_1_1.html * or packager/legal/LICENSE.txt. See the License for the specific * language governing permissions and limitations under the License. * * When distributing the software, include this License Header Notice in each * file and include the License file at packager/legal/LICENSE.txt. * * GPL Classpath Exception: * Oracle designates this particular file as subject to the "Classpath" * exception as provided by Oracle in the GPL Version 2 section of the License * file that accompanied this code. * * Modifications: * If applicable, add the following below the License Header, with the fields * enclosed by brackets [] replaced by your own identifying information: * "Portions Copyright [year] [name of copyright owner]" * * Contributor(s): * If you wish your version of this file to be governed by only the CDDL or * only the GPL Version 2, indicate your decision by adding "[Contributor] * elects to include this software in this distribution under the [CDDL or GPL * Version 2] license." 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However, if you add GPL Version 2 code * and therefore, elected the GPL Version 2 license, then the option applies * only if the new code is made subject to such option by the copyright * holder. */ // Portions Copyright [2019] [Payara Foundation and/or its affiliates] /* * SSLHandlers.java * * Created on June 25, 2009, 11:30 PM * */ package org.glassfish.admingui.common.handlers; import com.sun.jsftemplating.annotation.Handler; import com.sun.jsftemplating.annotation.HandlerInput; import com.sun.jsftemplating.annotation.HandlerOutput; import com.sun.jsftemplating.layout.descriptors.handler.HandlerContext; import org.glassfish.admingui.common.util.GuiUtil; import java.util.*; import java.util.function.Function; import java.util.function.Predicate; /** * * @author anilam * */ public class NewSSLHandlers { private static Set<String> COMMON_CIPHERS = Collections.unmodifiableSet(new HashSet<>(Arrays.asList( "SSL_RSA_WITH_RC4_128_MD5", "SSL_RSA_WITH_RC4_128_SHA", "TLS_RSA_WITH_AES_128_CBC_SHA", "TLS_RSA_WITH_AES_256_CBC_SHA", "SSL_RSA_WITH_3DES_EDE_CBC_SHA" ))); private static Set<String> BIT_CIPHERS = Collections.unmodifiableSet(new HashSet<>(Arrays.asList( "SSL_RSA_WITH_DES_CBC_SHA", "SSL_DHE_RSA_WITH_DES_CBC_SHA", "SSL_DHE_DSS_WITH_DES_CBC_SHA", "SSL_RSA_EXPORT_WITH_RC4_40_MD5", "SSL_RSA_EXPORT_WITH_DES40_CBC_SHA", "SSL_DHE_RSA_EXPORT_WITH_DES40_CBC_SHA", "SSL_DHE_DSS_EXPORT_WITH_DES40_CBC_SHA" ))); public NewSSLHandlers() { } @Handler(id="convertToDifferentCiphersGroup", input={ @HandlerInput(name="ciphers")}, output={ @HandlerOutput(name="CommonCiphersList", type=String[].class), @HandlerOutput(name="EphemeralCiphersList", type=String[].class), @HandlerOutput(name="OtherCiphersList", type=String[].class), @HandlerOutput(name="EccCiphersList", type=String[].class)} ) public static void convertToDifferentCiphersGroup(HandlerContext handlerCtx) { List<String> ciphersList = null; Object ciphers = handlerCtx.getInputValue("ciphers"); if (ciphers != null) { if (ciphers instanceof String) { ciphersList = Arrays.asList(getSelectedCiphersList((String) ciphers)); } else { ciphersList = Arrays.asList((String[]) ciphers); } } handlerCtx.setOutputValue("CommonCiphersList", getCommonCiphers(ciphersList)); handlerCtx.setOutputValue("EphemeralCiphersList", getEphemeralCiphers(ciphersList)); handlerCtx.setOutputValue("OtherCiphersList", getOtherCiphers(ciphersList)); handlerCtx.setOutputValue("EccCiphersList", getEccCiphers(ciphersList)); } @Handler(id="convertCiphersItemsToStr", input={ @HandlerInput(name="common", type=String[].class), @HandlerInput(name="ephemeral", type=String[].class), @HandlerInput(name="other", type=String[].class), @HandlerInput(name="ecc", type=String[].class)}, output={ @HandlerOutput(name="ciphers")} ) public static void convertCiphersItemsToStr(HandlerContext handlerCtx) { String[] common = (String[])handlerCtx.getInputValue("common"); String[] ephemeral = (String[])handlerCtx.getInputValue("ephemeral"); String[] other = (String[])handlerCtx.getInputValue("other"); String[] ecc = (String[])handlerCtx.getInputValue("ecc"); String ciphers = processSelectedCiphers(common, ""); ciphers = processSelectedCiphers(ephemeral, ciphers); ciphers = processSelectedCiphers(other, ciphers); ciphers = processSelectedCiphers(ecc, ciphers); handlerCtx.setOutputValue("ciphers", ciphers); } private static String[] getSelectedCiphersList(String selectedCiphers){ if(selectedCiphers != null){ return filterCiphers( Arrays.asList(selectedCiphers.split(",")), cipher -> cipher.startsWith("+"), cipher -> cipher.substring(1)); } return new String[0]; } private static String processSelectedCiphers(String[] selectedCiphers, String ciphers){ StringBuilder sb = new StringBuilder(); String sep = ""; if ( ! GuiUtil.isEmpty(ciphers)){ sb.append(ciphers); sep = ","; } if(selectedCiphers != null){ for (String selectedCipher : selectedCiphers) { sb.append(sep).append("+").append(selectedCipher); sep = ","; } } return sb.toString(); } private static String[] getCommonCiphers(List<String> ciphers){ return filterCiphers(ciphers, cypher -> COMMON_CIPHERS.contains(cypher)); } private static String[] getEccCiphers(List<String> ciphers){ return filterCiphers( ciphers, cipher -> !BIT_CIPHERS.contains(cipher) && (cipher.contains("_ECDH_") || cipher.contains("_ECDHE_")) ); } private static String[] getEphemeralCiphers(List<String> ciphers){ return filterCiphers( ciphers, cipher -> !BIT_CIPHERS.contains(cipher) && (cipher.contains("_DHE_RSA_") || cipher.contains("_DHE_DSS_")) ); } private static String[] getOtherCiphers(List<String> ciphers){ return filterCiphers(ciphers, cypher -> BIT_CIPHERS.contains(cypher)); } private static String[] filterCiphers(List<String> ciphers, Predicate<String> filter){ return filterCiphers(ciphers, filter, str -> str); } private static String[] filterCiphers(List<String> ciphers, Predicate<String> filter, Function<String, String> transformation){ if (ciphers != null) { return ciphers.stream() .filter(filter) .map(transformation) .toArray(String[]::new); } return new String[0]; } } | Low | [
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Related literature {#sec1} ================== For structurally similar tetrameric complexes with U^VI^, *M* ~4~\[(UO~2~)~4~(μ~3~-O)~2~ *L* ~4~\] (*M* = NH~4~ ^+^, K^+^, Cs^+^; *L* = phthalate), see: Charushnikova *et al.* (2005[@bb3]), and with Bi, \[Bi~2~(μ~3~-O)(OCH(CF~3~)~2~)~2~(μ-OCH(CF~3~)~2~)~2~(Solv)\]~2~ (Solv = C~7~H~8~, Et~2~O, thf), see: Andrews *et al.* (2008[@bb2]). For a planar, mixed valent U^V^ ~2~U^VI^ ~2~ alkoxide, see: Zozulin *et al.* (1982[@bb11]). For a *p*-benzylcalix\[7\]arene complex containing a hexanuclear U^VI^ cluster with a planar tetrameric core, see: Thuéry *et al.* (1999[@bb8]), and for dinuclear uranyl-containing salen \[*N*,*N*′-ethylenebis(salicylimine)\] complexes, see: Amato *et al.* (2007[@bb1]). For bond-valence-sum calculations, see: Wills (2010[@bb10]). Experimental {#sec2} ============ {#sec2.1} ### Crystal data {#sec2.1.1} \[U~4~(C~2~H~3~O~2~)~4~O~10~(H~2~O)~4~\]·2CH~4~O*M* *~r~* = 1484.44Monoclinic,*a* = 8.334 (3) Å*b* = 10.649 (3) Å*c* = 16.763 (5) Åβ = 107.632 (4)°*V* = 1417.8 (8) Å^3^*Z* = 2Mo *K*α radiationμ = 22.87 mm^−1^*T* = 163 K0.10 × 0.07 × 0.05 mm ### Data collection {#sec2.1.2} Rigaku Saturn70 CCD diffractometerAbsorption correction: numerical (*ABSCOR*; Higashi, 1999[@bb4]) *T* ~min~ = 0.638, *T* ~max~ = 0.88015149 measured reflections3255 independent reflections3136 reflections with *I* \> 2σ(*I*)*R* ~int~ = 0.076 ### Refinement {#sec2.1.3} *R*\[*F* ^2^ \> 2σ(*F* ^2^)\] = 0.034*wR*(*F* ^2^) = 0.088*S* = 1.093255 reflections188 parameters6 restraintsH atoms treated by a mixture of independent and constrained refinementΔρ~max~ = 1.71 e Å^−3^Δρ~min~ = −2.85 e Å^−3^ {#d5e786} Data collection: *CrystalClear-SM Expert* (Rigaku, 2009[@bb6]); cell refinement: *CrystalClear-SM Expert*; data reduction: *CrystalClear-SM Expert*; program(s) used to solve structure: *SHELXS97* (Sheldrick, 2008[@bb7]); program(s) used to refine structure: *SHELXL97* (Sheldrick, 2008[@bb7]); molecular graphics: *Mercury* (Macrae *et al.*, 2006[@bb5]); software used to prepare material for publication: *publCIF* (Westrip, 2010[@bb9]). Supplementary Material ====================== Crystal structure: contains datablock(s) I, global. DOI: [10.1107/S1600536811050549/br2182sup1.cif](http://dx.doi.org/10.1107/S1600536811050549/br2182sup1.cif) Structure factors: contains datablock(s) I. DOI: [10.1107/S1600536811050549/br2182Isup2.hkl](http://dx.doi.org/10.1107/S1600536811050549/br2182Isup2.hkl) Additional supplementary materials: [crystallographic information](http://scripts.iucr.org/cgi-bin/sendsupfiles?br2182&file=br2182sup0.html&mime=text/html); [3D view](http://scripts.iucr.org/cgi-bin/sendcif?br2182sup1&Qmime=cif); [checkCIF report](http://scripts.iucr.org/cgi-bin/paper?br2182&checkcif=yes) Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: [BR2182](http://scripts.iucr.org/cgi-bin/sendsup?br2182)). The Egyptian Government is thanked for the scholarship to HS. LND would like to acknowledge Dr Amy Sarjeant, Northwestern University, for a helpful discussion about heavy atom structure refinements. Financial support from the Dean of Science and the Chemistry Department, Memorial University of Newfoundland, is acknowledged. Comment ======= In connection with our on-going studies on metal-binding properties of a new series of macrocylic polyamide compounds, we were interested in determining whether such macrocycles, by analogy with analogous salen (N,N\'-Ethylenebis(salicylimine)) compounds, would also form stable uranyl complexes. Using similar conditions to those which Amato *et al.* (2007) employed with their salens, the title compound crystallized out in the form reported herein. Bond valence sum calculations (Wills, 2010) performed on the title compound indicate that both crystallographically independent uranium atoms are in the +6 oxidations state (U1 = 6.095, U2 = 6.074). The centrosymmetric U(VI) tetramer consists of two hexagonal bipyramids, and two pentagonal bipyramids (U1 and U2, and symmetry equivalents (-*x* + 1, -*y*, -*z* + 1), respectively; Figure 1), with (UO~2~)^2+^ oxygen-atoms occupying the axial positions for both U1 and U2. For U1, the equatorial plane consists of *trans*-bidentate acetate anions, each with one bridging µ~2~-O-atom (O1 and O3), and a µ~3~-O^2-^ anion (O5) *trans* to a water molecule. The equatorial plane of U2 is therefore composed of the aforementioned µ~2~-O and µ~3~-O atoms, and their inversion-symmetry generated counter-parts, as well as water molecule (O11). Similar to the description given by Andrews *et al.* (2008) for \[Bi~2~(µ~3~-O)(OCH(CF~3~)~2~)~2~(µ-OCH(CF~3~)~2~)~2~(Solv)\]~2~ (Solv = C~7~H~8~, Et~2~O, thf) tetramers, this complex consists of a near planar, ten atom \"raft\", with maximum deviation from the least squares plane \[U1, U2, O1--5 and symmetry equivalents (-*x* + 1, -*y*, -*z* + 1)\] of 0.294 (6) Å for O5. Examination of longer range interactions reveals numerous hydrogen bonds, including a lattice solvent methanol molecule bound to one of the pentagonal bipyramidal uranyl oxygen atoms (O12---H12···O9; Figure 1), which further bridges to a bound water molecule of a second tetramer (O8---H8B···O12^iii^, (iii) *x*, -*y*+1/2, *z*-1/2; Figure 2, green dashed lines.) The tetramers interact *via* an additional hydrogen bond, wherby the aforementioned water molecule acts as a donor to one of the hexagonal bipyramidal uranyl oxygen atoms on the first assembly (O8---H8A···O7^ii^, (ii) -*x*+1, *y*+1/2, -*z*+1/2; Figure 2, black dashed lines) leading to a 24-membered H-bonded ring (graph set notation *R*^4^~4~(24)) which spans all four tetramers present in the unit cell. Experimental {#experimental} ============ 160 mg (0.337 mmol) of uranyl acetate dihydrate (UO~2~(CH~3~COO)~2~.2H~2~O) was dissolved in 1 ml methanol, and warmed in a hot water bath (323 K) for 5 minutes. The solution was left at room temperature (293 K) for slow evaporation. Yellow prismatic crystals, suitable for analysis by X-ray diffraction, formed after one week. Refinement {#refinement} ========== The water H-atoms, H8(A,B) and H11(A,B), were located from difference Fourier maps, and were refined with distance and angle restraints: O---H = 0.87 (2) Å, H---O---H = 104.50 (4)°. The C-bound methyl and methanolic H-atoms were included in calculated positions and treated as riding atoms: *X*---H = 0.98 and 0.84 Å for *H*-methyl and H-OMe H-atoms, respectively. For all H atoms, *U*~iso~(H) = k × *U*~eq~(parent atom), where k = 1.2 for *H*-methyl and k = 1.5 for all O-bound H-atoms. The final electron density synthesis shows the highest peak of 1.71 eÅ^3^ located 0.98 Å from U2 and the deepest hole of -2.85 eÅ^3^ located 0.72 Å from U1 and may be the result of residual absorption effects. Figures ======= {#Fap1} {#Fap2} Crystal data {#tablewrapcrystaldatalong} ============ -------------------------------------------------- --------------------------------------- \[U~4~(C~2~H~3~O~2~)~4~O~10~(H~2~O)~4~\]·2CH~4~O *F*(000) = 1296 *M~r~* = 1484.44 *D*~x~ = 3.477 Mg m^−3^ Monoclinic, *P*2~1~/*c* Mo *K*α radiation, λ = 0.71075 Å Hall symbol: -P 2ybc Cell parameters from 4946 reflections *a* = 8.334 (3) Å θ = 1.9--29.5° *b* = 10.649 (3) Å µ = 22.87 mm^−1^ *c* = 16.763 (5) Å *T* = 163 K β = 107.632 (4)° Prism, yellow *V* = 1417.8 (8) Å^3^ 0.10 × 0.07 × 0.05 mm *Z* = 2 -------------------------------------------------- --------------------------------------- Data collection {#tablewrapdatacollectionlong} =============== ------------------------------------------------------------ -------------------------------------- Rigaku Saturn70 CCD diffractometer 3255 independent reflections Radiation source: fine-focus sealed tube 3136 reflections with *I* \> 2σ(*I*) graphite - Rigaku SHINE *R*~int~ = 0.076 Detector resolution: 14.63 pixels mm^-1^ θ~max~ = 27.5°, θ~min~ = 3.1° ω scans *h* = −10→10 Absorption correction: numerical (*ABSCOR*; Higashi, 1999) *k* = −13→13 *T*~min~ = 0.638, *T*~max~ = 0.880 *l* = −21→21 15149 measured reflections ------------------------------------------------------------ -------------------------------------- Refinement {#tablewraprefinementdatalong} ========== ------------------------------------- ------------------------------------------------------------------------------------------------- Refinement on *F*^2^ Primary atom site location: structure-invariant direct methods Least-squares matrix: full Secondary atom site location: difference Fourier map *R*\[*F*^2^ \> 2σ(*F*^2^)\] = 0.034 Hydrogen site location: inferred from neighbouring sites *wR*(*F*^2^) = 0.088 H atoms treated by a mixture of independent and constrained refinement *S* = 1.09 *w* = 1/\[σ^2^(*F*~o~^2^) + (0.0469*P*)^2^ + 6.6005*P*\] where *P* = (*F*~o~^2^ + 2*F*~c~^2^)/3 3255 reflections (Δ/σ)~max~ = 0.001 188 parameters Δρ~max~ = 1.71 e Å^−3^ 6 restraints Δρ~min~ = −2.85 e Å^−3^ ------------------------------------- ------------------------------------------------------------------------------------------------- Special details {#specialdetails} =============== ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Geometry. All e.s.d.\'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.\'s are taken into account individually in the estimation of e.s.d.\'s in distances, angles and torsion angles; correlations between e.s.d.\'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.\'s is used for estimating e.s.d.\'s involving l.s. planes. Refinement. Refinement of *F*^2^ against ALL reflections. The weighted *R*-factor *wR* and goodness of fit *S* are based on *F*^2^, conventional *R*-factors *R* are based on *F*, with *F* set to zero for negative *F*^2^. The threshold expression of *F*^2^ \> σ(*F*^2^) is used only for calculating *R*-factors(gt) *etc*. and is not relevant to the choice of reflections for refinement. *R*-factors based on *F*^2^ are statistically about twice as large as those based on *F*, and *R*- factors based on ALL data will be even larger. ----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å^2^) {#tablewrapcoords} ================================================================================================== ------ -------------- ------------- --------------- -------------------- -- *x* *y* *z* *U*~iso~\*/*U*~eq~ U1 0.41912 (3) 0.20869 (2) 0.332933 (15) 0.01529 (10) U2 0.71490 (3) 0.06455 (2) 0.542406 (14) 0.01236 (10) O1 0.1576 (7) 0.0796 (5) 0.3408 (3) 0.0247 (11) O2 0.1274 (7) 0.1931 (5) 0.2295 (3) 0.0272 (12) O3 0.7084 (7) 0.2370 (6) 0.4457 (4) 0.0296 (13) O4 0.6738 (7) 0.3262 (6) 0.3266 (4) 0.0306 (13) O5 0.4581 (6) 0.0936 (5) 0.4484 (3) 0.0217 (11) O6 0.3486 (7) 0.3399 (5) 0.3788 (4) 0.0277 (12) O7 0.4880 (7) 0.0816 (5) 0.2841 (4) 0.0277 (12) O8 0.3755 (7) 0.3336 (5) 0.2040 (3) 0.0230 (11) H8A 0.403 (12) 0.406 (4) 0.188 (5) 0.034\* H8B 0.367 (13) 0.286 (6) 0.160 (4) 0.034\* O9 0.6588 (7) 0.1628 (5) 0.6159 (4) 0.0264 (12) O10 0.7947 (6) −0.0283 (5) 0.4734 (3) 0.0236 (11) O11 0.9960 (6) 0.1499 (5) 0.5992 (3) 0.0202 (10) H11A 1.075 (7) 0.121 (8) 0.580 (5) 0.030\* H11B 1.047 (9) 0.200 (7) 0.641 (4) 0.030\* O12 0.3208 (9) 0.2904 (6) 0.5615 (4) 0.0376 (15) H12 0.3876 0.2346 0.5557 0.056\* C1 0.0629 (9) 0.1183 (7) 0.2696 (4) 0.0207 (14) C2 −0.1168 (10) 0.0795 (8) 0.2383 (6) 0.0332 (19) H2A −0.1601 0.0663 0.2859 0.040\* H2B −0.1261 0.0013 0.2064 0.040\* H2C −0.1825 0.1454 0.2020 0.040\* C3 0.7675 (10) 0.2993 (7) 0.3966 (5) 0.0239 (16) C4 0.9472 (12) 0.3420 (11) 0.4242 (7) 0.049 (3) H4A 0.9639 0.4053 0.3850 0.059\* H4B 1.0212 0.2701 0.4252 0.059\* H4C 0.9741 0.3785 0.4803 0.059\* C5 0.4006 (16) 0.4061 (10) 0.5715 (6) 0.051 (3) H5A 0.4034 0.4418 0.6258 0.062\* H5B 0.3388 0.4628 0.5267 0.062\* H5C 0.5159 0.3955 0.5692 0.062\* ------ -------------- ------------- --------------- -------------------- -- Atomic displacement parameters (Å^2^) {#tablewrapadps} ===================================== ----- -------------- -------------- -------------- -------------- -------------- ------------- *U*^11^ *U*^22^ *U*^33^ *U*^12^ *U*^13^ *U*^23^ U1 0.01397 (15) 0.01724 (15) 0.01456 (16) 0.00003 (8) 0.00417 (11) 0.00355 (8) U2 0.00972 (14) 0.01612 (15) 0.01148 (15) −0.00104 (8) 0.00357 (10) 0.00029 (8) O1 0.018 (3) 0.031 (3) 0.021 (3) −0.001 (2) 0.000 (2) 0.014 (2) O2 0.023 (3) 0.037 (3) 0.018 (3) −0.006 (2) 0.002 (2) 0.015 (2) O3 0.020 (3) 0.034 (3) 0.033 (3) −0.006 (2) 0.005 (2) 0.016 (3) O4 0.022 (3) 0.043 (3) 0.025 (3) −0.007 (2) 0.003 (2) 0.005 (2) O5 0.012 (2) 0.031 (3) 0.019 (3) −0.006 (2) 0.0002 (19) 0.010 (2) O6 0.019 (3) 0.032 (3) 0.029 (3) 0.006 (2) 0.003 (2) −0.001 (2) O7 0.026 (3) 0.029 (3) 0.029 (3) 0.002 (2) 0.011 (2) −0.001 (2) O8 0.023 (3) 0.025 (3) 0.022 (3) 0.001 (2) 0.008 (2) 0.011 (2) O9 0.021 (3) 0.029 (3) 0.032 (3) 0.000 (2) 0.011 (2) −0.008 (2) O10 0.016 (2) 0.032 (3) 0.022 (3) −0.004 (2) 0.004 (2) −0.009 (2) O11 0.014 (2) 0.027 (3) 0.022 (3) −0.006 (2) 0.009 (2) −0.010 (2) O12 0.042 (4) 0.040 (4) 0.033 (3) 0.004 (3) 0.014 (3) 0.004 (3) C1 0.017 (3) 0.020 (3) 0.020 (3) 0.000 (3) −0.001 (3) 0.006 (3) C2 0.016 (4) 0.043 (5) 0.036 (5) −0.006 (3) 0.001 (3) 0.014 (4) C3 0.023 (4) 0.021 (3) 0.031 (4) −0.005 (3) 0.012 (3) 0.003 (3) C4 0.028 (5) 0.073 (7) 0.044 (6) −0.014 (5) 0.006 (4) 0.021 (5) C5 0.072 (8) 0.041 (5) 0.032 (5) 0.009 (5) 0.002 (5) −0.005 (4) ----- -------------- -------------- -------------- -------------- -------------- ------------- Geometric parameters (Å, °) {#tablewrapgeomlong} =========================== -------------------- ------------- ------------------- ------------- U1---O7 1.765 (6) O4---C3 1.230 (10) U1---O6 1.779 (6) O5---U2^i^ 2.252 (5) U1---O5 2.230 (5) O8---H8A 0.87 (2) U1---O8 2.469 (5) O8---H8B 0.87 (2) U1---O4 2.494 (6) O11---H11A 0.87 (2) U1---O2 2.528 (6) O11---H11B 0.87 (2) U1---O3 2.592 (6) O12---C5 1.385 (12) U1---O1 2.614 (5) O12---H12 0.8400 U2---O9 1.784 (5) C1---C2 1.487 (10) U2---O10 1.795 (5) C2---H2A 0.9800 U2---O5^i^ 2.252 (5) C2---H2B 0.9800 U2---O5 2.261 (5) C2---H2C 0.9800 U2---O11 2.422 (5) C3---C4 1.498 (12) U2---O3 2.438 (5) C4---H4A 0.9800 U2---O1^i^ 2.461 (5) C4---H4B 0.9800 O1---C1 1.284 (8) C4---H4C 0.9800 O1---U2^i^ 2.461 (5) C5---H5A 0.9800 O2---C1 1.262 (9) C5---H5B 0.9800 O3---C3 1.268 (9) C5---H5C 0.9800 O7---U1---O6 178.0 (3) O5---U2---O1^i^ 136.78 (17) O7---U1---O5 89.9 (2) O11---U2---O1^i^ 77.77 (18) O6---U1---O5 92.1 (2) O3---U2---O1^i^ 156.28 (18) O7---U1---O8 89.4 (2) C1---O1---U2^i^ 159.4 (5) O6---U1---O8 88.6 (2) C1---O1---U1 94.1 (4) O5---U1---O8 179.2 (2) U2^i^---O1---U1 101.70 (18) O7---U1---O4 88.0 (2) C1---O2---U1 98.8 (4) O6---U1---O4 91.2 (2) C3---O3---U2 153.0 (5) O5---U1---O4 114.24 (18) C3---O3---U1 92.6 (5) O8---U1---O4 66.05 (18) U2---O3---U1 103.06 (19) O7---U1---O2 90.7 (2) C3---O4---U1 98.3 (5) O6---U1---O2 88.5 (2) U1---O5---U2^i^ 122.8 (2) O5---U1---O2 114.60 (17) U1---O5---U2 122.6 (2) O8---U1---O2 65.10 (17) U2^i^---O5---U2 109.9 (2) O4---U1---O2 131.14 (18) U1---O8---H8A 140 (6) O7---U1---O3 93.8 (2) U1---O8---H8B 112 (5) O6---U1---O3 87.1 (2) H8A---O8---H8B 102 (4) O5---U1---O3 64.64 (17) U2---O11---H11A 118 (5) O8---U1---O3 115.72 (17) U2---O11---H11B 136 (5) O4---U1---O3 50.00 (18) H11A---O11---H11B 105 (4) O2---U1---O3 175.5 (2) C5---O12---H12 109.5 O7---U1---O1 90.8 (2) O2---C1---O1 117.2 (6) O6---U1---O1 90.1 (2) O2---C1---C2 122.2 (7) O5---U1---O1 64.63 (17) O1---C1---C2 120.5 (7) O8---U1---O1 115.07 (17) C1---C2---H2A 109.5 O4---U1---O1 178.31 (18) C1---C2---H2B 109.5 O2---U1---O1 49.97 (16) H2A---C2---H2B 109.5 O3---U1---O1 129.03 (16) C1---C2---H2C 109.5 O9---U2---O10 173.7 (2) H2A---C2---H2C 109.5 O9---U2---O5^i^ 94.8 (2) H2B---C2---H2C 109.5 O10---U2---O5^i^ 90.1 (2) O4---C3---O3 118.9 (7) O9---U2---O5 90.6 (2) O4---C3---C4 120.7 (7) O10---U2---O5 94.8 (2) O3---C3---C4 120.4 (8) O5^i^---U2---O5 70.1 (2) C3---C4---H4A 109.5 O9---U2---O11 86.2 (2) C3---C4---H4B 109.5 O10---U2---O11 87.5 (2) H4A---C4---H4B 109.5 O5^i^---U2---O11 144.73 (18) C3---C4---H4C 109.5 O5---U2---O11 145.17 (18) H4A---C4---H4C 109.5 O9---U2---O3 93.4 (2) H4B---C4---H4C 109.5 O10---U2---O3 85.7 (2) O12---C5---H5A 109.5 O5^i^---U2---O3 136.25 (19) O12---C5---H5B 109.5 O5---U2---O3 66.93 (18) H5A---C5---H5B 109.5 O11---U2---O3 78.65 (18) O12---C5---H5C 109.5 O9---U2---O1^i^ 87.5 (2) H5A---C5---H5C 109.5 O10---U2---O1^i^ 90.8 (2) H5B---C5---H5C 109.5 O5^i^---U2---O1^i^ 67.08 (17) -------------------- ------------- ------------------- ------------- Symmetry codes: (i) −*x*+1, −*y*, −*z*+1. Hydrogen-bond geometry (Å, °) {#tablewraphbondslong} ============================= ---------------------- ---------- ---------- ------------ --------------- *D*---H···*A* *D*---H H···*A* *D*···*A* *D*---H···*A* O12---H12···O9 0.84 2.31 3.009 (10) 141 O12---H12···O5 0.84 2.54 3.257 (9) 143 O8---H8A···O7^ii^ 0.87 (6) 2.07 (6) 2.859 (8) 151 (7) O8---H8B···O12^iii^ 0.88 (7) 1.78 (6) 2.645 (8) 170 (9) O11---H11A···O10^iv^ 0.87 (7) 1.88 (7) 2.736 (7) 166 (8) O11---H11B···O2^v^ 0.88 (7) 1.83 (7) 2.705 (7) 173 (7) ---------------------- ---------- ---------- ------------ --------------- Symmetry codes: (ii) −*x*+1, *y*+1/2, −*z*+1/2; (iii) *x*, −*y*+1/2, *z*−1/2; (iv) −*x*+2, −*y*, −*z*+1; (v) *x*+1, −*y*+1/2, *z*+1/2. ###### Hydrogen-bond geometry (Å, °) *D*---H⋯*A* *D*---H H⋯*A* *D*⋯*A* *D*---H⋯*A* ----------------------- ---------- ---------- ------------ ------------- O12---H12⋯O9 0.84 2.31 3.009 (10) 141 O8---H8*A*⋯O7^i^ 0.87 (6) 2.07 (6) 2.859 (8) 151 (7) O8---H8*B*⋯O12^ii^ 0.88 (7) 1.78 (6) 2.645 (8) 170 (9) O11---H11*A*⋯O10^iii^ 0.87 (7) 1.88 (7) 2.736 (7) 166 (8) O11---H11*B*⋯O2^iv^ 0.88 (7) 1.83 (7) 2.705 (7) 173 (7) Symmetry codes: (i) ; (ii) ; (iii) ; (iv) . | Mid | [
0.6341463414634141,
29.25,
16.875
] |
Wells typically contain sub-surface safety valves (SSV), which are actuated from the surface through a control line, which runs down to the valve. These valves have a biased closure member, known as a flapper. The flapper is biased into contact with a mating seat for isolation of a zone in the well from the surface. The flapper is positioned perpendicularly to the longitudinal axis of the wellbore, when it is in the closed position. To open the valve, pressure through the control line causes a flow tube to shift against a bias force. The flow tube engages the flapper to rotate it 90 degrees. The flow tube continues to advance as the flapper is positioned behind it. In certain wells, with the SSV closed and formation pressure acting on the flapper in the closed position, it is desirable to equalize the pressure on both sides of the flapper before attempting to rotate it with the flow tube. A pressure imbalance can occur because there is gas at low pressure above the flapper and high pressure from the formation below the flapper. One costly way to equalize the pressure is to add heavy fluid above the flapper. An easier way is to install and equalizing valve in the flapper so that when the flow tube starts moving down it strikes the plunger of the equalizing valve first. This causes the plunger to move to equalize the pressure across the flapper before the flapper is pushed away from its seat by the flow tube. A few examples of this design are U.S. Pat. Nos. 4,475,599 and 4,478,286. The layout of the principal components of an SSV in the closed position is illustrated in FIG. 1. The SSV 10 has a body 12 and a flapper 14 pinned at pin 16 to body 12. The flapper 14 is biased to the closed position shown by a spring 18. Flapper 14 is in contact with a seat 20, in the closed position shown in FIG. 1. A flow tube 22 is driven by pressure in a control line (not shown) against the force of a spring 24. The equalizer valve 26 is disposed in the flapper 14 so that upon initial downward movement of the flow tube 22, the initial contact occurs between the equalizer valve 26 and the flow tube 22, which results in pressure equalization before the flow tube 22 pushes the flapper 14 off of seat 20. When the flow tube 22 moves down completely, as shown in FIG. 2, the flapper 14 is behind the flow tube 22. FIG. 2 also illustrates the initial position of equalizer valve 26 when the flapper 14 is in the closed position of FIG. 1. It can be seen that the equalizer valve is engaged off-center by the flow tube 22. One reason for this offset contact is the limited choice of placement of the equalizer valve 26. FIG. 3 shows a view of the underside of the flapper 14 showing the bore 28 located in the thick segment 30 of flapper 14. In order to get a sufficiently long bore, it was located in the remotest part of the thick segment 30. FIG. 6 illustrates the need for offset contact. The equalizer valve 26 comprises a plunger 32 and a bore 34 that extends from the upper end 36 to lateral bores 38. When depressed by the flow tube 22 the lateral bores 38 extend below the lower end 40 of the flapper 14 and equalizing flow is established. The offset contact is used in this design to avoid obstructing the bore 34 during initial movement of the plunger 32. FIG. 2 illustrates another aspect of the prior design. The plunger 32 had a chamfer 42 so as to avoid contact with the flow tube 22 when the SSV was in the open position. This need for clearance made the end of the plunger 32 asymmetrical, making the installed orientation critical to achieve the desired clearance with the flow tube 22 when the SSV was opened. The offset contact between the flow tube 22 and the plunger 32 tended to put a counterclockwise moment on the plunger 32 and resulted in abnormal wear on portion 44, closest to the point of offset contact. To combat this problem of wear, the plunger 32 was first produced and measured. Thereafter, bore 28 was machined to about 0.001 inch over the diameter of the plunger 32 and both surfaces were polished to 8 RMS. The problem was that each plunger 32 was custom fit to each bore 28 so that it was not possible to maintain a store of spare parts that could be counted on to provide adequate service. Even with expensive machining, the problem of premature wear due to offset contact, created a reliability and maintenance concern. Accordingly, the objective of the present invention is to provide design features to minimize or otherwise cope with the wear issue from offset contact. Another feature of the invention is to work around offset contact that caused the wear and still allow the equalizer valve 26 to effectively function. Those skilled in the art will appreciate how the invention addresses these objectives from a review of the detailed description of the preferred embodiment, which appears below. | Mid | [
0.587755102040816,
36,
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export const colorGroups = { gray: ['black', 'dark-gray', 'gray', 'accent-gray', 'light-gray', 'white'], teal: ['teal', 'accent-teal', 'light-teal'], blue: ['dark-blue', 'blue', 'accent-blue', 'light-blue'], red: ['dark-red', 'red', 'light-red'], green: ['green', 'accent-green', 'light-green'], yellow: ['decorative-yellow', 'light-yellow'] }; export const colorNames = Object.keys(colorGroups).reduce((memo, key) => [ ...memo, ...colorGroups[key] ], []); | Low | [
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“If the Democrats are successful in removing the President from office (which they will never be), it will cause a Civil War like fracture in this Nation from which our Country will never heal,” Trump tweeted, adding his own parenthetical to a quote from Robert Jeffress, a Southern Baptist preacher speaking on “Fox & Friends Weekend” on Sunday. Watch more! Trump’s tweet invoking civil war marks a notable escalation in his rhetoric about the impeachment inquiry and also highlights his close relationship with Jeffress, a pastor known for viciously attacking other faiths who holds sway over both evangelical voters and the president. The tweet drew an immediate reaction, becoming the lead story on the Drudge Report and prompting critics — including one sitting Republican congressman — to accuse Trump of stoking violence and diminishing the reality of true civil war. “I have visited nations ravaged by civil war. @realDonaldTrump I have never imagined such a quote to be repeated by a President,” tweeted Rep. Adam Kinzinger (R-Ill.), a decorated Air Force veteran who served as a pilot in Iraq and Afghanistan. “This is beyond repugnant.” House Democrat Don Beyer of Virginia urged other Republicans to join Kinzinger in denouncing Trump’s rhetoric, tweeting, “The president is testing to see who will echo or silently accept threats of violence.” Presidential hopeful Beto O’Rourke, too, called upon GOP members to speak out. Trump’s words can have violent consequences, the former Democratic representative tweeted, citing the mass shooting in El Paso and asking for Republicans to decry him “before more are harmed in his name.” Two Senate Democrats, Chris Murphy (Conn.) and Brian Schatz (Hawaii), also condemned the president’s tweet in a back-and-forth in which Murphy described the message as “so frightening.” “He is going to keep talking like this,” Murphy tweeted, “and some people are going to listen and do what he asks.” The idea of a U.S. civil war did not come from Trump directly. Instead, he quoted a high-profile and contentious Texas pastor who has stood with the president since the earliest days of the 2016 campaign. Jeffress, who fronts a megachurch in Dallas that attracts 14,000 worshipers and hosts his own religious television and radio shows, introduced then-candidate Trump at a campaign rally in January 2016. A month later, he gave an impassioned speech in Fort Worth, endorsing Trump, who he said would be a “true friend” to evangelical Christians, at a time when many religious conservatives still wavered on whether to support the former Democrat with a scandalous past. Since then, the pastor has been one of Trump’s most outspoken supporters. He uses the Bible to defend the president’s actions and brushes away allegations of immoral conduct, from extramarital affairs to alleged sexual assault, by emphasizing Trump’s record on filling the judiciary with conservative justices and pushing for policies that limit access to abortion. Jeffress has called “Never Trump” Christians “absolutely spineless morons” and compared them to the German Christians in the 1930s who did not try to stop the Nazis. He has called the Mormon Church a “cult,” and personally attacked Republican Mitt Romney over his faith in 2011. He once compared Trump’s border wall to the gates to heaven, because both signify “not everybody’s going to be allowed in.” Since Democrats began moving toward impeachment last week, Jeffress has repeatedly sounded grim warnings. On Friday, he told Fox Business Network host Lou Dobbs, “I really don’t like what’s going to happen to this nation” if impeachment succeeds, adding, “If he is removed, this country is finished.” The Jeffress quote that Trump tweeted Sunday evening is the first time the president has referenced civil war on Twitter. But as The Washington Post’s Greg Jaffe and Jenna Johnson have reported, cable news pundits on both sides of the spectrum have already begun using the term with regularity to describe the nation’s political conflict. In one notable case in February, former U.S. attorney Joseph diGenova on Fox News and Trump critic and political analyst Nicolle Wallace on MSNBC both declared that the U.S. was “in a civil war,” though both pundits later walked back their rhetoric to claim they meant a war of words and ideas. Although it is “not entirely out of the question,” Stanford University political scientist James Fearon told The Post in March that he dismissed the idea of the United States being on the verge of a war with itself as “basically absurd.” It’s not clear from Trump’s tweet or Jeffress’s interview whether he was referencing actual violence as the outcome of an impeachment, but many critics said that the president’s use of the term was troubling. The White House did not immediately respond to a request for comment clarifying the president’s intentions. The Oath Keepers, a far-right militia group composed of former military and law enforcement officers, apparently took the message literally, saying in a Twitter thread that the United States is “on the verge of a HOT civil war. Like in 1859.” The group claims to protect the Constitution “against all enemies,” which, they say, includes Democrats who are trying to impede Trump’s “rightful power." The organization is described by the Southern Poverty Law Center as “one of the largest radical anti-government groups in the U.S. today." “Lincoln created the Republican Party and gave his life in order to save the Union. Trump ruined the Republican Party and now threatens to destroy the Union in order to save his job,” tweeted Rep. Jamie B. Raskin (D-Md.). Schatz echoed that concern. | Low | [
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Ben Foster continues a hot streak with “Galveston” It’s hard to find a more underrated actor in the industry than Ben Foster. For years now, he’s been doing incredibly good work, often in very solid films, without receiving the acclaim that he deserves. Luckily, he’s slowly getting more time in the spotlight. His brush with an Academy Award nomination (he was unjustly snubbed) for Hell or High Water got him to a new level. Then, Foster followed it up earlier this year with a 180 of a performance in Leave No Trace. Now, this week brings something in between with Galveston, a starring vehicle for the man. We rarely get those, so it’s something to cherish. This movie is a noir of sorts, which is to be expected, considering Nic Pizzolatto penned the novel and wrote his own adaptation. The film follows Roy Cady (Foster), a middle aged hitman in New Orleans. Given a terminal diagnosis of lung cancer, he immediately leaves the doctor’s office an lights a cigarettes. That’s who Roy is. When he’s given a job by his mobster boss (Beau Bridges), it seems like an easy gig. Of course, he’s instead double crossed. He escapes, rescuing a young prostitute named Rocky (Elle Fanning) in the process. Now looking to survive, and with revenge on his mind, he whisks her off towards Galveston to plan his next move. Rocky has her own problems too, and soon they’ve picked up her young sister, complicating matters. It’s gritty stuff, with a bold third act that you won’t see coming. Actress turned filmmaker Melanie Laurent directs the script Pizzolatto wrote with Jim Hammett. This is mostly a two hander, though the cast also includes Adepero Oduye, Anniston Price, Tinsley Price, Lili Reinhart, and more. The evocative cinematography and music comes from Arnaud Potier and Marc Chouarain, respectively. Foster delivers reliably good work here. It’s another quiet character for him, but one that’s not nearly silent, as was Leave No Trace. He doesn’t quite develop chemistry with Fanning, but that’s by design. He’s the center of attention, and since that doesn’t happen too often, that’s a real plus. There are a few narrative turns that might make you roll your eyes, but Foster’s work keeps you on board the whole time. Fanning’s work is praiseworthy too, is the filmmaking from Laurent. Galveston suggests that Laurent is capable of directing just about any type of movie. Her skillset is deeply malleable and she has an eye for lived in performances. Fanning and Foster are in good hands here. I’d actually love to see Laurent continue to work in genre. Hell, Jason Blum just spoke of how hard it is to find female directors to make his horror outings. Give her a call. She’d knock it out of the park. If you love Foster, Galveston should be up your alley. It begins its theatrical run this weekend, and while it probably won’t find a huge audience, it may well find a small yet appreciative one. Frankly, in addition to Foster’s work, Laurent’s filmmaking is so subtly effective, that’s worth taking in as well. As good an actress as she is, Laurent may very well be a better filmmaker. At the very least, I now am eager to see what she does next. Together, they make this a flick worth giving a shot to. | Mid | [
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/* * Copyright (C) NEC Electronics Corporation 2004-2006 * * This file is based on the arch/mips/ddb5xxx/ddb5477/irq.c * * Copyright 2001 MontaVista Software Inc. * * This program is free software; you can redistribute it and/or modify * it under the terms of the GNU General Public License as published by * the Free Software Foundation; either version 2 of the License, or * (at your option) any later version. * * This program is distributed in the hope that it will be useful, * but WITHOUT ANY WARRANTY; without even the implied warranty of * MERCHANTABILITY or FITNESS FOR A PARTICULAR PURPOSE. See the * GNU General Public License for more details. * * You should have received a copy of the GNU General Public License * along with this program; if not, write to the Free Software * Foundation, Inc., 59 Temple Place, Suite 330, Boston, MA 02111-1307 USA */ #include <linux/init.h> #include <linux/interrupt.h> #include <linux/irq.h> #include <linux/types.h> #include <linux/ptrace.h> #include <linux/delay.h> #include <asm/irq_cpu.h> #include <asm/system.h> #include <asm/mipsregs.h> #include <asm/addrspace.h> #include <asm/bootinfo.h> #include <asm/emma/emma2rh.h> static void emma2rh_irq_enable(unsigned int irq) { u32 reg_value; u32 reg_bitmask; u32 reg_index; irq -= EMMA2RH_IRQ_BASE; reg_index = EMMA2RH_BHIF_INT_EN_0 + (EMMA2RH_BHIF_INT_EN_1 - EMMA2RH_BHIF_INT_EN_0) * (irq / 32); reg_value = emma2rh_in32(reg_index); reg_bitmask = 0x1 << (irq % 32); emma2rh_out32(reg_index, reg_value | reg_bitmask); } static void emma2rh_irq_disable(unsigned int irq) { u32 reg_value; u32 reg_bitmask; u32 reg_index; irq -= EMMA2RH_IRQ_BASE; reg_index = EMMA2RH_BHIF_INT_EN_0 + (EMMA2RH_BHIF_INT_EN_1 - EMMA2RH_BHIF_INT_EN_0) * (irq / 32); reg_value = emma2rh_in32(reg_index); reg_bitmask = 0x1 << (irq % 32); emma2rh_out32(reg_index, reg_value & ~reg_bitmask); } struct irq_chip emma2rh_irq_controller = { .name = "emma2rh_irq", .ack = emma2rh_irq_disable, .mask = emma2rh_irq_disable, .mask_ack = emma2rh_irq_disable, .unmask = emma2rh_irq_enable, }; void emma2rh_irq_init(void) { u32 i; for (i = 0; i < NUM_EMMA2RH_IRQ; i++) set_irq_chip_and_handler_name(EMMA2RH_IRQ_BASE + i, &emma2rh_irq_controller, handle_level_irq, "level"); } static void emma2rh_sw_irq_enable(unsigned int irq) { u32 reg; irq -= EMMA2RH_SW_IRQ_BASE; reg = emma2rh_in32(EMMA2RH_BHIF_SW_INT_EN); reg |= 1 << irq; emma2rh_out32(EMMA2RH_BHIF_SW_INT_EN, reg); } static void emma2rh_sw_irq_disable(unsigned int irq) { u32 reg; irq -= EMMA2RH_SW_IRQ_BASE; reg = emma2rh_in32(EMMA2RH_BHIF_SW_INT_EN); reg &= ~(1 << irq); emma2rh_out32(EMMA2RH_BHIF_SW_INT_EN, reg); } struct irq_chip emma2rh_sw_irq_controller = { .name = "emma2rh_sw_irq", .ack = emma2rh_sw_irq_disable, .mask = emma2rh_sw_irq_disable, .mask_ack = emma2rh_sw_irq_disable, .unmask = emma2rh_sw_irq_enable, }; void emma2rh_sw_irq_init(void) { u32 i; for (i = 0; i < NUM_EMMA2RH_IRQ_SW; i++) set_irq_chip_and_handler_name(EMMA2RH_SW_IRQ_BASE + i, &emma2rh_sw_irq_controller, handle_level_irq, "level"); } static void emma2rh_gpio_irq_enable(unsigned int irq) { u32 reg; irq -= EMMA2RH_GPIO_IRQ_BASE; reg = emma2rh_in32(EMMA2RH_GPIO_INT_MASK); reg |= 1 << irq; emma2rh_out32(EMMA2RH_GPIO_INT_MASK, reg); } static void emma2rh_gpio_irq_disable(unsigned int irq) { u32 reg; irq -= EMMA2RH_GPIO_IRQ_BASE; reg = emma2rh_in32(EMMA2RH_GPIO_INT_MASK); reg &= ~(1 << irq); emma2rh_out32(EMMA2RH_GPIO_INT_MASK, reg); } static void emma2rh_gpio_irq_ack(unsigned int irq) { irq -= EMMA2RH_GPIO_IRQ_BASE; emma2rh_out32(EMMA2RH_GPIO_INT_ST, ~(1 << irq)); } static void emma2rh_gpio_irq_mask_ack(unsigned int irq) { u32 reg; irq -= EMMA2RH_GPIO_IRQ_BASE; emma2rh_out32(EMMA2RH_GPIO_INT_ST, ~(1 << irq)); reg = emma2rh_in32(EMMA2RH_GPIO_INT_MASK); reg &= ~(1 << irq); emma2rh_out32(EMMA2RH_GPIO_INT_MASK, reg); } struct irq_chip emma2rh_gpio_irq_controller = { .name = "emma2rh_gpio_irq", .ack = emma2rh_gpio_irq_ack, .mask = emma2rh_gpio_irq_disable, .mask_ack = emma2rh_gpio_irq_mask_ack, .unmask = emma2rh_gpio_irq_enable, }; void emma2rh_gpio_irq_init(void) { u32 i; for (i = 0; i < NUM_EMMA2RH_IRQ_GPIO; i++) set_irq_chip_and_handler_name(EMMA2RH_GPIO_IRQ_BASE + i, &emma2rh_gpio_irq_controller, handle_edge_irq, "edge"); } static struct irqaction irq_cascade = { .handler = no_action, .flags = 0, .name = "cascade", .dev_id = NULL, .next = NULL, }; /* * the first level int-handler will jump here if it is a emma2rh irq */ void emma2rh_irq_dispatch(void) { u32 intStatus; u32 bitmask; u32 i; intStatus = emma2rh_in32(EMMA2RH_BHIF_INT_ST_0) & emma2rh_in32(EMMA2RH_BHIF_INT_EN_0); #ifdef EMMA2RH_SW_CASCADE if (intStatus & (1UL << EMMA2RH_SW_CASCADE)) { u32 swIntStatus; swIntStatus = emma2rh_in32(EMMA2RH_BHIF_SW_INT) & emma2rh_in32(EMMA2RH_BHIF_SW_INT_EN); for (i = 0, bitmask = 1; i < 32; i++, bitmask <<= 1) { if (swIntStatus & bitmask) { do_IRQ(EMMA2RH_SW_IRQ_BASE + i); return; } } } /* Skip S/W interrupt */ intStatus &= ~(1UL << EMMA2RH_SW_CASCADE); #endif for (i = 0, bitmask = 1; i < 32; i++, bitmask <<= 1) { if (intStatus & bitmask) { do_IRQ(EMMA2RH_IRQ_BASE + i); return; } } intStatus = emma2rh_in32(EMMA2RH_BHIF_INT_ST_1) & emma2rh_in32(EMMA2RH_BHIF_INT_EN_1); #ifdef EMMA2RH_GPIO_CASCADE if (intStatus & (1UL << (EMMA2RH_GPIO_CASCADE % 32))) { u32 gpioIntStatus; gpioIntStatus = emma2rh_in32(EMMA2RH_GPIO_INT_ST) & emma2rh_in32(EMMA2RH_GPIO_INT_MASK); for (i = 0, bitmask = 1; i < 32; i++, bitmask <<= 1) { if (gpioIntStatus & bitmask) { do_IRQ(EMMA2RH_GPIO_IRQ_BASE + i); return; } } } /* Skip GPIO interrupt */ intStatus &= ~(1UL << (EMMA2RH_GPIO_CASCADE % 32)); #endif for (i = 32, bitmask = 1; i < 64; i++, bitmask <<= 1) { if (intStatus & bitmask) { do_IRQ(EMMA2RH_IRQ_BASE + i); return; } } intStatus = emma2rh_in32(EMMA2RH_BHIF_INT_ST_2) & emma2rh_in32(EMMA2RH_BHIF_INT_EN_2); for (i = 64, bitmask = 1; i < 96; i++, bitmask <<= 1) { if (intStatus & bitmask) { do_IRQ(EMMA2RH_IRQ_BASE + i); return; } } } void __init arch_init_irq(void) { u32 reg; /* by default, interrupts are disabled. */ emma2rh_out32(EMMA2RH_BHIF_INT_EN_0, 0); emma2rh_out32(EMMA2RH_BHIF_INT_EN_1, 0); emma2rh_out32(EMMA2RH_BHIF_INT_EN_2, 0); emma2rh_out32(EMMA2RH_BHIF_INT1_EN_0, 0); emma2rh_out32(EMMA2RH_BHIF_INT1_EN_1, 0); emma2rh_out32(EMMA2RH_BHIF_INT1_EN_2, 0); emma2rh_out32(EMMA2RH_BHIF_SW_INT_EN, 0); clear_c0_status(0xff00); set_c0_status(0x0400); #define GPIO_PCI (0xf<<15) /* setup GPIO interrupt for PCI interface */ /* direction input */ reg = emma2rh_in32(EMMA2RH_GPIO_DIR); emma2rh_out32(EMMA2RH_GPIO_DIR, reg & ~GPIO_PCI); /* disable interrupt */ reg = emma2rh_in32(EMMA2RH_GPIO_INT_MASK); emma2rh_out32(EMMA2RH_GPIO_INT_MASK, reg & ~GPIO_PCI); /* level triggerd */ reg = emma2rh_in32(EMMA2RH_GPIO_INT_MODE); emma2rh_out32(EMMA2RH_GPIO_INT_MODE, reg | GPIO_PCI); reg = emma2rh_in32(EMMA2RH_GPIO_INT_CND_A); emma2rh_out32(EMMA2RH_GPIO_INT_CND_A, reg & (~GPIO_PCI)); /* interrupt clear */ emma2rh_out32(EMMA2RH_GPIO_INT_ST, ~GPIO_PCI); /* init all controllers */ emma2rh_irq_init(); emma2rh_sw_irq_init(); emma2rh_gpio_irq_init(); mips_cpu_irq_init(); /* setup cascade interrupts */ setup_irq(EMMA2RH_IRQ_BASE + EMMA2RH_SW_CASCADE, &irq_cascade); setup_irq(EMMA2RH_IRQ_BASE + EMMA2RH_GPIO_CASCADE, &irq_cascade); setup_irq(CPU_IRQ_BASE + CPU_EMMA2RH_CASCADE, &irq_cascade); } asmlinkage void plat_irq_dispatch(void) { unsigned int pending = read_c0_status() & read_c0_cause() & ST0_IM; if (pending & STATUSF_IP7) do_IRQ(CPU_IRQ_BASE + 7); else if (pending & STATUSF_IP2) emma2rh_irq_dispatch(); else if (pending & STATUSF_IP1) do_IRQ(CPU_IRQ_BASE + 1); else if (pending & STATUSF_IP0) do_IRQ(CPU_IRQ_BASE + 0); else spurious_interrupt(); } | Low | [
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The 9 Best Complex Carbs for Weight Loss If you’re looking to shed unwanted weight fast, there are more efficient ways to whittle your middle than giving up your morning toast or occasional pasta dinner. Yes, it’s true: You can lose weight eating carbs, but only if you eat the right ones. The key to hacking your weight-loss plan is limiting your intake of simple carbohydrates and nourishing your body with complex carbohydrates—high-fiber carbs that keep you full for longer because they take more time for your body to digest. Another solid reason to swap simple carbs for their complex counterparts: quick-burning, highly-refined simple carbs don’t usually contain the plethora of slimming vitamins and minerals that complex carbs do. Black Beans Shutterstock Next time you bust out the slow cooker to make homemade beef chili, don’t forget to add some black beans to the mix. Out of all beans, this dark legume has the highest amount of the antioxidant anthocyanin, which forms a strong defense against cardiovascular disease. A daily half-cup serving of canned beans provides 7 grams of protein and 8.5 grams of fiber, according to the USDA National Nutrient Database. We also like peas, lentils, and pinto, kidney, fava, and lima beans. EAT THIS! TIP Buy a brand that’s low-sodium or salt-free—like Eden Foods—or make them fresh. And here’s a recipe we love for Black Bean and Tomato Salsa: Dice 4 tomatoes, 1 onion, 3 cloves garlic, 2 jalapeños, 1 yellow bell pepper and 1 mango. Mix in a can of black beans and garnish with 1/2 cup chopped cilantro and the juice of 2 limes. 2 100% Whole Grain Bread Shutterstock With whole-wheat bread, you’re getting all three parts of the grain: the bran, germ, and endosperm. Refined grains lack the bran and germ, which the Whole Grains Council says contain 25 percent of a grain’s protein. You’ll want to be careful picking out a loaf in the grocery store, as many breads are filled with high fructose corn syrup or a blend of whole and white wheats. Make sure your bag says “100% Whole Wheat” and know that it’s worth splurging on the pricier stuff. For more tips, check out 20 Best & Worst Store-Bought Breads. EAT THIS! TIP We like Ezekiel 4:9 Sprouted Cinnamon Raisin Bread. The millet, spelt and cholesterol-lowering barley in this slightly-sweet loaf help boost its fiber, a nutrient that wards off hunger while keeping calories low. Toast up a slice and smear it with some natural peanut butter for a quick, nutrient-packed breakfast that both big and little kids alike are sure to love. 3 Oatmeal Shutterstock Start your day with a warm and comforting bowl of steel-cut oats. These crunchy grains are your best bet when choosing which a.m. staple to spoon because they’re less processed than quick-cook oats and therefore retain more fiber and protein. Specifically, oats contain 5 grams of protein and 4 grams of fiber per half-cup serving. This essential macronutrient combo will help crush cravings and keep hunger pangs at bay—especially since the specific soluble fiber found in oats, known as beta-glucans, has been shown to enhance feelings of satiety. EAT THIS! TIP Top your oats with omega-3-rich chia seeds and antioxidant-rife cacao nibs to add healthy fats and round out your morning meal. If you find yourself in a time crunch or even just want to keep a healthy snack stashed in your desk drawer, check out our round-up of the best and worst instant oatmeals for weight loss. 4 Kamut Shutterstock Kamut, or Khorasan wheat, is an ancient grain that’s brimming with nearly 10 grams of protein and about 7 grams of fiber per cooked cup. Plus, the buttery-flavored grain contains high levels of inflammation-fighting cytokines, according to a study published in the European Journal of Clinical Nutrition, which can help ward off weight gain. For more foods that’ll help you banish belly fat and bloat, check out these 30 Best Anti-Inflammatory Foods. EAT THIS! TIP Buy it and boil it. Or try Eden Foods Kamut Spaghetti. In addition to serving up a good amount of protein and fiber, the noodles have 20 percent of the day’s magnesium—a nutrient not normally found in pasta. Not getting enough magnesium has been linked to insulin resistance, metabolic syndrome, and coronary heart disease. 5 Acorn Squash Shutterstock Drizzle acorn squash with heart-healthy olive oil before baking for a wholesome dinner side that’s sure to please. The orange-fleshed veggie is jam-packed with blood-sugar-regulating soluble fiber, diabetes-preventing magnesium, and 30 percent of your daily vitamin C needs. The body uses this nutrient to form muscle and blood vessels, and Arizona State University researchers claim it can even boost the fat-burning effects of exercise. EAT THIS! TIP For a simple—yet sweet—side dish, halve an acorn squash, scoop out the seeds and add a little butter, cinnamon and a drizzle of maple syrup. Bake for about an hour at 400 degrees F. Or try this delicious Avocado and Quinoa Stuffed Acorn Squash. 6 Barley Shutterstock Give regular ol’ wheat a break from your weekly lunch rotation and switch it up with barley. The high-fiber whole-grain is loaded with essential vitamins and minerals such as mood-boosting B vitamins, immunity-protecting selenium, and bone-building manganese. What’s more, a study published in the Journal of the American College of Nutrition found that barley helped participants lower their weight, cholesterol levels, and reduced feelings of hunger. EAT THIS! TIP Try barley by buying Kashi 7 Whole Grain Nuggets Cereal. Cereals rich in fiber and whole grains reduce the risk of disease and early death, say Harvard School of Public Health researchers. Lucky for you, these nuggets are made with fiber-rich whole grains like oats, red wheat, rye, brown rice, triticale, barley, buckwheat, and sesame seeds. 7 Whole-Wheat Pasta Shutterstock Regular pasta is made with white wheat flour, which has been stripped of the grain’s nutrient-dense bran and germ, which are brimming with fiber, protein, and vitamins and minerals. Go for whole-wheat or whole-grain pasta to reap some satiating benefits. Here’s another waist-whittling trick: After cooking your penne, pop it into the fridge and then dig in when it’s cold. Cooling the noodle turns its starch into resistant starch, which digests more slowly, discouraging you from spooning into a second helping. EAT THIS! TIP Jovial Einkorn Rigatoni is our go-to brand for whole wheat pasta. (Also try varieties made with chickpeas, black beans, quinoa, or lentils, like Modern Table’s Lentil Rotini.) Because it has never been hybridized, Einkorn is one of the purest species of wheat out there, say its proponents. The whole grain is rich in protein and fiber, and just one serving of this pasta dishes up a quarter of the day’s phosphorus (a nutrient that’s typically only found in milk and meat) and 80 percent of the day’s manganese, an essential nutrient that helps the body process cholesterol, carbs and proteins. And, bonus health tip: If you’re whipping up a pasta sauce, try throwing some flax seeds in the mix, suggests Rachel Fine, MS, RD, CDN. “They’re a great source of healthy unsaturated fats, which are powerhouses for the body’s immune system,” she says. See, because our bodies are exposed to pollutants in the environment, they’re in a constant state of low-severity inflammation. Thanks to their unsaturated fat content, flax seeds help the body battle that inflammation, according to Fine. 8 Green Peas Shutterstock Beyond the abundance of vitamins and minerals, a cup of peas contains more than a third of your kid’s daily fiber intake—more than most whole-wheat breads. In one four-week Spanish study, researchers found that eating a calorie-restricted diet that includes four weekly servings of legumes aids weight loss more effectively than an equivalent diet that doesn’t include them. Those who consumed the legume-rich diet also saw improvements in their “bad” LDL cholesterol levels and systolic blood pressure. To reap the benefits at home, work lentils, chickpeas, peas and beans into your diet throughout the week. EAT THIS! TIP Add frozen peas to a pasta sauce at the last second, or puree them up with garlic and olive oil as a simple, sweet dip. Or: “A handful of Snapea Crisps provides a whopping five grams of satiety-boosting protein and four grams of fiber for a mere 110 calories,” says Lisa De Fazio, MS, RD, Los Angeles-based Registered Dietitian. “Plus, this snack is non-perishable, so it can be easily eaten just about anywhere.” 9 Quinoa Shutterstock It has a light, mild flavor, making it ideal for people who dislike other “cardboard-y” whole grains. It gets better: quinoa is higher in protein than any other grain—with 6 grams per half-cup—and packs a hefty dose of heart-healthy, unsaturated fats. “Quinoa is also a great source of fiber and B vitamins,” says Christopher Mohr, PhD, RD, a professor of nutrition at the University of Louisville. EAT THIS! TIP Try Quinoa in the morning! It has twice the protein of most cereals, and fewer carbs. Boil 1 cup quinoa in 2 cups of water. Let cool. In a large bowl, toss it with 2 diced apples, 1 cup fresh blueberries, 1/2 cup chopped walnuts and 1 cup plain fat-free yogurt. This recipe serves four, so stash any leftovers in the fridge for easy breakfasts throughout the week. And if you’re having a hard time doing anything interesting with this tricky grain, try these easy and filling 20 Delicious Quinoa Bowls for Breakfast. Get 5 Free Gifts When You Subscribe! Look, feel and live great while getting on the path to better health with the new Eat This, Not That! Magazine. | Mid | [
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1. Field of the Invention Generally, the present disclosure relates to the fabrication of integrated circuits, and, more particularly, to field effect transistors, such as P-channel transistors, comprising an embedded strain-inducing semiconductor alloy and a high-k metal gate electrode formed in an early manufacturing stage. 2. Description of the Related Art The fabrication of complex integrated circuits requires the provision of a large number of transistor elements, which represent the dominant circuit element in complex integrated circuits. For example, several hundred millions of transistors may be provided in presently available complex integrated circuits. Generally, a plurality of process technologies are currently practiced, wherein, for complex circuits, such as microprocessors, storage chips and the like, CMOS technology is currently the most promising approach due to the superior characteristics in view of operating speed and/or power consumption and/or cost efficiency. In CMOS circuits, complementary transistors, i.e., P-channel transistors and N-channel transistors, are used for forming circuit elements, such as inverters and other logic gates to design highly complex circuit assemblies, such as CPUs, storage chips and the like. During the fabrication of complex integrated circuits using CMOS technology, millions of transistors, i.e., N-channel transistors and P-channel transistors, are formed on a substrate including a crystalline semiconductor layer. A MOS transistor or generally a field effect transistor, irrespective of whether an N-channel transistor or a P-channel transistor is considered, comprises so-called PN junctions that are formed by an interface of highly doped drain and source regions and an inversely or weakly doped channel region disposed between the drain region and the source region. The conductivity of the channel region, i.e., the drive current capability of the conductive channel, is controlled by a gate electrode formed in the vicinity of the channel region and separated therefrom by a thin insulating layer. The conductivity of the channel region, upon formation of a conductive channel due to the application of an appropriate control voltage to the gate electrode, depends on, among other things, the dopant concentration, the mobility of the charge carriers and, for a given extension of the channel region in the transistor width direction, on the distance between the source and drain regions, which is also referred to as channel length. Thus, the reduction of the channel length, and associated therewith the reduction of the channel resistivity, is a dominant design criterion for accomplishing an increase in the operating speed of the integrated circuits. The continuing shrinkage of the transistor dimensions, however, involves a plurality of issues associated therewith that have to be addressed so as to not unduly offset the advantages obtained by steadily decreasing the channel length of MOS transistors. For example, highly sophisticated dopant profiles, in the vertical direction as well as in the lateral direction, are required in the drain and source regions to provide low sheet and contact resistivity in combination with desired channel controllability. Upon continuously reducing the channel length of field effect transistors, generally, an increased degree of capacitive coupling is required in order to maintain controllability of the channel region, which may typically require an adaptation of a thickness and/or material composition of the gate dielectric material. For example, for a gate length of approximately 80 nm, a gate dielectric material based on silicon dioxide with a thickness of less than 2 nm may be required in high speed transistor elements, which may, however, result in increased leakage currents caused by hot carrier injection and direct tunneling of charge carriers through the extremely thin gate dielectric material. Since a further reduction in thickness of silicon dioxide-based gate dielectric materials may become increasingly incompatible with thermal power requirements of sophisticated integrated circuits, other alternatives have been developed in increasing the charge carrier mobility in the channel region, thereby also enhancing overall performance of field effect transistors. One promising approach in this respect is the generation of a certain type of strain in the channel region, since the charge carrier mobility in silicon strongly depends on the strain conditions of the crystalline material. For example, for a standard crystallographic configuration of the silicon-based channel region, a compressive strain component in a P-channel transistor may result in a superior mobility of holes, thereby increasing switching speed and drive current of P-channel transistors. The desired compressive strain component may be obtained according to well-established approaches by incorporating a strain-inducing semiconductor material, for instance in the form of a silicon/germanium mixture or alloy, in the drain and source areas within the active region of the P-channel transistor. For example, after forming the gate electrode structure, corresponding cavities may be formed laterally adjacent to the gate electrode structure in the active region and may be refilled with the silicon/germanium alloy which, when grown on the silicon material, may have an internal strained state, which in turn may induce a corresponding compressive strain component in the adjacent channel region. Consequently, a plurality of process strategies have been developed in the past in order to incorporate a highly strained silicon/germanium material in the drain and source areas of P-channel transistors, wherein the efficiency of the strain mechanism critically depends on the material composition of the silicon/germanium mixture, i.e., on the germanium concentration, and the amount of the mixture and its offset from the channel region. These aspects, in turn, are determined by the depth and shape of the cavities formed in the active region. During the continuous reduction of the critical dimensions of transistors, also an appropriate adaptation of the material composition of the gate dielectric material has been proposed such that, for a physically appropriate thickness of a gate dielectric material, i.e., for reducing the gate leakage currents, nevertheless, a desired high capacitive coupling may be achieved. Thus, material systems have been proposed which have a significantly higher dielectric constant compared to the conventionally used silicon dioxide-based materials, silicon oxynitride materials and the like. For example, dielectric materials including hafnium, zirconium, aluminum and the like may have a significantly higher dielectric constant and are, therefore, referred to as high-k dielectric materials, which are to be understood as materials having a dielectric constant of 10.0 or higher when measured in accordance with typical measurement techniques. As is well known, the electronic characteristics of the transistor elements also strongly depend on the work function of the gate electrode material which influences the band structure of the semiconductor material in the channel region separated from the gate electrode material by the gate dielectric material. In well-established polysilicon/silicon dioxide-based gate electrode structures, the corresponding threshold voltage, strongly influenced by the gate dielectric material and the adjacent electrode material, is adjusted by appropriately doping the polysilicon material in order to adjust the work function of the polysilicon material at the interface between the gate dielectric material and the electrode material. Similarly, in gate electrode structures, including a high-k gate dielectric material, the work function has to be appropriately adjusted for N-channel transistors and P-channel transistors, respectively, which may require appropriately selected work function adjusting metal species, such as lanthanum for N-channel transistors and and aluminum for P-channel transistors. For this reason, corresponding metal-containing conductive materials may be positioned close to the high-k gate dielectric material in order to form an appropriately designed interface that results in the target work function of the gate electrode structure. In many conventional approaches, the work function adjustment may be performed at a very late manufacturing stage, i.e., after any high temperature processes, which may require the replacement of a placeholder material of the gate electrode structures, such as polysilicon, and the incorporation of appropriate work function adjusting species in combination with an electrode metal, such as aluminum and the like. In this case, however, very complex patterning and deposition process sequences may be required on the basis of gate electrode structures having critical dimensions of 50 nm and significantly less, which may result in severe variations of the resulting transistor characteristics. Therefore, other process strategies have been proposed in which the work function adjusting materials may be applied in an early manufacturing stage, i.e., upon forming the gate electrode structures, wherein the corresponding metal species may be thermally stabilized and encapsulated in order to obtain the desired work function and thus threshold voltage of the transistors without being unduly influenced by the further processing. For this purpose, it turns out that, for P-channel transistors, an appropriate adaptation of the valence band energy of the channel semiconductor material may be required in order to appropriately set the work function of the P-channel transistors. For this reason, frequently, a so-called threshold adjusting semiconductor material, for instance in the form of a silicon/germanium mixture, may be formed on the active regions of the P-channel transistors prior to forming the gate electrode structures, thereby obtaining the desired offset in the band gap of the channel semiconductor material. The threshold adjusting semiconductor alloy, such as the silicon/germanium material, is typically provided within the active region of P-channel transistors on the basis of a selective epitaxial growth process, wherein, frequently, the active region may be recessed prior to actually depositing the semiconductor alloy. Consequently, upon forming sophisticated semiconductor devices comprising strain-inducing mechanisms, threshold adjusting semiconductor alloys and the like, complex etch processes may have to be performed in order to form recesses or cavities for accommodating the epitaxially grown semiconductor alloy, wherein the overall transistor characteristics may critically depend on the uniformity of the involved etch processes, as will be described in more detail with reference to FIGS. 1a-1d. FIG. 1a schematically illustrates a cross-sectional view of a semiconductor device 100 in which a strain-inducing mechanism is to be implemented in at least one type of transistor on the basis of a strain-inducing embedded semiconductor material. In the manufacturing stage shown in FIG. 1a, the semiconductor device 100 comprises a substrate 101 above which is formed a semiconductor layer 103, such as a silicon layer. The semiconductor layer 103 and the substrate 101 may form a bulk configuration when the semiconductor layer 103 is a part of a crystalline material of the substrate 101. In other cases, as indicated by the dashed lines, a buried insulating layer 102, such as a silicon dioxide layer and the like, is frequently formed below the semiconductor layer 103, thereby providing an SOI (silicon-in-insulator) configuration. It should be appreciated that bulk architectures and SOI architectures are both used in many fields of semiconductor products in order to implement very sophisticated circuit elements on the basis of critical dimensions of 50 nm and less. The semiconductor layer 103 comprises an isolation structure 103C, for instance in the form of a shallow trench isolation and the like, thereby laterally delineating a plurality of semiconductor regions or active regions, wherein, for convenience, a single active region 103A is illustrated in FIG. 1a. The active region 103A represents a portion of the layer 103 in which an appropriate basic doping is provided in order to form the PN junctions of at least one transistor 120, which in the present example represents a P-channel transistor. In the manufacturing stage shown, a gate electrode structure 110 is formed on the active region 103A and comprises a gate dielectric material 113 which separates an electrode material 112 from a channel region 123, which represents a portion of the active region 103A. The gate electrode structure 110 may further comprise a dielectric cap layer 111, such as a silicon nitride material, a silicon dioxide material and the like, which may cover the electrode material 112, while a sidewall spacer structure 114, for instance comprised of silicon nitride, possibly in combination with an appropriate liner material (not shown), may protect the materials 112 and 113 during the further processing. It should be appreciated that the gate electrode structure 110 may have incorporated therein any sophisticated material systems, such as high-k dielectric materials in the gate insulation layer 113, as will also be described later on in more detail, possibly in combination with metal-containing electrode materials, while in other cases the electrode material 112 is provided in the form of a semiconductor material, such as amorphous or polycrystalline silicon and the like. Furthermore, in some approaches, any other sophisticated material or material systems may be provided in a very later manufacturing stage by replacing at least a portion of the material 112 according to well-established replacement gate approaches. It should further be appreciated that a length of the gate electrode structure 110, i.e., in FIG. 1a, the horizontal extension of the electrode material 112, may be 50 nm and less in sophisticated semiconductor devices. The semiconductor device 100 as illustrated in FIG. 1a may be formed on the basis of any appropriate process strategy. For example, the isolation structure 103C is formed on the basis of sophisticated lithography, etch, deposition and planarization techniques, thereby laterally delineating the active region 103A so as to define the lateral size of the active region 103A in accordance with the design rules. Next, the gate electrode structure 110 may be formed on the basis of sophisticated deposition and patterning strategies, which may also include appropriate process strategies for forming the sidewall spacer structure 114, which may substantially define the lateral offset of cavities 104 to be provided within the active region 103A. As previously discussed, performance of transistors such as the transistor 120 may be significantly enhanced by creating a specific strain in the channel region 123, which may be accomplished by incorporating a semiconductor alloy having a different natural lattice constant compared to the semiconductor base material of the active region 103A. To this end, the cavities 104 may be formed on the basis of any appropriate etch strategy and subsequently well-established epitaxial growth techniques may be applied in order to grow the semiconductor alloy on the base material of the active region 103A, wherein the mismatch in natural lattice constants between the semiconductor alloy and the base material may thus provide a certain strain component, which may thus be efficiently transferred into the channel region 123, thereby also creating a corresponding “deformation,” which may thus increase charge carrier mobility. The efficiency of the strain-inducing effect may significantly depend on the material composition, for instance on the concentration of germanium in a silicon/germanium mixture, which, however, may be restricted by available deposition recipes, wherein typically a germanium concentration of up to 30 or 35 atomic percent may be practical in view of avoiding undue lattice defects. Other important factors that determine the finally achieved strain in the channel region 123 are the lateral offset of the material from the channel region 123 and the amount of material. These factors may significantly depend on the size and shape of the cavities 104. Upon further reducing dimensions of the transistor 120, superior control of the etch process may be required since any process non-uniformities may over-proportionally affect the final transistor characteristics. Therefore, in sophisticated process sequences, an efficient control mechanism is implemented, in which the result of the etch process for forming the cavities 104 is monitored, for instance, by measuring the degree of material removal and comparing the measured values with a target depth of the cavities 104, which may be in the range of 50-80 nm, depending on the overall process and device requirements. FIG. 1b schematically illustrates the semiconductor device 100 in an early manufacturing stage in which sophisticated etch processes may also have to be applied in order to form a semiconductor alloy, such as a silicon/germanium alloy, in a corresponding recess. As illustrated, the device 100 comprises the active region 103A and a further active region 103B, which are delineated by the isolation structure 103C, as previously discussed. The active region 103A is to receive a semiconductor alloy so as to modify the electronic characteristics of a channel region of the transistor to be formed in and above the active region 103A, for instance for appropriately adjusting the threshold voltage in combination with a high-k metal gate electrode structure, as is also discussed above. To this end, a recess 105 may be selectively formed in the active region 103A, which may be accomplished by applying sophisticated etch processes, such as wet chemical etch processes on the basis of HCl and the like. Thereafter, the semiconductor alloy may be selectively grown in the recess 105 based on well-established selective epitaxial growth techniques, wherein the active region 103B may be masked by any appropriate dielectric material. It should be appreciated that the resulting threshold voltage may significantly depend on the material composition and the thickness of the semiconductor alloy and thus on the depth of the recess 105. For example, typically, a depth of approximately 10 nm may be required so as to obtain the desired threshold voltage for a given material composition of the silicon/germanium alloy. FIG. 1c schematically illustrates the device 100 in a further advanced manufacturing stage. As illustrated, a semiconductor alloy 121, such as a silicon/germanium alloy, is incorporated in the active region 103A so as to provide the desired band gap offset, as discussed above. Furthermore, the gate electrode structures 110 for the transistor 120 and a second transistor 120B may be provided in an early manufacturing stage. The gate electrode structures 110 may comprise the gate dielectric material 113 in the form of a sophisticated material system, for instance comprising a high-k dielectric material based on hafnium oxide, zirconium oxide, nitrogen-enriched hafnium oxide and the like. Furthermore, a metal-containing electrode material 115 may be formed on the gate dielectric material 113, wherein, in particular, the material 115 in combination with the semiconductor alloy 121 may determine the resulting threshold voltage of the transistor 120. Therefore, even small variations in layer thickness of the material 121 may result in a significant change of the resulting threshold voltage, which may thus result in a significant variability of transistor characteristics when considering a plurality of the transistors 120. Consequently, in addition to providing a high process uniformity in forming the complex gate electrode structures 110, superior process control for forming the semiconductor alloy 121 is also required, wherein an appropriate provision of the recess 105 (FIG. 1b) is an essential aspect and thus requires a thorough control of the results of the etch process. It should be appreciated, as indicated in FIG. 1c, that, in this manufacturing stage, for instance after providing any sidewall spacer structure, as previously discussed, the cavities 104 may be provided in the active region 103A, as explained with reference to FIG. 1a. FIG. 1d schematically illustrates a measurement strategy in which the quality of sensitive etch processes during any process modules for providing a semiconductor alloy on the basis of a corresponding recess etch process may be monitored. In the case shown in FIG. 1d, it may be assumed that the process for forming the recess 105 is to be monitored, which may be accomplished by using an ellipsometer and a corresponding ultraviolet radiation 106 in order to determine a change in layer thickness caused by the corresponding etch process. To this end, typically, appropriate test areas may be provided, for instance in the scribe line of the semiconductor wafer, i.e., in the vicinity of the actual die region, which may comprise the active regions, which receive the recess 105. The measurement strategy on the basis of an ellipsometer may be efficiently applied to an SOI architecture in which the buried insulating material 102 may provide an appropriate interface with the semiconductor layer 103 in order to optically respond to the probing radiation 106. Consequently, the radiation 106 may be sensitive to changes in layer thickness of several nanometers in order to assess the quality of the etch process for forming the recess 105. Similarly, measurement processes on the basis of elipsometry may also be applied when assessing any etch processes for forming the cavities 104 (FIG. 1a), thereby enabling an efficient control of any process modules for forming semiconductor alloys for sophisticated transistors. It turns out, however, that elipsometry may not be efficiently used in the context of bulk devices in which the semiconductor layer 103 may directly connect to a crystalline material of the substrate 101 so that an optically active interface, as is provided in SOI configurations by means of the buried insulating material 102, is not available. Therefore, an optically effective thickness of the crystalline material of the layer 103 and a portion of the substrate 101 may be significantly greater than any change of layer thickness caused by the etch processes to be monitored, so that the corresponding measurement sensitivity is insufficient for appropriately evaluating the process sequences of interest. The present disclosure is directed to various methods and devices that may avoid, or at least reduce, the effects of one or more of the problems identified above. | Mid | [
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Monoclonal antibody-based therapy for neuroblastoma. Dose-intensive combination chemotherapy can improve the clinical response of many pediatric solid tumors. However, cure remains elusive. Stage 4 neuroblastoma stands out as an exception. Part of this success is a result of antibody-based strategies, which include immunomagnetic purging of autologous marrow prior to autologous marrow transplantation and immunotherapy directed at minimal residual disease. It is striking that treatment with monoclonal antibodies, even when targeted at a single antigen, namely, ganglioside G(D2), can affect long-term progression-free survival among these patients. The potential role of the idiotype network in tumor control can be exploited clinically. The genetic engineering of these antibodies into novel forms holds great promise for more specific and effective targeting possibilities, including the delivery of cytokines and cells. Preclinical results are also promising. It is expected that the availability of novel antibodies directed at a broader spectrum of pediatric solid tumors will facilitate the successful application of this approach to more patients. Experience with metastatic neuroblastoma has provided proof of this principle. It is likely that other tumors will fall. | High | [
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Related Articles One of only three Ducati MotoGP riders circulating on Wednesday - the other being test rider Michele Pirro -, Laverty felt the new electronics initially appear to suit the Ducati machinery better than HRC machinery. "Today was just about bedding in the bike and understanding it ahead of the next two days of testing. We spent the majority of the time getting the electronics dialed in with the settings for throttle connection, engine braking and stuff like that getting focused on. "We did 25 laps today just to get ready for tomorrow. We didn't do anything today where we went looking for times other than two laps at the end of the day where we evaluated if the setting from Valencia would work here. "We'll need to make some changes to that and with these tyres you need to be careful. We'll change the setting direction for tomorrow but that's normal when you come to a place that's so different to Valencia. "It does seem that it suits our bike better. For the Ducati, the transition did seem to be pretty seamless. At Valencia, it was probably easier, because Pirro had already tested there and Redding and the guys just hopped on something that was already ready. And I guess that's what Pirro has been doing today, and what we've been doing today, so I can get a proper feel tomorrow, and have a better idea." Because of limited track time, Laverty was unable to give a full assessment of the Michelin rubber but said initial impressions were positive. The former World Superbike runner-up, who scored a famous double victory for Aprilia at the Andalusian track in 2013, went on to speak of the official Ducati presence in his garage. After enduring a year in the relative wilderness with uncompetitive 'Open' Honda machinery, in which there was little factory input, Laverty is confident that Ducati's technical guru Gigi Dall'Igna will ensure all eight Ducatis will be as competitive as possible on the 2016 MotoGP grid. "Today we had Gigi into the box twice and it's a massive thing when you have that kind of support from the factory. We went out today just to make sure that we're ready to test from tomorrow but even though it was a set-up day there was still interest from Ducati to help us. The factory boys weren't running, so they could give us a bit more assistance. "It's a nice way, and it's Gigi's approach. It's always been that way, before too. He always helps everybody. If you're on his bikes, then you're part of the family. He doesn't just want bikes to fill the grid, he wants his bikes to be competitive, and that makes a big difference to us as well." Laverty is also seeing the fact that shared data between the Pramac, Avinita and Aspar squads as another positive. "For us it was me and Nicky [in 2015], and Nicky's a great rider, but having the other guys as a reference would have been better. It's good to have more guys, and we've got the factory guys and Pramac, the other Ducati guys, we've got to try and close that gap. It was 0.7s at Valencia, which was a hell of a lot closer than what we were on the Honda in the past season. So that's something to aim for. "We've got all the data available, which is great. And there's no secrecy, everything's there. If you ask something, they will let you see it. There's no reason for one rider not to share his data." | Mid | [
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Yes... David West is similar to Blake Griffin, in terms of athleticism, conditioning, and strength. It would be the same thing. You've got me there. Part of defending well is to ensure your man never gets off the ground. Blake Griffin's vertical leap is completely useless if you box him out correctly, preventing him from jumping up in the first place. The solution is the run and gun, which won't work against Heat cause of LeBron and Wade. | Mid | [
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A baseline study for the development of an instrument for the assessment of pain. This study was designed to establish a foundation for the further development of a pain assessment tool for use in clinical practice. It was earlier reported that there existed a significant difference in the intensity of the words pain, ache and hurt and that each of these concepts had their own specific sensory and affective word descriptors. This study was designed to: 1 find out if the above results could be verified by using subjects with a different background from those included in the previous study; 2 determine the intensity of word descriptors; and 3 determine if patients, nurses and nursing students use the same word descriptors to describe pain-like experiences. Pain assessment tools used were the McGill Pain Questionnaire, a visual analogue scale and a pain, ache and hurt questionnaire. The results of the earlier reported study were confirmed. In addition, a significant difference was found in intensity of the word descriptors. Patients, nurses and nursing students used basically the same word descriptor to describe pain-like experiences. The sensory word descriptors (crushing, sharp, tearing, cutting, penetrating, gnawing, dull, pulling, sore, stinging, pricking and pinching) and the affective word descriptors (dreadful, torturing, killing, unbearable, terrifying, suffocating, exhausting, unhappy, troublesome, annoying, irritating and fearful) are suggested as a foundation upon which a pain assessment tool could be developed for use in clinical practice. | High | [
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Introduction {#sec1} ============ Eosinophilic cystitis is a rare inflammatory pathology of the bladder wall whose origin and physiopathology are still unknown.[@bib1], [@bib2] Since the first description in 1960, one hundred cases have been reported, 20 of which a pseudotumor forms.[@bib1] Clinical symptoms, as well as the radiological endoscopic appearance are nonspecific. The diagnosis is based solely on histological examination.[@bib1], [@bib2] The therapeutic management is usually based on corticosteroids or nonsteroidal anti-inflammatory drugs, sometimes on the endoscopic resection of lesions, exceptionally on surgery.[@bib1], [@bib2] We report the observation of pseudotumoral eosinophilic cystitis treated with endoscopic resection with favorable outcome. Case report {#sec2} =========== A 72 year old man, smoker, without any special occupational exposure consults for irritative urinary symptoms with terminal hematuria since 2 months. His physical examination was normal. An ultrasonography ([Figure 1](#fig1){ref-type="fig"}, [Figure 2](#fig2){ref-type="fig"}) shows a bud of 14 mm at the bladder dome and is vascularized in doppler. We performed a cystoscopy which shows a budding lesion measuring 1.5 cm below the bottom which has been resectioned. The adjacent mucosa is slightly inflammatory. Pathological examination concluded at an edematous and congestive shuffle with a rich inflammatory infiltrate composed predominantly of eosinophils in the lamina propria without signs of malignancy. The outcome was favorable with no symptoms at 1, 3 and 6 months postoperatively controls. Discussion {#sec3} ========== Eosinophilic cystitis has two main presentations, affecting two types of distinct populations. On the one hand for children and the young woman, the surface shape and diffuse is the most common and found in 30% of cases atopy.[@bib3] The other type of population affected is that of middle-aged men, often on a pre-existing uropathy field.[@bib4], [@bib5] It is in these frameworks that are found most often eosinophilic cystitis pseudo tumor shape. The onset of symptoms is often brutal. Clinical signs of superficial forms are dominated by an irritative syndrome: intense urinary frequency, pelvic pain, hematuria. The tumor forms more readily cause dysuria or urinary retention.[@bib5] A case of spontaneous bladder perforation has been reported.[@bib2] In cystoscopy, the mucosa is inflammatory, edematous or necrotic and ulcerated. Sometimes there are polypoid areas or real tumors making discuss a malignant epithelial tumor.[@bib5], [@bib6] The imagery contributes little to the diagnosis. It can at best bring out the tumor syndrome without prejudging its nature.[@bib1], [@bib2] The formal diagnosis is histological: infiltration of layers of the bladder wall by inflammatory cells in which predominantly eosinophils, together with high levels of IgE and IgA in cells infiltrating the wall[@bib1] ([Figure 3](#fig3){ref-type="fig"}, [Figure 4](#fig4){ref-type="fig"}). The pseudotumoral forms are marked by the discreet nature of the superficial infiltrate contrasting with the frequency of lesions necrosis and fibrosis of the deeper layers. These lesions, whose development is focal and willingly changeable, require profound and multiple biopsies.[@bib1] In biology, a peripheral eosinophilia is present in about 30% of cases[@bib1], [@bib6] and is more common in case of allergic terrain, diffuse form or in children.[@bib1], [@bib4] Increased serum IgE and IgA is sometimes found.[@bib3] In pseudotumoral forms, the entire laboratory tests may be normal. The disease progresses to the extension of the lesions, the invasion of adjacent structures, recurrence and chronicity.[@bib1], [@bib3], [@bib5] In pseudotumoral forms, the spontaneous evolution is never favorable, unlike some diffuse forms and especially childhood forms.[@bib7] The treatment of eosinophilic cystitis is mainly based on corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs),[@bib1], [@bib2] optionally in combination with antihistamines or azathioprine.[@bib1] The pseudotumoral forms, however, seem to respond poorly to these treatments. This is why other types of protocols have been proposed: cotrimoxazole,[@bib1], [@bib5] cyclophosphamide, and actinomycin D,[@bib8] azathioprine and DMSO instillations.[@bib9] In case of proven allergy, the eviction of the allergen responsible is required.[@bib7] In case of failure of medical treatment or to the impact of the lesions (bladder retraction, ureteral obstruction) the surgery is inevitable. Resection (or electrocautery) endoscopic lesions often provide good results.[@bib2] In case of failure, partial cystectomy with bladder expansion must be avoided as possible.[@bib5] Indeed, a surgical aggression on an inflammatory bladder could be the cause of a hyperacute evolution. Cystectomy appears as an effective alternative.[@bib9] Conclusion {#sec4} ========== Pseudotumoral eosinophilic cystitis is an exceptional pathology that falls within the scope of the differential diagnosis of bladder cancer. His presentation is misleading and the differential diagnosis is possible only after histological examination. It occurs most often in older men with multiple pathologies history of lower urinary tract. The development is done toward the extension of the lesions to the whole of the bladder but also to the adjacent structures. The frequency of recurrence and the tendency to chronicity require close monitoring. Medical treatment is the first line (corticosteroids, NSAIDs, cotrimoxazole, DMSO or immunosuppressants), combined with transurethral resection of the lesions. In case of failure, cystectomy seems a preferable alternative to partial surgery. Conflict of interest {#sec5} ==================== The authors declare that they have no conflicts of interest related to this article. Available online 26 February 2015 {#fig1} {#fig2} {#fig3} {#fig4} | Mid | [
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Manpower reports that the 35 percent of employers that report talent shortages this year is the highest percentage since 2007. The top five jobs employers globally are having difficulty filling are skilled trade workers, engineers, sales representatives, technicians, and accounting and finance staff. According to the 2013 survey results: For the second consecutive year, the most severe talent shortages are in Japan (85 percent) and Brazil (68 percent). When compared with 2012, talent shortages are a growing issue across China (35 percent), Japan (85 percent), and India (61 percent), where the proportion of employers reporting skills gaps increased 12, 4, and 13 percent, respectively. The percentage of difficulty reported by employers in Japan is now the highest recorded in the eight-year history of the survey. Reported shortages are also at a six-year high in both Canada (34 percent), where the proportion has grown 9 percent year-over-year, and in France (33 percent) where the percentage climbed 4 percent. Meanwhile, employers in the U.S. (39 percent) and Germany (35 percent) report fewer difficulties filling jobs compared to 2012; percentages in both countries dipped to the lowest levels reported since 2010. | Mid | [
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# [0.1.6] - 2018-10-31 ## Added - (CI) Integrate missing Grammar ## Fixed - Retrieve the appropriate operation type with operation definition. - (SDL) Remove useless type and add Line/Col info propagation - Add missing "UnknownDirectiveDefinition" imports | Mid | [
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Hydrops of the gallbladder in a child: diagnosis by ultrasonography. Hydrops of the gallbladder is a rare cause of right upper quadrant mass in children. A case of acute hydrops of the gallbladder in a 5-year-old child is reported. A specific and accurate diagnosis can be made preoperatively only by sonography. Characteristic sonographic findings are described. | High | [
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1. Field of the Invention Embodiments of the present invention generally relate to indexed color spaces and, more particularly, to a method and apparatus for reconstructing indexed color spaces. 2. Description of the Related Art Many image container formats, such as Tagged Image File Format (TIFF), Portable Document Format (PDF), PHOTOSHOP® Document (PSD), ADOBE® ILLUSTRATOR® (AI), and the like, hold multiple images, each with its own indexed color space. The use of multiple indexed color spaces typically results in the image container including redundant color information. For example, an image container may hold an ADOBE® PHOTOSHOP® image. Each layer of a PHOTOSHOP® image is stored as an image stream. Similarly, each image included in a PDF is an image stream. When an image stream is encoded, color information may not be directly carried by the image pixel data, but is stored in a separate piece of data called a palette or an indexed color space. The palette is an array of unique color elements, in which every color element is identified by its position within the array. Accordingly, it is not necessary that each pixel of an image stream contain an independent and full specification of its color, and instead each image pixel need only refer to a position within the palette where its unique color is located. Hence, the palette is used as an index to look up the full specification of the color for that pixel. Since each image stream includes its own indexed color space, when an image container includes multiple image streams, redundant color specification information is often maintained. Redundancy of color information in image containers unnecessarily and undesirably increases the size of the overall image data stored in the given image container. Currently, attempts to reduce redundancy include quantizing all of the colors to fit a palette by using, for example, color diffusion, and then indexing the resulting reduced color space. However, color quantization techniques result in the loss of important color information, and often deteriorate the original image after transformation. Therefore, there is a need for a method and apparatus for reconstructing indexed color spaces. | High | [
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india Updated: Dec 17, 2018 07:13 IST India may prune by half a potential order to import hi-tech unmanned aerial vehicles (UAVs) from the United States due to financial constraints, two government officials familiar with the Navy’s modernisation plans said on Sunday. Instead of pursuing the navy’s original requirement of 22 MQ-9B SeaGuardian UAVs to boost its intelligence, surveillance and reconnaissance capabilities, India now plans to buy only 10 such systems under the US government’s foreign military sales (FMS) programme, one of the officials cited above said on condition of anonymity. The 22 UAVs, made by General Atomics, were estimated to cost $2 billion. India began the FMS process in 2016 by issuing a Letter of Request (LOR) to the US. “Responding to the LOR, the US has supplied us with the price and availability (P&A) data for the SeaGuardian systems. The navy has studied it and rationalised its requirement from 22 to 10 UAVs because of the cost and the requirement of the other services,” said the second official, asking not to be named. The Indian Air Force (IAF) is also keen to buy Predator Avenger UAVs from the US. The downsizing of the order will mean that the navy will have to prioritise the areas it wants to keep under surveillance using the SeaGuardian UAVs, said a senior navy officer on condition of anonymity. “We had arrived at a figure of 22 on the basis of our requirements. But we have to manage with the resources we have. The navy has several aerial surveillance platforms such P-8I aircraft, IL-38s, Dornier planes and other UAVs,” he said. A government-to-government deal does away with the need to float a tender. Such transactions may be complicated in their conception and execution but are more transparent to financial scrutiny. “If financial constraints are there, then there’s no choice but to order fewer UAVs,” said military affairs expert Rear Admiral (retd) Sudarshan Shrikhande. The MQ-9B SeaGuardian systems will provide unmatched intelligence and surveillance capabilities to the navy, he said. The navy currently operates a mix of Israeli-built Heron and Searcher UAVs for intelligence-gathering and surveillance. It has a vast area of responsibility in the Indian Ocean Region (IOR) spanning millions of square kilometres, with warships being deployed to as far as the Persian Gulf to the Strait of Malacca and northern Bay of Bengal to the southeast coast of Africa. With their range and endurance, SeaGuardian UAVs will provide India advanced capabilities for ocean surveillance, especially at a time when Chinese naval presence in the region has gone up. India’s exclusive economic zone alone measures 2.4 million square kilometres, which is also the navy’s responsibility. Navy chief Admiral Sunil Lanba had highlighted the significance of the Indian Ocean earlier this month, calling it the navy’s only front. “As we surge ahead in the 21st century, the attention of the entire world is focused on the Indian Ocean Region, where our navy is increasingly seen as a ‘net security provider’…Our security strategy is aimed at providing a maritime environment that is free from all forms of traditional and non-traditional threats to our national development,” Lanba had said. The P-8I planes, the mainstay of the navy’s long-range maritime surveillance fleet, have also been imported from the US. India currently operates eight Boeing P-8I planes and four more will join the fleet by 2021. General Atomics has also designed the electromagnetic aircraft launch and recovery system (EMALS), which is likely to be fitted on India’s second Indigenous Aircraft Carrier (IAC-II). The navy is getting more American equipment. India issued an LOR to the US government in November for 24 MH-60R Seahawk multirole helicopters under the FMS programme. Since 2008, India has bought or ordered military equipment worth $15 billion from the US. This includes C-130J special operations planes, C-17 transport aircraft and P-8I submarine hunter planes. | Mid | [
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The Father Who didn’t spare His Son Rom 8:32 – He who did not spare his own Son, but gave him up for us all—how will he not also, along with him, graciously give us all things? 2 Cor. 8:9 – For you know the grace our Lord Jesus Christ, that though he was rich, yet for your sake became poor, so that you through his poverty might be rich. God gives us more leeway than He gave His own Son. Jesus’ mission wasn’t to get married, enjoy marital intimacy, or to raise children. We’re called to Christlikeness, though that’s a goal we can’t perfectly attain. Christ and the Church have different paths with one end goal: God’s glory. Christ’s atonement on the Cross secured not only our salvation but also our joy, wellbeing and fulfillment, even sexually (John 10:10). God gives us the freedom to enjoy Couples Nursing, but unfortunately, some self-punishing Christians have gotten things twisted. A famous preacher said “God doesn’t care about your happiness, he cares about your soul.” Is that in the Bible? Another quote I read online stated: “Jesus was around hostile people, so I don’t need to be around people like me.” But Jesus also surrounded Himself with disciples, of whom He had 3 favorites. Still, we’re not Jesus. He had direct access to God and was perfectly able to tune out the sinful distractions you and I wrestle with. That’s why we need intimacy and accountability. Jesus didn’t need His disciples to hold Him accountable. The opposite was true. Surrounding yourself with friends is actually the expectation. It glorifies God. And surrounding yourself with your wife’s comforting lactating abundance, or husband’s suckling warmth was the expectation in Solomon’s day. It also glorifies God. Yet it was the will of the LORD to crush him; he has put him to grief; when his soul makes an offering for guilt, he shall see his offspring; he shall prolong his days; the will of the LORD shall prosper in his hand. | Mid | [
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Genetics of Gender Dimorphism in Higher Plants Abstract Upon the rediscovery of Mendel’s laws, biologists became very interested in the genetics that distinguished males from females. Many plant systems were examined in the early part of the century for the genetic basis of gender dimorphism. In most cases, herbaceous plants with relatively short generation times were studied for practical reasons and tree species, many of which produce unisexual flowers, were largely ignored. Even though only a sampling of species was studied, the most obvious feature was a lack of uniformity in the genetic mechanisms to distinguish staminate (male) from pistillate (female) flowering plants (previously reviewed in (Dellaporta and Calderon-Urrea 1993; Grant et al. 1994a; Irish and Nelson 1989). Most of the monoecious and dioecious species studied are more closely related to hermaphroditic species that they are to other unisexual species. Only three plant families, the Cucurbitaceae (melons, squash and cucumbers) (Robinson et al. 1976), the Salicaceae (willows) (Westergaard 1958) and the Cannabidaceae (with only three species) (Parker 1990) have predominantly unisexual species. In other families, unisexual species are rare and they are scattered among clades (Yampolsky and Yampolsky 1922). Their phylogenetic distribution indicates that monoecious and dioecious species have evolved independently from hermaphroditic progenitors in many lineages. Therefore, it is not surprising that a variety of genetic mechanisms have emerged to distinguish male and female flower development from hermaphroditic. The only limits to the possible mechanisms are the following demands for reproduction: (1) the development of one type of reproductive organ must be impeded without inhibiting the development of the other (and with minimal change to other floral organs); (2) mating of male and female should result in progeny that are also male and female. Some of the very different genetic mechanisms described are briefly summarized in Table 1. The purpose of this chapter is to illustrate the extent of the variety of genetic mechanisms regulating gender dimorphism in monoecious and dioecious plants. | High | [
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That is a lot of smoked malt! How much of the juniper and yeast came through with that much smoked malt? The juniper is subtle, as it was used as a means to sanitize and clean equipment traditionally. It does come through. The yeast, I'm not sure what strain it is, so I'm unsure what it's bringing to the beer. I will say that it is delicious, and the folks that have tasted it so far agree, at least when I'm present. On a separate note, the recipe that I shared is what I meant to brew, but I goofed when I placed the grain order, which was ground and mixed for pickup, ordering 1 Kg of each grain! This might explain why it doesn't seem overpowering at all and is a delight. This link points to the 1 Kg version https://www.brewersfriend.com/homebrew/recipe/view/552700/norwegian-wood-1kg-version I had been meaning to correct my mistake and try the intended version I shared, originally. | Low | [
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Reports on surveillance of antimicrobial resistance in individual countries. In preparation for the meeting of the World Health Organization Working Group on Monitoring and Management of Bacterial Resistance to Antimicrobial Agents, representatives of 10 countries were asked to provide brief reports on the status of surveillance in their countries. Some gave extensive information on the methods used to test susceptibility of nosocomial pathogens to a variety of antibiotics; some described in detail the network of reference laboratories available to hospitals and individual clinicians for monitoring, identifying, and testing infectious agents; others chose to describe how their countries deal with the resistance of the most frequently isolated pathogen to a commonly used drug. The following summary of these reports shows the broad range of problems encountered and solutions undertaken by these 10 countries in dealing with the increasingly alarming problem of bacterial resistance to antimicrobial agents. | High | [
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THE NATION Romney Taxed as a Utah Resident BOSTON — Mitt Romney, the former Salt Lake City Olympics chief now running for Massachusetts governor, paid property taxes on a Utah home as his "primary residence" from 1999 to 2001, and received a $54,000 tax discount as a result, the Boston Globe reported Wednesday. The tax records could add to debate about whether Romney meets Massachusetts' residential requirements to be governor. The state constitution requires a candidate to live in Massachusetts for seven years before an election. Romney also has a home in Belmont. A Romney spokesman said Romney never sought the "primary residence" designation for his Park City, Utah, home, and both Romney and the county assessor in Summit County, Utah, blamed it on a clerical mistake. "Mitt was under-billed for his property tax," said Romney's spokesman Eric Fehrnstrom. In Utah, nonresidents pay taxes on 100% of the assessed value of a home, while residents pay on 55%. Romney paid $22,599 on the home, valued at $3.8 million, about $54,000 less than he would have paid as a nonresident, the Globe reported. | Mid | [
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Q: How to calculate UITextView first baseline position relatively to the origin How can I calculate UITextView first baseline position? I tried calculating it this way: self.textView.font!.descender + self.textView.font!.leading However, the value I'm getting is not correct. Any ideas, hints? A: There is a diagram from the Apple document From my understanding, font.descender + font.leading gives the distance between the first baseline and starting of the second line. I would imagine font.lineHeight would give you the right number, if UITextField doesn't have a secret padding. EDIT UITextField and UITextView shared same UIFont property. For UITextView, there's an extra textContainerInset can be set. EDIT 2 A further look at the UITextView gives more clue about what can be achieved: It actually has a textContainer property, which is a NSTextContainer. The NSTextContainer class defines a region in which text is laid out. An NSLayoutManager object uses one or more NSTextContainer objects to determine where to break lines, lay out portions of text, and so on. And it's been used by layoutManager, theoretically the padding to the top of first line of text could be found by usedRectForTextContainer(_:). I will need to test this once I have a Mac in hand. :) | Mid | [
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Introduction {#sec1-1} ============ Stroke is a leading cause of death in the world and a common reason for hospitalization. The two main types of stroke are ischemic stroke and hemorrhagic stroke, with the former representing the most common (80%) type. Ischemic stroke is subclassified as thrombotic or embolic in nature. A thrombotic stroke or infarction occurs when a clot forms in an artery supplying the brain and accounts for approximately 50% of all strokes, whereas an embolic stroke is the result of a clot formed elsewhere in the body and then transported through the bloodstream to the brain. Hemorrhagic stroke entails bleeding within the brain due to a blood vessel or an aneurysm rupturing inside the brain, with consequent damage to surrounding tissues. Treatment for stroke depends upon whether it is ischemic or hemorrhagic. The only FDA approved treatment for ischemic strokes is intravenous administration of tissue plasminogen activator (tPA *e.g*., alteplase) that acts by dissolving the blood clot and improving blood flow to the part of the brain being deprived of blood. When administered within 4.5 hours from stroke onset, tPA may improve the chances of recovery. The short time interval for treatment and increased risk of intracranial hemorrhage result in only a small percentage (5--15%) of patients receiving tPA (Lloyd-Jones et al., 2010). Another treatment procedure involves removing the blood clot by introducing a catheter to the site of the blocked blood vessel in the brain. Sometimes this procedure involves tPA being administered directly into the blood clot to help dissolve the blockage. There is clearly a need for alternative treatments for stroke that are effective when applied within a longer time period than 4.5 hours from stroke onset. Transcranial laser therapy (TLT) may provide a suitable treatment option and involves applying low level laser irradiation to the scalp to be transmitted through the skull to penetrate the brain. Alterations to Cellular Structure and Function in Cerebral Ischemia {#sec1-2} =================================================================== Many changes take place at the cellular level when a stroke occurs. The obstruction of a major cerebral vessel (usually the middle cerebral artery, MCA), if not resolved within a short period of time, will lead to a core of severely ischemic brain tissue that may not be salvageable. The ultimate size of the brain infarct depends on the penumbra, a zone of tissue around the core of the infarct where neuronal electrophysiology is not compromised and blood flow is still maintained above a neuronal disabling level (*i.e*., the critical 20--25% of normal blood flow). If blood flow in the penumbral zone decreases below this critical level and/or energy requirements are exceeded, the infarct zone will expand. Decreased blood flow leads to a reduction in phosphocreatinine and adenosine triphosphate (ATP) and if ischemia is prolonged, the energy depletion will be sufficient to lead to severe impairment of cellular function by disruption of ATP-dependent processes. The disruption of ionic gradients across excitable (neuronal) and nonexcitable (glial) membranes owing to loss of ATP is characterized by efflux of K^+^ from the cells, cellular depolarization, and influx of Na^+^, Cl^-^, and Ca^2+^ into the cells (Siesjo, 1992a, b). In the phase of increased extracellular K^+^ together with a decrease in pH, ATP stores are rapidly depleted and ultimately result in marked changes in ion conductance. The increase in K^+^ can reach levels sufficient to release neurotransmitters such as glutamate, which in turn will stimulate Na^+^/Ca^2+^ channels coupled to the N-methyl-D-aspartate (NMDA) receptor; these will further lead to Na^+^, Cl^-^, and H~2~O accumulation, cell swelling, and cytotoxic edema. Transient extracellular K^+^- induced depolarizations can also contribute to the expansion of the neuronal infarct. Peri-infarct depolarization produces disruption of ionic gradients and transmitter release, with the associated accumulation of Ca^2+^ in the cells leading to rapid and extensive breakdown of phospholipids, proteins, and nucleic acids by activation of calcium-dependent phospholipases, proteases, and endonucleases. Depolarization causes an increase in intracellular Ca^2+^ and an increase in extracellular glutamate. Glutamate, an excitatory neurotransmitter implicated in ischemic neuronal damage, results in excitotoxicity in which excessive extracelluar glutamate kills neurons through an increase in intracellular Ca^2+^ (Barone and Feuerstein, 1999). Accumulation of products such as free fatty acids that are metabolized to toxic lipid peroxides further contribute to structural and functional alterations of the membrane and cell function. Free radicals which are a group of highly reactive oxygen species (ROS) are formed during ischemia and cause considerable damage to lipids, DNA, and proteins, and contribute to the process of neuronal death. Free radicals also contribute to the breakdown of the blood-brain barrier and brain edema. Levels of free radical scavenging enzymes (*e.g*., superoxide dismutase, SOD) decrease during ischemia and nitric oxide levels are elevated. Nitric oxide (NO) produced primarily by neuronal and inducible nitric oxide synthases promote neuronal damage after ischemia (Barone and Feuerstein, 1999). Inflammation Injury in Acute Cerebral Ischemia {#sec1-3} ============================================== Evidence demonstrates that inflammation and immune response play an important role in the outcome of ischemic stroke (Famakin, 2014). Inflammation after stroke involves leukocyte infiltration in brain parenchyma that contributes to cerebral damage. Peripherally derived mononuclear phagocytes, T lymphocytes, natural killer (NK) cells, and polymorphonuclear leukocytes, which produce and secrete cytokines, can all contribute to central nervous system (CNS) inflammation and gliosis (Brea et al., 2009). Blood-derived leukocytes and resident microglia are the more activated inflammatory cells, accumulating in the brain tissue after cerebral ischemia, leading to inflammatory injury (Akopov et al., 1996). Microglia, the major source of cytokines and other immune molecules of the CNS, are the first non-neuronal cells that respond to CNS injury, becoming phagocytic when fully activated by neuronal death. Neutrophils are the first leukocytes recruited to the ischemic brain and occurs between 6 and 12 hours following stroke onset, progressing for up to 24 hours, and then declining (Akopov et al., 1996). Monocytes accumulate in the injury area around 12 to 24 hours after onset of ischemic injury, and are rapidly transformed into tissue macrophages capable of aggressive phagocytosis. Other immune/inflammatory cells such as lymphocytes are present at later time points (Brea et al., 2009). Mediators released by activated leukocytes, such as ROS, proteases and cytokines, cause damage to neurons and other brain cells (del Zoppo et al., 1991). Studies in rodents have shown that microglia and macrophages are the principal CNS source of cytokines such as interleukin-1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and transforming growth factor-β (TGF-β) (Gregersen et al., 2000). Following ischemia, astrocytes are activated in the brain and are capable of secreting inflammatory factors such as cytokines, chemokines and inducible nitric oxide synthase (iNOS) (Dong and Benveniste, 2001). iNOS from astrocytes has been shown to enhance ischemia-like injury to neurons (Hewett et al., 1996). Low-level Laser Therapy (LLLT) {#sec1-4} ============================== Low-level laser therapy or low-level light therapy uses low-power lasers or light-emitting diodes (LEDs) to alter cellular function; this is in contrast to high-power lasers that cause tissue ablation. The absorption of light by chromophores within cells increases the chemical energy within cells in the form of ATP, increases deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), promotes NO release, increases cytrochrome c oxidase activity, ROS production, intracellular membrane activity particularly in mitochondria, Ca^2+^ flux and stress proteins (Karu et al., 2005; Khuman et al., 2012). Mitochondria are the single most important organelle governing the cellular response to LLLT, with cytochrome c oxidase on the mitochondrial inner membrane being the crucial chromophore. The effects of LLLT on cells and tissues involve a complex cascade of pathways with altered intracellular signaling and changes to redox states. Mitochondrial ROS may act as a modulatable redox signal, reversibly affecting the activity of a range of functions in the mitochondria, cytosol and nucleus. LLLT produces a shift in overall cellular redox potential towards oxidation and which is associated with cellular vitality (Karu, 1999), increased ROS generation and cellular redox activity (Lubart et al., 2005). Several transcription factors are regulated by changes in cellular redox state including nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) that enter the nucleus and cause transcription of a range of new gene products (Meyer et al., 1994). LLLT Therapy for Stroke {#sec1-5} ======================= Animal studies {#sec2-1} -------------- Most studies have used near infrared light with wavelength 808 nm, but a few studies have also employed red visible light of wavelength 633, 660 or 710 nm. Several *in vitro* ischemic models have been tested for effect of light irradiation. LED irradiation (710 nm, 4 J/cm^2^) of rat primary cortical neurons (isolated from embryonic brain) exposed to oxygen-glucose deprivation, followed by reoxygenation and normal conditions, promoted neurite outgrowth and synaptogenesis through mitogen-activated protein kinase (MAPK) activation and protected against ischemic damage (Choi et al., 2012a). Laser irradiation (810 nm) of mouse primary cortical neurons induced an increase in Ca^2+^, ATP and mitochondrial membrane potential (MMP) at 3 J/cm^2^. ROS was significantly increased at 0.03 and 0.3 J/cm^2^, with a peak at 3 J/cm^2^, followed by a decrease at 10 J/cm^2^ and a second increase at 30 J/cm^2^. NO levels followed the same general triphasic pattern as the ROS levels but the increase was less prominent compared to ROS (Sharma et al., 2011). Laser irradiation (633 nm) of rat hippocampal brain slices exposed to perfusion of oxygen-free/low glucose medium increased the time required for loss of electrical excitability and increased recovery from ischemic injury. Injury in this system is known to result at least in part from free radical production (Iwase et al., 1996). *In vivo* studies in rats and rabbits have shown that laser irradiation can result in significant clinical improvement when administered at an appropriate time after onset of ischemic stroke. In one study, rats were subjected to 90-minute middle cerebral artery occlusion (MCAO) followed by reperfusion, LED irradiation (710 nm, 1.8 J/cm^2^) applied randomly to each animal 12 hours each day for 3 weeks after MCAO establishment. Helper T cell (CD4^+^) count was reduced after MCAO but significantly increased by LED irradiation. Infarct sizes were decreased in MCAO + irradiation group compared with MCAO control group. IL-10 mRNA expression and immunoreactivity of regulatory T cells were increased in MCAO + irradiation group compared with MCAO control group. IL-4 mRNA expression tended to be decreased in MCAO + irradiation group compared with MCAO control group but was not significantly changed. Increased microglia activation after MCAO was reduced by irradiation. Irradiation group showed improved neurological severity scores after MCAO (Choi et al., 2012b). In another rat study, two sets of experiments were performed. In experiment 1, stroke was induced by permanent occlusion of MCA and scored for cumulative neurological deficit at 3 hours post stroke. At 4 and 24 hours post stroke, transcranial laser irradiation (808 nm, 1.8 J/cm^2^) of the hemisphere contralateral to the stroke was performed. In experiment 2, stroke was induced by permanent occlusion of MCA by insertion of a filament through the carotid artery and scored for neurological deficit at 24 hours post stroke. Laser irradiation (808 nm, 1.8 J/cm^2^) was administered transcranially at 24 hours post stroke. In both models, laser irradiation significantly reduced neurological deficits when applied 24 hours post stroke. Laser treatment at 4 hours post stroke did not affect the neurological outcome of the stroke-induced rats as compared with controls. There was no statistically significant difference in the stroke lesion area between control and laser-irradiated rats. The number of newly formed neuronal cells as well as migrating cells was significantly increased in the subventricular zone of the hemisphere ipsilateral to the induction of stroke when treated by laser (Oron et al., 2006). In a further study using rats with acute stroke induced by insertion of a filament into MCA and with marked neurological deficit at 24 hours, laser irradiation (808 nm, 1.8 J/cm^2^) applied transcranially either ipsilateral, contralateral or to both sides of induced stroke resulted in an improvement in neurological deficit from 14 to 28 days post stroke. At 28 days there was only a 32% reduction in neurological score in the control non-laser group while in the laser-treated groups a 63% reduction occurred. Moreover, at 28 days there were no significant differences in neurological score between the groups of rats to which the laser was applied to different regions of the brain (DeTaboada et al., 2006). In a rat study involving occlusion of MCA by a surgical clip and release of the artery after 1 hour for reperfusion, laser irradiation (660 nm) was applied through a burr hole to the cerebrum to deliver 2.64 J/cm^2^/min, pulse frequency 10 kHz for 1, 5 or 10 minutes. After ischemia and reperfusion, the activity of NOS increased from day 3, becoming significantly greater on days 4 to 6, and then returning to normal levels after day 7. Activity and expression of the three isoforms of NOS at post-injury day 4 were significantly suppressed to different extents after laser irradiation. In addition, the expression of TGF-β at day 4 post-injury was up-regulated after laser irradiation (Leung et al., 2002). Using the rabbit small clot embolic stroke model (RSCESM), laser treatment (808 nm, 15 J/cm^2^) given transcranially 1 to 24 hours post embolization showed laser treatment reduced the neurological deficit if initiated up to 6 hours but not 24 hours post embolization (Lapchak et al., 2004). Furthermore, using this same model and applying continuous wave (CW) or pulse wave (P) laser therapy (808 nm) transcranially at 6 or 12 hours after embolization, there was a decrease in the neurological deficit for *P* wave but not CW wave administered at 6 hours post embolization. At 12 hours post embolization treatment, there was a trend for an improvement in neurological deficit by CW and P modes (Lapchak et al., 2007). These animal trials inform studies examining the effects of TLT in human subjects. However, differences in cranial size and skull thickness may be important critical factors for LLLT in rats, rabbits and humans. In humans, the mean cranial thickness at frontal and occipital sites were 7.04 and 7.83 mm for males, and 6.68 and 7.60 mm for females, respectively (Lynnerup, 2001). Rat skull bone ranged in thickness from approximately 0.5--1 mm, while the rabbit skull was thicker than 1.5 mm (O'Reilly et al., 2011). Human studies {#sec2-2} ------------- A small number of studies have been performed in patients. The NEST-1 trial showed safety and effectiveness of TLT for the treatment of ischemic stroke when initiated within 24 hours of stroke onset (median time to treatment of 18 hours, range 2 to 24 hours) (Lampl et al., 2007). The NEST-2 study of patients with moderate to moderately severe ischemic stroke concluded that 36% of patients had a favorable outcome when treated with TLT within 24 hours of stroke onset (median time to treatment of 15 hours, range 3 to 24 hours) (Zivin et al., 2009). The NEST-3 double-blind, randomized, sham-controlled, parallel, multi-centre trial was to demonstrate the safety and efficacy of TLT (808 nm) in the treatment of ischemic stroke when initiated between 4.5 and 24 hours of stroke onset with outcomes assessed at 90 days (Zivin et al., 2014). The study was terminated after a futility analysis found no difference between TLT and sham treatment in the primary endpoint which was disability at 90 days. The patients included in the study were unsuitable for treatment by thrombolytic agent or thrombectomy (Hacke et al., 2014). There are concerns regarding the sites of application of the laser light, the amount of energy that would penetrate the skull and be received by deeper structures in the brain, and the time from stroke onset to treatment initiation of 16 hours, and potentially = or \< 24 hours, which extends well beyond the time window at which powerful treatments have been shown to confer benefit. Only a few of the 20 skull sites used for light application were likely to be adjacent to penumbral tissue and a single 2 minute application of laser energy is probably insufficient. The power of the laser was not specified. While penetration of the skull had been confirmed in human cadavers, the energy would reach only 2 cm into the brain cortex. Interestingly there was a lower reporting of serious adverse events in patients with TLT than in patients with sham treatment. Future Perspectives {#sec1-6} =================== The studies in rats and rabbits demonstrated a neuroprotective effect of TLT following ischemic stroke. There is a need to find a way to make TLT effective in improving neurological outcome in human patients with ischemic stroke. The time from stroke onset at which TLT administration can benefit ischemic stroke patients needs to be established, as well as optimal laser parameters such as continuous or pulsed waveform, wavelength, power, duration of irradiation, energy dose, number of sites and days of application. Near infrared laser light has a greater transmission through the skull and greater depth of penetration of the brain than red laser light. In addition, combinatorial treatments may lead to better outcomes. In a small exploratory study involving patients with acute ischemic stroke, TLT was well tolerated in combination with intravenous tPA and no patients experienced intracranial hemorrhage (Hemmen et al., 2014). Statins given within 4 weeks of stroke onset improve stroke outcomes at 90 days compared with patients not given statins (Stead et al., 2009), and may when given following TLT result in more favorable outcomes. The pleiotropic effects of statins are probably more important at least in the first 3 to 7 days after stroke and include dose-dependent elevation of endothelial NOS, enhanced endogenous tPA, exertion of an anti-thrombotic effect, improved collateral blood flow, and decreased inflammatory mediators. Collectively, these dose-dependent effects of statins improve blood flow to the penumbra and promote autolysis of blood clot, decrease the likelihood of reocclusion, decrease infarct size, and improve clinical outcomes (Moonis, 2012). TLT in combination with specific agents to reduce inflammation and/or immune response could be trialed in animal stroke models. Possible agents are anti-IL-1β, anti-IL-6, anti-TNF-α monoclonal antibody or cytokine receptor antagonists, TGF-β and IL-10 analogues. Administration of an inhibitor of TNF-α production up to 6 hours after ischemia reduced brain edema in MCAO rats (Vakili et al., 2011). Intraventricular injection of an adenoviral vector encoding human IL-10 after MCAO in spontaneous hypertensive rats decreased brain infarct volume, with fewer infiltrations of leukocytes and macrophages, and attenuated IL-1β (Ooboshi et al., 2005). | High | [
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24/01/2007 Enlightenment fundamentalism or racism of the anti-racists? Pascal Bruckner defends Ayaan Hirsi Ali against Ian Buruma and Timothy Garton Ash, condemning their idea of multiculturalism for chaining people to their roots "What to say to a man who tells you he prefers to obey God than to obey men, and who is consequently sure of entering the gates of Heaven by slitting your throat?" - Voltaire "Colonisation and slavery have created a sentiment of culpability in the West that leads people to adulate foreign traditions. This is a lazy, even racist attitude." – Ayaan Hirsi Ali There's no denying that the enemies of freedom come from free societies, from a slice of the enlightened elite who deny the benefits of democratic rights to the rest of humanity, and more specifically to their compatriots, if they're unfortunate enough to belong to another religion or ethnic group. To be convinced of this one need only glance through two recent texts: "Murder in Amsterdam" by the British-Dutch author Ian Buruma on the murder of Theo Van Gogh (1) and the review of this book by English journalist and academic Timothy Garton Ash in the New York Review of Books (2). Buruma's reportage, executed in the Anglo-Saxon style, is fascinating in that it gives voice to all of the protagonists of the drama, the murderer as well as his victim, with apparent impartiality. The author, nevertheless, cannot hide his annoyance at the former Dutch member of parliament of Somali origin, Ayaan Hirsi Ali, a friend of Van Gogh's and also the subject of death threats. Buruma is embarrassed by her critique of the Koran. Ayaan Hirsi Ali. © Bettina Flitner Garton Ash is even harder on her. For him, the apostle of multiculturalism, Hirsi Ali's attitude is both irresponsible and counter-productive. His verdict is implacable: "Ayaan Hirsi Ali is now a brave, outspoken, slightly simplistic Enlightenment fundamentalist." (3). He backs up his argument with the fact that this outspoken young woman belonged in her youth to the Muslim Brotherhood in Egypt. For Garton Ash, she has merely exchanged one credo for another, fanaticism for the prophet for that of reason. This argument of equivalence is not new. It was used throughout the 19th century by the Catholic Church to block reforms, and more recently in France at the time of the "Islamic Headscarf Affair" by those opposed to the law. In the case of Hirsi Ali, herself subject to female circumcision and forced marriage, who escaped Africa to the Netherlands, the accusation is simply false. The difference between her and Muhammad Bouyeri, the killer of Theo Van Gogh, is that she never advocated murder to further her ideas. "The Koran is the work of man and not of God," she writes. "Consequently we should feel free to interpret and adapt it to modern times, rather than bending over backwards to live as the first believers did in a distant, terrible time." (4) One searches this sentence in vain for the least hint of sectarianism. Hirsi Ali's sole weapons are persuasion, refutation and discourse. Far from the pathology of proselytism, she never transgresses the domain of reason. Her hope of pushing back tyranny and superstition does not seem to result from unsound or unhealthy exaltation. But in the eyes of our genteel professors, Ayaan Hirsi Ali, like the dissenting Muslims Taslima Nasreen, Wafa Sultan, (see her interview on al Jazeera), Irshad Manji, Seyran Ates and Necla Kelek, has committed an unpardonable offence: she has taken democratic principles seriously. It is well known that in the struggle of the weak against the strong, it is easier to attack the former. Those who resist will always be accused by the cowardly of exciting the hatred of the powerful. Not without perfidy, Ian Buruma denies Ayaan Hirsi Ali the right to refer to Voltaire. Voltaire, he writes, confronted one of the most powerful institutions of his time, the Catholic Church, while Hirsi Ali contents herself with offending "a vulnerable minority in the heart of Europe." (5) However, this statement disregards the fact that Islam has no borders: the Muslim communities of the Old World are backed up by a billion faithful. Crisscrossed by diverse currents, they can either become the advance wing of a fundamentalist offensive or exemplify a type of religiosity more in harmony with reason. Far from being a negligible affair, this is one of the major challenges of the 21st century! It's not enough that Ayaan Hirsi Ali has to live like a recluse, threatened with having her throat slit by radicals and surrounded by bodyguards. She - like the French philosophy professor Robert Redeker who has also been issued death threats on Islamicist websites - has to endure the ridicule of the high-minded idealists and armchair philosophers. She has even been called a Nazi in the Netherlands. (6) Thus the defenders of liberty are styled as fascists, while the fanatics are portrayed as victims! This vicious mechanism is well known. Those who revolt against barbarism are themselves accused of being barbarians. In politics as in philosophy, the equals sign is always an abdication. If thinking involves weighing one's words to name the world well, drawing comparisons in other words, then levelling distinctions testifies to intellectual bankruptcy. Shouting CRS = SS as in May '68, making Bush = Bin Laden or equating Voltaire to Savonarola is giving cheap satisfaction to questionable approximations. Similarly, the Enlightenment is often depicted as nothing but another religion, as mad and intransigent as the Catholicism of the Inquisition or radical Islam. After Heidegger, a whole run of thinkers from Gadamer to Derrida have contested the claims of the Enlightenment to embody a new age of self-conscious history. On the contrary, they say, all the evils of our epoch were spawned by this philosophical and literary episode: capitalism, colonialism, totalitarianism. For them, criticism of prejudices is nothing but a prejudice itself, proving that humanity is incapable of self-reflection. For them, the chimeras of certain men of letters who were keen to make a clean slate of God and revelation, were responsible for plunging Europe into darkness. In an abominable dialectic, the dawn of reason gave birth to nothing but monsters (Horkheimer, Adorno). The entire history of the 20th century attests to the fanaticism of modernity. And it's incontestable that the belief in progress has taken on the aspect of a faith, with its high priests from Saint Simon to August Comte, not forgetting Victor Hugo. The hideous secular religions of Nazism and communism, with their deadly rituals and mass massacres, were just as gruesome as the worst theocracies - of which they, at least as far as communism goes, considered themselves the radical negation. More people were killed in opposition to God in the 20th century than in the name of God. No matter that first Nazism and then communism were defeated by democratic regimes inspired by the Enlightenment, human rights, tolerance and pluralism. Luckily, Romanticism mitigated the abstraction of the Enlightenment and its claims to having created a new man, freed from religious sentiment and things of the flesh. Today we are heirs to both movements, and understand how to reconcile the particularity of national, linguistic and cultural ties with the universality of the human race. Modernity has been self-critical and suspicious of its own ideals for a long time now, denouncing the sacralisation of an insane reason that was blind to its own zeal. In a word, it acquired a certain wisdom and an understanding of its limits. The Enlightenment, in turn, showed itself capable of reviewing its mistakes. Denouncing the excesses of the Enlightenment in the concepts that it forged means being true to its spirit. These concepts are part and parcel of the contemporary make up, to the point that even religious fanatics make use of them to promote their cause. Whether we like it or not, we are the sons of this controversial century, compelled to damn our fathers in the language they bequeathed to us. And since the Enlightenment triumphed even over its worst enemies, there is no doubt that it will also strike down the Islamist hydra, provided it believes in itself and abstains from condemning the rare reformers of Islam to the darkness of reprobation. Today we combine two concepts of liberty: one has its origins in the 18th century, founded on emancipation from tradition and authority. The other, originating in anti-imperialist anthropology, is based on the equal dignity of cultures which could not be evaluated merely on the basis of our criteria. Relativism demands that we see our values simply as the beliefs of the particular tribe we call the West. Multiculturalism is the result of this process. Born in Canada in 1971, it's principle aim is to assure the peaceful cohabitation of populations of different ethnic or racial origins on the same territory. In multiculturalism, every human group has a singularity and legitimacy that form the basis of its right to exist, conditioning its interaction with others. The criteria of just and unjust, criminal and barbarian, disappear before the absolute criterion of respect for difference. There is no longer any eternal truth: the belief in this stems from naïve ethnocentrism. Anyone with a mind to contend timidly that liberty is indivisible, that the life of a human being has the same value everywhere, that amputating a thief's hand or stoning an adulteress is intolerable everywhere, is duly arraigned in the name of the necessary equality of cultures. As a result, we can turn a blind eye to how others live and suffer once they've been parked in the ghetto of their particularity. Enthusing about their inviolable differentness alleviates us from having to worry about their condition. However it is one thing to recognise the convictions and rites of fellow citizens of different origins, and another to give one's blessing to hostile insular communities that throw up ramparts between themselves and the rest of society. How can we bless this difference if it excludes humanity instead of welcoming it? This is the paradox of multiculturalism: it accords the same treatment to all communities, but not to the people who form them, denying them the freedom to liberate themselves from their own traditions. Instead: recognition of the group, oppression of the individual. The past is valued over the wills of those who wish to leave custom and the family behind and - for example - love in the manner they see fit. One tends to forget the outright despotism of minorities who are resistant to assimilation if it isn't accompanied by a status of extraterritoriality and special dispensations. The result is that nations are created within nations, which, for example, feel Muslim before they feel English, Canadian or Dutch. Here identity wins out over nationality. Worse yet: under the guise of respecting specificity, individuals are imprisoned in an ethnic or racial definition, and plunged back into the restrictive mould from which they were supposedly in the process of being freed. Black people, Arabs, Pakistanis and Muslims are imprisoned in their history and assigned, as in the colonial era, to residence in their epidermis, their beliefs. Thus they are refused what has always been our privilege: passing from one world to another, from tradition to modernity, from blind obedience to rational decision making. "I left the world of faith, of genital cutting (7) and marriage for the world of reason and sexual emancipation. After making this voyage I know that one of these two worlds is simply better than the other. Not for its gaudy gadgetry, but for its fundamental values", Ayaan Hirsi Ali wrote in her autobiography (8). The protection of minorities also implies the right of individual members to extract themselves with impunity, through indifference, atheism and mixed marriage, to forget clan and family solidarities and to forge their own destinies, without having to reproduce the pattern bequeathed to them by their parents. Out of consideration for all the abuses they may have suffered, ethnic, sexual, religious and regional minorities are often set up as small nations, in which the most outrageous patriotism is passed off as nothing more than the expression of legitimate self-esteem. Instead of celebrating freedom as the power to escape determinism, the repetition of the past is being encouraged, reinforcing the power of collective coercion over private individuals. Marginal groups now form a sort of ethos-police, a flag-waving micro-nationalism which certain countries of Europe unfortunately see fit to publicly support. Under the guise of celebrating diversity, veritable ethnic or confessional prisons are established, where one group of citizens is denied the advantages accorded to others. So it comes as no surprise that Ayaan Hirsi Ali is sanctioned by our intellectuals. Nothing is missing from the portrait of the young woman painted by Timothy Garton Ash, not even an outmoded machismo. In his eyes, only the beauty and glamour of the Dutch parliamentarian can explain her media success; not the accuracy of what she says. (9) Garton Ash does not ask whether the fundamentalist theologian Tariq Ramadan, to whom he sings enflamed panegyrics, also owes his fame to his Playboy looks. Ayaan Hirsi Ali, it is true, does elude current stereotypes of political correctness. As a Somali, she proclaims the superiority of Europe over Africa. As a woman, she is neither wife nor mother. As a Muslim, she openly denounces the backwardness of the Koran. So many flouted cliches make her a true rebel, unlike the sham insurgents our societies produce by the dozen. It is her wilful, short-fused, enthusiastic, impervious side to which Ian Buruma and Timothy Garton Ash object, in the spirit of the inquisitors who saw devil-possessed witches in every woman too flamboyant for their tastes. Reading their utterly condescending words, it becomes clear that the war against Muslim fundamentalism will have to be won first on a symbolic level, and by women. Because they represent the pivot of the family and social order. Liberating them, guaranteeing them equal rights in all fields, is the first condition of progress in Arab Muslim societies. Incidentally, each time a Western country has wanted to codify minority rights, it is the members of these minorities, mostly women, who have risen up in protest. The generous desire to be accomodating - like that of the Canadian province of Ontario which sought to judge Muslims according to the Sharia, at least for litigations of succession and family - or the proposition of a former German constitutional judge, Jutta Limbach, to create a minority status in the German Basic Law excusing Muslim girls from gym class, is experienced as a regression, a new imprisonment (10). The mystique of respect for others which is developing in the West is highly dubious. Because etymologically, respect means looking on from a distance. Remember that in the 19th century native peoples were seen as so different from us that it was unthinkable that they should adopt the European model, or even French citizenship. Once considered inferiority, the difference is now experienced as an impassable distance. Pushed to the extreme, this eulogy of autarky is at the base of ill-starred political measures. What was apartheid in South Africa if not the respect of singularity pushed to the point that the other no longer has the right to approach me? So the search for religious equilibrium may frustrate the desire for change in a confession, maintaining the minority status of part of the population, in general women, and condoning a subtle segregation camouflaged as diversity. Unabashed praise for the beauty of all the cultures may hide the same twisted paternalism as that of the colonialists of yesteryear. One may counter that since Islam appeared in the 7th century, it will inevitably be somewhat behind or, as Tariq Ramadan maintains, the faithful masses have not matured to the point where they can abandon practices such as stoning (he himself calls for a moratorium on stoning, not a full stop) (11). This flies in the face of "the impatience for liberty" (Michel Foucault) which seizes Muslim elites when faced with the spectacle of secular nations, freed from the fetters of restrictive dogma and retrograde morals. The Enlightenment belongs to the entire human race, not just to a few privileged individuals in Europe or North America who have taken it upon themselves to kick it to bits like spoiled brats, to prevent others from having a go. Anglo-Saxon multiculturalism is perhaps nothing other than a legal apartheid, accompanied - as is so often the case - by the saccarine cajolery of the rich who explain to the poor that money doesn't guarantee happiness. We bear the burdens of liberty, of self-invention, of sexual equality; you have the joys of archaism, of abuse as ancestral custom, of sacred prescriptions, forced marriage, the headscarf and polygamy. The members of these minorities are put under a preservation order, protected from the fanaticism of the Enlightenment and the "calamities" of progress. Those termed "Muslims" (North Africans, Pakistanis, Africans) are prohibited from not believing, or from believing periodically, from not giving a damn about God, from creating a life for themselves far away from the Koran and the rites of the tribe. Multiculturalism is a racism of the anti-racists: it chains people to their roots. Thus Job Cohen, mayor of Amsterdam and one of the mainstays of the Dutch state, demands that one accept "the conscious discrimination of women by certain groups of orthodox Muslims" on the basis that we need a "new glue" to "hold society together." In the name of social cohesion, we are invited to give our roaring applause for the intolerance that these groups show for our laws. The coexistence of hermetic little societies is cherished, each of which follows a different norm. If we abandon a collective criterion for discriminating between just and unjust, we sabotage the very idea of national community. A French, British or Dutch citizen will be prosecuted for beating his wife, for example. But should the crime go unpunished if it turns out that the perpetrator is a Sunni or Shiite? Should his faith give him the right to transgress the law of the land? This is the glorification in others of what we have always beaten ourselves up about: outrageous protectionism, cultural narcissism and inveterate ethnocentrism! This tolerance harbours contempt, because it assumes that certain communities are incapable of modernising. Could it be that the dissidence of British Muslims is not only a function of the retrograde rigorism of their leaders, but also stems from a vague suspicion that all the consideration show to them by the state is little more than a subtle form of disdain, basically telling them that they are just too backward for modern civilisation ? Several communes in Italy are planning to reserve certain beaches for Muslim women, so they may bathe unexposed to male eyes. And within a few years the first "Islamic hospital," complying in all points with the prescriptions of the Koran, may open in Rotterdam. Anyone would think we are reliving the days of segregation in the southern United States. Yet this segregation has the full backing of Europe's most prominent progressives! Theirs is a fight on two fronts: minorities must be protected from discrimination (for example by encouraging the teaching of regional languages and cultures and adapting the school calendar to religious holidays); and private individuals must be protected from intimidation by the community in which they live. Finally, one last argument militates against Anglo-Saxon multiculturalism: on the government's own avowal it doesn't work. Not content to have serves as an asylum for Jihad for years on end, with the dramatic consequences known to all, the United Kingdom must admit today that its social model based on communitarianism and separatism doesn't work. Many people scoffed at French authoritarianism when parliament voted to foribid women and young girls from wearing headscarves in school and in government offices (news story). Timothy Garton Ash for his part, who starts his review in Seine Saint-Denis, demonstrates a Francophobia worthy of Washington's Neocons. Yet now political leaders in Great Britain, the Netherlands and Germany, shocked by the spread of hijab and burqa, are considering passing laws against them (12). The facts speak against the appeasers, who enjoin Europe to fit in with Islam rather than vice versa. For the more we give in to the radicalism of the bearded, the more they will harden their tone. Appeasement politics only increase their appetite. The hope that benevolence alone will disarm the brutes remains for the moment unfounded. We in France also have our Jihad collaborators, on the extreme left as on the right: at the time of the Muhammad cartoon affair last year, deputies of the UMP proposed to institute blasphemy laws that would have taken us back to the Ancien Regime. But modern France was forged in the struggle against the hegemony of the Catholic Church. And two centuries after the Revolution it will not support the yoke of a new fanaticism. That is why attempts by revanchist Islamic tendencies such as the Saudi Wahabites, the Muslim Brotherhood, the Salafists or Al Qaida to gain ground on European territory and reconquer Andalousia resembles a colonial enterprise that must be opposed (13). How did Europe and France become secular societies? Through an unrelenting struggle against the Church, and its hold on the right to regiment people's minds, punish recalcitrants, block reforms and maintain the people - primarily the poorest - in the stranglehold of resignation and fear. The fight was extraordinarily violent on both sides, but it brought about incontestable progress and eventually led to the law of the separation of Church and state being passed in 1905. The superiority of the French model (copied by the Turkey of Mustafa Kemal) is a result of the victory over obscurantism and events like the St. Bartholomew's Day massacre. How could we tolerate in Islam that which we no longer tolerate in Catholicism? Secularism, which incidentally is written into the Gospels, is based on a few simple principles: freedom of religious affiliation, peaceful coexistence, neutrality of the public space, respect of the social contract, and the common acceptance that religious laws are not above civil ones but reside in the hearts of believers. France, said the philosopher Hannah Arendt, treated its colonies both as brothers and subjects. Happily, the time of colonies is over. But the republican egalitarian ideal postulates that all human beings have the same rights, independently of their race, sex and confession. This ideal is far from being realised. It is even in crisis, as the riots of November 2005 proved. Nevertheless it seems to be a better guiding light than the questionable worship of diversity. Against the right to difference, it is necessary to ceaselessly reaffirm the right to resemblance. What unites us is stronger than what divides us. The positions of Ian Buruma and Timothy Garton Ash fall in with American and British policies (even if the two disapprove of these policies): the failure of George W. Bush and Tony Blair in their wars against terror also result from their focussing on military issues to the detriment of intellectual debate. The diehard sanctimoniousness of these two leaders, their blend of strategic bravado and starry-eyed naivete, prevented them from striking where it was necessary: on the terrain of dogma, on the reinterpretation of holy scriptures and religious texts (14). Yesterday the Cold War was caught up in a global combat against communism, where the confrontation of ideas, the cultural struggle in cinema, music and literature played a key role. Today we observe with consternation as the British government and its circle of Muslim "advisers" flirts with the credo: better fundamentalism than terrorism - unable to see that the two go hand in hand, and that given a chance, fundamentalism will forever prevent the Muslims of Europe from engaging in reform. Yet fostering an enlightened European Islam is capital: Europe may become a model, a shining example for reform which will hopefully take place along the lines of Vatican II, opening the way to self-criticism and soul-searching. However we must be sure not to speak to the wrong audience, styling the fundamentalists as friends of tolerance, while in fact they practise dissimulation and use the left or the intelligentsia to make their moves for them, sparing themselves the challenge of secularism (15). It is time to extend our solidarity to all the rebels of the Islamic world, non-believers, atheist libertines, dissenters, sentinels of liberty, as we supported Eastern European dissidents in former times. Europe should encourage these diverse voices and give them financial, moral and political support. Today there is no cause more sacred, more serious, or more pressing for the harmony of future generations. Yet our continent kneels before God's madmen, muzzling and libelling free thinkers with suicidal heedlessness. Blessed are the sceptics and non-believers if they can calm the murderous ardour of faith! It is astonishing that 62 years after the fall of the Third Reich and 16 years after the fall of the Berlin Wall, an important segment Europe's intelligentsia is engaged in slandering the friends of democracy. They maintain it is best to cede and retreat, and pay mere lip-service to the ideals of the Enlightenment. Yet we are a long way off the dramatic circumstances of the 1930s, when the best minds threw themselves into the arms of Berlin or Moscow in the name of race, class or the Revolution. Today the threat is more diffuse and fragmented. There is nothing that resembles the formidable peril of the Third Reich. Even the government of Mullahs in Tehran is a paper tiger that could be brought to its knees with a minimum dose of rigour. Nevertheless the preachers of panic abound. Kant defined the Enlightenment with the motto: Sapere aude - dare to know. A culture of courage is perhaps what is most lacking among today's directors of conscience. They are the symptoms of a fatigued, self-doubting Europe, one that is only too ready to acquiesce at the slightest alarm. Yet their good-willed rhetorical molasses covers a different tune: that of capitulation! -------------------------------------------------------------- (1) Ian Buruma: "Murder in Amsterdam: The Death of Theo Van Gogh and the Limits of Tolerance", New York (Penguin Press) 2006 (2) "Islam in Europe" in: New York Review of Books, October 5, 2006 (3) Buruma too speaks of "Enlightenment fundamentalists", p. 27. (4) Ayaan Hirsi Ali: "Infidel", Free Press, 2007 (5) Buruma, op. cit., p. 179. (6) According to Ian Buruma, the well-known Dutch author Geert Mak compares Ayaan Hirsi Ali's film "Submission" with the anti-Semitic Nazi propaganda film "Jud Süß" ("Murder in Amsterdam", page 240). (7) In France, 30,000 women of African origin have been subject to genital cutting, and another 30,000 women risk cutting in the future. France has long been the only country to prosecute genital cutting, and the law 4/04/06 has reinforced these measures. (8) Ayaan Hirsi Ali, "Infidel". (9) Timothy Garton Ash, in "Islam in Europe." For Garton Ash, Ayaan Hirsi Ali "is irresistible copy for journalists, being a tall, strikingly beautiful, exotic, brave, outspoken woman with a remarkable life story, now living under permanent threat of being slaughtered like van Gogh. (...) It's no disrespect to Ms. Ali to suggest that if she had been short, squat, and squinting, her story and views might not be so closely attended to." (10) Jutta Limbach: "Making multiculturalism work", in: signandsight.com (11) Ramadan reiterated this position during a debate with Nicolas Sarkozy on November 20, 2003 on French television. His brother, Hani Ramadan, also a Swiss citizen, defends stoning as punishment. (12) According to various surveys, 87 percent of British Muslims feel primarily Muslim; in France it is 46 percent. So the majority of Muslims stand behind the republican ideal, puting their religious principles behind their loyalty to the French nation. (13) Remember the communiques of Al Qaida on September 18, 2001: "We shall break the cross. Your only choice is Islam or the sword!" And in September 2006 after the declarations of Benedict XVI in his Ratisbonne speech on violence and religion, demonstrators in Jerusalem and Naplouse bore signs saying "The conquest of Rome is the solution." And Chiek Youssef Al-Quaradhawi, spiritual leader of the Muslim Brotherhood and mentor of Tariq Ramadan, said in one of his most famous sermons that he was certain that "Islam would return to Europe as a victorious conqueror, after having been twice expelled. I maintain that this time the conquest will not come of the sword, but of preaching and ideology." Al Quaradhawi also condones suicide attacks. (14) In 2004, Tony Blair printed up two Christmas cards, one of which was addressed to non-Christians and made no reference to the birth of Christ. What paternalism lurks behind this debauchery of good intent! (15) On Tariq Ramadan's duplicity and deep-seated anti-Semitism: he believes the machinations of the deeply reactionary "Zionist Lobby" are responsible for the bad reputation of his grandfather, Hassan al-Banna, founder of the Muslim Brotherhood in Egypt. The very well-researched and convincingly argumented book "Frere Tariq" by Caroline Fourest (Paris, Grasset, 2004) is highly recommendable in this context. After it was published, the author was physically threatened on the webside of the friends of Ramadan, Ouma.com. Subjected to a witch hunt, she had to be protected by the police for some time. * The article originally appeared in German in the online magazine Perlentaucher on January 24, 2007. Pascal Bruckner, born in 1948, counts among the best-known French "nouveaux philosophes". He studied philosophy at the Sorbonne under Roland Barthes. His works include The Temptation of Innocence - Living in the Age of Entitlement (Algora Publishing, 2000), The Tears of the White Man: Compassion As Contempt (The Free Press, 1986) The Divine Child: A Novel of Prenatal Rebellion (Little Brown & Co, 1994) Evil Angels (Grove Press, 1987) Translation: jab. Get the signandsight newsletter for regular updates on feature articles. signandsight.com - let's talk european. | Mid | [
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