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We doubt anyone outside of the Palestinian street really believes the stream of Hamas hyperbole that it emerged from Operation Pillar Of Defense in a better position than before. Of course, we have come to expect this sort of fantasy-based spin from much of the Arab world. Indeed, all reports prior to the cease-fire indicated that Hamas's military capacity had been severely degraded and its ability to shoot rockets at Israel largely neutralized, at least for now. And Hamas lost some of its top military commanders.
In a sober, understated report, OC Southern Command Maj. Gen. Tal Russo said that "Hamas's long-range rocket fire has been all but destroyed" and that "Hamas's drone capabilities were destroyed."
"We can measure results only after a reasonable period of time passes," he noted. "Hamas has been badly damaged. Deterrence is in place, despite the victory cries we heard in Gaza. Israel and Hamas both know Hamas has been hit hard."
We were initially dismayed by the text of the cease-fire agreement, which in addition to providing for the end of all hostilities also opened the door for discussions about opening the crossings between Gaza and the outside world. Did this not suggest that Hamas's intensified rocket attacks had, in the end, succeeded moving along an issue long pursued by Hamas?
A fuller story will doubtless emerge in the coming weeks. But it already appears that Israel came out ahead of the game beyond even what Maj.General Russo indicated. The perpetuation of the Israeli-Egyptian treaty is of vital interest to both Israel and the U.S. in terms of Israel's security needs and regional stability. And Israel's overriding reason for the Gaza blockade is to stanch the rampant weapons smuggling from Syria and Iran.
According to news reports, the Obama administration has come to accept that any relaxation of restrictions on Gaza would require assurances that arms smuggling end. The Jerusalem Post cited comments by an unnamed senior American official who said Washington understands that stopping the smuggling is a "critical element" of the cease-fire and that the U.S. will make it a priority in its discussions with Egypt and other international players.
The same official said that both Prime Minister Netanyahu and President Obama recognized early on that Egypt was the "only party that could influence Hamas and get them to accept certain things," and Egyptian President Morsi seems to have delivered. But Mr. Morsi, desperate for American financial aid and wanting to please President Obama, had to deliver something to Hamas. Ergo, there will be discussions designed to ease travel restrictions but Egypt will now also be the guarantor for the cessation of weapons smuggling.
And there are other added dividends. Because of U.S. involvement, Egypt and Israel seem to be on the same side of the smuggling issue which can only enhance their interaction and strengthen prospects for the continued life of the peace treaty. (This of course will depend at least somewhat on Mr. Morsi's surviving the current crisis in Egypt precipitated by his presidential order granting himself near dictatorial powers.)
It also seems clear that the conflict has resulted in a dramatic uptick in cooperation between Israel and the U.S. This was noted in an analytical New York Times piece last week in the aftermath of the truce agreement:
The conflict that ended, for now, in a cease-fire between Hamas and Israel seemed like the latest episode in a periodic showdown. But there was a second, strategic agenda unfolding, according to American and Israeli officials: the exchange was something of a practice run for any future armed confrontation with Iran, featuring improved rockets that can reach Jerusalem and new antimissile systems to counter them.
It is Iran, of course, that most preoccupies Prime Minister Benjamin Netanyahu and President Obama. While disagreeing on tactics, both have made it clear that time is short, probably measured in months, to resolve the standoff over Iran's nuclear program.
And one key to their war-gaming has been cutting off Iran's ability to slip next-generation missiles into the Gaza Strip or Lebanon, where they could be launched by Iran's surrogates, Hamas, Hezbollah and Islamic Jihad, during any crisis over sanctions or an Israeli strike on Iran's nuclear facilities.
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Dear Pres. Obama, A "deal" in which one side makes all the concessions is, of course, a "surrender."
ALLY is a terrific read because Oren has a mission: Defending&protecting the Jewish State of Israel.
George Soros: "European anti-Semitism is the result of the policies of Israel and the United States"
Sources say seemingly irreconcilable differences between the 2 main parties, Washington and Tehran.
Instead of accepting reality, the President is trying to hold on to an illusion.
Those who suggest further capitulation to Iran are wrongly harming the interests of the West.
Few Arab Israelis found anything positive in the decision of its MKS to join any Gaza flotilla.
US Jews prefer to be like their non-Jewish liberal friends complaining about "settlements" and Bibi
New Israel Fund & its supporters must be countered; Israel's in the midst of an unprecedented storm
PM Netanyahu this week identified ISIS and Iran as Israel's primary threat. It is a planetary threat that carries the promise of peace.
Haym Solomon, overlooked hero of the Revolutionary War, was America's "Funding Father."
Latvia, July 4, 1941 they forced many Jews in the shul putting it on fire; everyone was burned alive
There's blood on the reporters' hands AND New Israel Fund for funding groups feeding lies to the UN
Respect & appreciation for our country is not only a civic value but an essential Jewish one as well
When words lose meaning, the world becomes an Orwellian dystopia; a veritable Tower of Babel
Israel, like the non-radical Islamic world. will be happy see the ISIS beheaded for once.
Can adoption agencies limit the placement of children to heterosexual couples only?
The court's finding that the president has exclusive jurisdiction in recognizing foreign countries might have been be apt if the issue at hand were a congressional attempt to grant recognition to "Palestine" as a state.
It wasn't too long ago that Mr. Erdogan, in his determination to burnish Turkey's credentials as an Islamist state at the cost of the secularism that had brought much economic and political success to Turkey, upended his country's decades-long cooperative relationship with Israel.
Does the pope really believe that Father Dehon's destructive anti-Jewish calumnies do not disqualify him from the highest honor of the Catholic Church because in his time everyone did it?
There was something else of great importance in play – something we would have liked to see him take into account before deciding to stand with the boycotters.
"Let's get something straight so we don't kid each other…[the Iranians] already have paved a path to a bomb's worth of material," said Mr. Biden. "Iran could get there now if they walked away in two to three months without a deal."
Beyond the particulars of this tragic death, however, we should all be concerned about the possibility that a criminal prosecution in a major American city is being driven by fear of mobs in the street.
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Type Zebra App for Google Chrome and Chromium
Productivity Sauce
Thanks to Google Web Fonts, you now have access to hundreds of high-quality open source fonts, and using a simple Bash shell script, you can easily install all of them on your Linux machine. But how can you find the font you like among the hundreds of typefaces installed on your system? The Type Zebra app provides an elegant solution to the conundrum.
When you evoke Type Zebra in the browser, the app automatically scans fonts installed on your machine and lists them in the left sidebar. Type then the text you want in the main area and select the desired font from the list to apply it to the text. Instead of custom text, you can select the Sample Layout option which displays a page filled with formatted text.
Type Zebra may well be a one-trick pony app, but when you often work with fonts, it can be a real time-saver.comments powered by Disqus
Issue 177/2015
Buy this issue as a PDF
NoScript Flaw
Mozilla's script blocker add-on could be putting malware sites on the whitelist.
RIP SSLv3
The Internet community officially banishes the notoriously unsafe Secure Sockets Layer protocol.
Mate 1.1 Arrives
Popular desktop environment continues the Gnome 2 legacy – with new support for the Gnome 3 toolkit.
US Government Requires HTTPS
The Obama White House has issued a memorandum telling all US government agencies they must use HTTPS for all websites and web communication.
Mozilla Signs Firefox Add-Ons
New program will dial up security for the Firefox browser.
Fedora 22 Arrives
Red Hat's community distro embraces the cloud.
Code.org and College Board Team Reach Out for Talented High School Coders
New partnership will bring more and better CS training to US schools
A Peek Inside TeslaCrypt Ransomware
Criminals offer online help over Tor network
Mumblehard Still Spams
Sophisticated malware is still present on Joomla and WordPress sites around the world.
Launchpad Gets Git
Future versions of Ubuntu's code service will support the popular Git version control system used with Linux and other open source projects.


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Albert Breer of the NFL Network tweeted out the 2013 restricted tender amounts for the upcoming offseason as we move towards the start of free agency. The numbers, as expected, only increased by the minimum 5%, as per the CBA, which shows that the 2013 salary cap won\'t rise much in 2013.
2013 Restricted Free Agent Tender Amounts
First-round tender $2.879 million
Second-round tender $2.023 million
Original round tender $1.323 million
Right of first refusal tender $1.323 million
The Pittsburgh Steelers have six restricted free agents this offseason that they will be able to restricted tender if they so choose and those players are: running back Jonathan Dwyer, punter Jeremy Kapinos, nose tackle Steve McLendon, running back Isaac Redman, line backer Stevenson Sylvester, and wide receiver Emmanuel Sanders.
Last offseason the Steelers tendered offers to six of their restricted free agent players and they were wide receiver Mike Wallace, cornerback Keenan Lewis, safety Ryan Mundy, tight end David Johnson, offensive guard Doug Legursky and offensive guard Ramon Foster.
Last year Wallace received a first round tender of $2.742 million, while the other five players received the lowest tender amount of $1.26 million. Wallace of course refused to sign his tender until the end of training camp as he was unhappy that he couldn\'t reach a long-term contract extension with the Steelers during the offseason.
When a team offers tenders to their restricted free agents they reserve the right to retain said players by matching any offer sheets that those players might sign with another team during the free agency signing period. Should they decide not to match the offer sheet, they would receive as compensation a draft pick from the team that matches the level of the tender offered the player.
For example, should the Steelers decide to tender Sanders at a second round level they would receive a second round draft pick from the team that signs him away should they decide to not match the offer sheet that Sanders signed. Should the Steelers only place an original round tender on Sanders instead, then they would receive a third round draft pick from the team signing him away as compensation as that was the round that Sanders was originally drafted in.
As far as players who were originally signed as undrafted free agents such as Redman and McLendon, the Steelers would not receive any draft pick compensation should they place the lowest right of first refusal tender on either of them. They would have the right, however, to match the offer sheet that either player were to sign.
I see them tendering all players mentioned… Sly and Kapinos have their work cut out for them though, unless Foote is not re-signed then Sly will definitely be given every chance to play a significant role in the middle of the Defense, but even then he'll be in a camp battle with Spence, Rolle and Mcfadden
With Colons health history I REALLY wish they wouldve locked up Foster before last season, he wouldve been soo cheap at the time
What is the minimum salary for 3rd and 4th year players?
I don't really understand why tender amounts and league minimum amounts keep going up at all when the cap is flat. It just makes it harder to fit under the cap when your more expensive guys already have their contracts, and it costs more to fill in the roster with the lower level guys.
I believe 3rd year is $555,000 and 4th is $630,000 in 2013.
Would like to see Kapinos nontendered and original round on Sanders, if somebody is willing to give up a 3rd round pick on a slot receiver, we can use it. Team needs to get younger, so it would be smart to let easily replaced players go and take the draft picks. Having said that, the WR they draft would have to become effective right away without Wallace or Sanders around
Thanks 4that helpful breakdown.
Im glad its not time yet for anyone to suggest/write "Tender Colon", bcaus that sounds painful.
– Shuld tender McClendon enuff to make sure we keep him. – Re Dwyer, see if we can wait til after draft to determine which of those tender amounts right for Dwyer. Assuming Steelers can wait til after the draft, see however high of RB we draft this year. We'll probly draft a RB who is starter material. Then tender the minimum to Dwyer IF Dwyer commits to staying in shape.
On 2nd thought, because we tendered Mundy last offseason, by that standard we shuld tender EVERYONE.
I'd like to see us keep Sanders, Lewis, Foster and McLendon for sure. It'd also be smart to keep Legursky and Johnson. The rest – not so much.
I think David Johnson is the most expendable of the group, I truly think they found a hidden gem in Will Johnson this past offseason
Although I would want guys like Redman and Sylvester to come back, I don't think I'd tender them at that amount. I might offer them a multi year deal that averaged around the tender with a pro-rated bonus or I'd just let them hit free agency and try to sign them at a lesser amount. To me, this is where Khan has to earn his salary. The contributions these guys are projected to make don't always justify the tender amount even when you want them on the team.
I think the cap went up around 400k for 2013.. but yea doesnt justify raising the tender amounts though, as it could nullify the cap increase based on the amount of RFA's a Team has
Sly is really on the bubble, especially if Foote is retained for one more year, they drafted Spence and brought in Brian Rolle AND they could very well draft another ILB as well… Sly might not even be tendered based on the Foote decision
I'd really consider putting the 2nd round tender on McLendon because I can see a team scooping him up if we put the original round tender on him. Yeah the Steelers can match, but it would probably be more than what the 2nd round tender is.
Thanks for publishing these details online.
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Harry Potter's Vincent Crabbe Got Arrested For Owning Bombs And Marijuana
Crabbe, what the hell are you doing with a bomb? You shouldn't mess with muggle weapons. They will only get you in trouble.
The 22-year-old actor was reportedly charged with possession of a petrol bomb during the London riots that ravaged the city over the summer, according to E! Online.
…But that's not all, authorities also found 15 cannabis plants in his home. An added charge that will certainly not bode well with a judge — Waylett was found guilty of growing marijuana in 2009, for which he served 120 hours of community service.
- Tunisia's president declared a state of emergency a week after a deadly terror attack on a beach hotel.
- Some 150 migrants stranded in the French city of Calais stormed the Channel Tunnel in an attempt to make it to British territory.
- Matt Stonie won the 2015 Nathan's Famous hot dog eating contest, beating 8-time champion Joey Chestnut ☀??


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text:
Attempted Murder
78-Year-Old Woman Says Son Handcuffed Her In Garage, Tried To Kill Her With Fumes
"He said … 'Mother I'm going to kill you. You're going to die. You have eight minutes.'"
Ex-Con Captured In Warren, Charged With Attempted Murder
The 30-year-old victim called police Friday, accusing Charles Anderson of strangling her until she was unconscious.
4 Held On Attempted Murder Charges Over 'Botched Robbery' In Bloomfield Hills
Three men and one woman are facing several charges, including attempted murder and home invasion, in what police are calling the botched robbery of a Bloomfield Hills attorney.
Clinton Township Woman Charged With Kidnapping, Attempted Murder Of Baby
She faces up to life in prison after she allegedly grabbed a infant from a Macomb County home and ran.
Rochester Hills Man Charged With Attempted Murder In Attack On Son
Authorities say James Bell choked and shot at his 20-year-old son.
Woman Found Guilty In Axe Attack On Parents
A 29-year-old woman has been convicted of attempted murder for attacking her sleeping mother and stepfather with an axe and a knife.
Texas Fugitive Found In Michigan After 36 Years
She's been on the run for nearly four decades — but not anymore.
Woman Charged In Alleged Shooting Of Boyfriend In the Groin
Authorities say 57-year-old Sheryl Lamothe shot a man in the groin in a Rochester Hills home.
2 Teens Charged In Homeless Man's Beating
A 13 and 14-year-old will be charged as adults with attempted murder.
Mich. Woman Accused Of Trying To Kill Autistic Daughter
A 45-year-old Northern Michigan woman faces charges in what police say was a failed attempt at killing herself and her 14-year-old daughter.


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AES Journal Forum
Perceptual Evaluation of Headphone Compensation in Binaural Synthesis Based on Non-Individual Recordings
The headphone transfer function (HpTF) is a major source of spectral coloration observable in binaural synthesis. Filters for frequency response compensation can be derived from measured HpTFs. Therefore, we developed a method for measuring HpTFs reliably at the blocked ear canal. Subsequently, we compared non-individual dynamic binaural simulations based on recordings from a head and torso simulator (HATS) directly to reality, assessing the effect of non-individual, generic, and individual headphone compensation in listening tests. Additionally, we tested improvements of the regularization scheme of an LMS inversion algorithm, the effect of minimum phase inverse filters, and the reproduction of low frequencies by a subwoofer. Results suggest that while using non-individual binaural recordings the HpTF of the individual used for the recordings – typically a HATS – should be used for headphone compensation.
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Product Description
This handsome Kiddush Cup is made from anodized aluminum and features a simple shape. The cup has a flat bottom, cylindrical sides and a top edge with a slightly rounded lip. The bottom of the cup is adorned with a matching silver stripe. This cup can be used to drink Kiddush wine or any other drink.
This item is an ideal holiday gift idea!
General Information
Material Aluminium
Dimensions 4x7cm
Estimated processing time:
3-5 Business Days.Learn More
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Publications (45)271.84 Total impact
- SourceAvailable from: Raman Deep Singh
Article: Prominin-2 expression increases protrusions, decreases caveolae and inhibits Cdc42 dependent fluid phase endocytosis[Show abstract] [Hide abstract]
ABSTRACT: BACKGROUND: Membrane protrusions play important roles in biological processes such as cell adhesion, wound healing, migration, and sensing of the external environment. Cell protrusions are subtype of membrane microdomains composed of cholesterol and sphingolipids, and can be disrupted by cholesterol depletion. Prominins are pentaspan membrane proteins that bind cholesterol and localize to plasma membrane (PM) protrusions. Prominin-1 is of great interest as a marker for stem and cancer cells, while Prominin-2 (Prom2) is reportedly restricted to epithelial cells. AIM: To characterize the effects of Prom-2 expression on PM microdomain organization. METHODS: Prom2-fluorescent protein was transfected in human skin fibroblasts (HSF) and Chinese hamster ovary (CHO) cells for PM raft and endocytic studies. Caveolae at PM were visualized using transmission electron microscopy. Cdc42 activation was measured and caveolin-1 knockdown was performed using siRNAs. RESULTS: Prom2 expression in HSF and CHO cells caused extensive Prom2-positive protrusions that co-localized with lipid raft markers. Prom2 expression significantly decreased caveolae at the PM, reduced caveolar endocytosis and increased caveolin-1 phosphorylation. Prom2 expression also inhibited Cdc42-dependent fluid phase endocytosis via decreased Cdc42 activation. Effects on endocytosis were reversed by addition of cholesterol. Knockdown of caveolin-1 by siRNA restored Cdc42 dependent fluid phase endocytosis in Prom2-expressing cells. CONCLUSION: Prom2 protrusions primarily localize to lipid rafts and recruit cholesterol into protrusions and away from caveolae, leading to increased phosphorylation of caveolin-1, which inhibits Cdc42-dependent endocytosis. This study provides a new insight for the role for prominins in the regulation of PM lipid organization.Biochemical and Biophysical Research Communications 04/2013; 434(3). DOI:10.1016/j.bbrc.2013.03.097 · 2.28 Impact Factor
Article: Role of Protein Kinase D in Golgi Exit and Lysosomal Targeting of the Transmembrane Protein, Mcoln1.[Show abstract] [Hide abstract]
ABSTRACT: The targeting of lysosomal transmembrane (TM) proteins from the Golgi apparatus to lysosomes is a complex process that is only beginning to be understood. Here, the lysosomal targeting of mucolipin-1 (Mcoln1), the TM protein defective in the autosomal recessive disease, mucolipidosis type IV, was studied by overexpressing full-length and truncated forms of the protein in human cells, followed by detection using immunofluorescence and immunoblotting. We demonstrated that a 53-amino acid C-terminal region of Mcoln1 is required for efficient exit from the Golgi. Truncations lacking this region exhibited reduced delivery to lysosomes and decreased proteolytic cleavage of Mcoln1 into characteristic ∼35-kDa fragments, suggesting that this cleavage occurs in lysosomes. In addition, we found that the co-expression of full-length Mcoln1 with kinase-inactive protein kinase D (PKD) 1 or 2 inhibited Mcoln1 Golgi exit and transport to lysosomes and decreased Mcoln1 cleavage. These studies suggest that PKDs play a role in the delivery of some lysosomal resident TM proteins from the Golgi to the lysosomes.Traffic 01/2012; DOI:10.1111/j.1600-0854.2012.01331.x · 4.71 Impact Factor
Article: Human remyelination promoting antibody inhibits apoptotic signaling and differentiation through Lyn kinase in primary rat oligodendrocytes.[Show abstract] [Hide abstract]
ABSTRACT: Human remyelination promoting IgM mAbs target oligodendrocytes (OLs) and function in animal models of multiple sclerosis (MS). However, their mechanism of action is unknown. This study seeks to identify the cellular mechanism of action of a recombinant human IgM on OL survival. Binding of rHIgM22 to the surface of rat OLs was studied by co-localization with various markers. RHIgM22-mediated effects on apoptotic signaling in OLs, differentiation markers, and signaling molecules were detected by Western blotting and immunoprecipitation. RHIgM22 co-localized with integrin β3 but not other integrin β-chains in OLs. Downstream of integrin β3 we identified Src family kinase (SFK) Lyn as a key player of rHIgM22-mediated actions in OLs. Lyn immunoprecipitated in a complex together with integrin αvβ3 and PDGFαR. Lyn expression was 9-fold up-regulated and Lyn activation was 3-fold higher inrHIgM22-treated OL cultures compared with controls. RHIgM22 inhibited apoptotic signaling by greater than 10-fold reduction of caspase-3 and capsase-9 cleavage and reduced by 4-fold expression of differentiation markers MBP and MOG in OLs. SFK inhibitors PP2 and SU6656 inhibited Lyn activity and restored caspase-cleavage in OLs. A human IgM that did not promote remyelination and medium wereused as controls. rHIgM22 prevented apoptotic signaling andinhibited OL differentiation by Lyn implying thatIgM-mediated remyelination is due toprotection of OPC and OLs rather than promotion of OPC differentiation.Glia 11/2010; 58(15):1782-93. DOI:10.1002/glia.21048 · 6.03 Impact Factor
Article: Stimulation of GLUT4 (glucose transporter isoform 4) storage vesicle formation by sphingolipid depletion.[Show abstract] [Hide abstract]
ABSTRACT: Insulin stimulates glucose transport in fat and skeletal muscle cells primarily by inducing the translocation of GLUT4 (glucose transporter isoform 4) to the PM (plasma membrane) from specialized GSVs (GLUT4 storage vesicles). Glycosphingolipids are components of membrane microdomains and are involved in insulin-regulated glucose transport. Cellular glycosphingolipids decrease during adipocyte differentiation and have been suggested to be involved in adipocyte function. In the present study, we investigated the role of glycosphingolipids in regulating GLUT4 translocation. We decreased glycosphingolipids in 3T3-L1 adipocytes using glycosphingolipid synthesis inhibitors and investigated the effects on GLUT4 translocation using immunocytochemistry, preparation of PM sheets, isolation of GSVs and FRAP (fluorescence recovery after photobleaching) of GLUT4-GFP (green fluorescent protein) in intracellular structures. Glycosphingolipids were located in endosomal vesicles in pre-adipocytes and redistributed to the PM with decreased expression at day 2 after initiation of differentiation. In fully differentiated adipocytes, depletion of glycosphingolipids dramatically accelerated insulin-stimulated GLUT4 translocation. Although insulin-induced phosphorylation of IRS (insulin receptor substrate) and Akt remained intact in glycosphingolipid-depleted cells, both in vitro budding of GLUT4 vesicles and FRAP of GLUT4-GFP on GSVs were stimulated. Glycosphingolipid depletion also enhanced the insulin-induced translocation of VAMP2 (vesicle-associated membrane protein 2), but not the transferrin receptor or cellubrevin, indicating that the effect of glycosphingolipids was specific to VAMP2-positive GSVs. Our results strongly suggest that decreasing glycosphingolipid levels promotes the formation of GSVs and, thus, GLUT4 translocation. These studies provide a mechanistic basis for recent studies showing that inhibition of glycosphingolipid synthesis improves glycaemic control and enhances insulin sensitivity in animal models of Type 2 diabetes.Biochemical Journal 04/2010; 427(1):143-50. DOI:10.1042/BJ20091529 · 4.78 Impact Factor
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ABSTRACT: Caveolae are plasma membrane domains involved in the uptake of certain pathogens and toxins. Internalization of some cell surface integrins occurs via caveolae suggesting caveolae may play a crucial role in modulating integrin-mediated adhesion and cell migration. Here we demonstrate a critical role for gangliosides (sialo-glycosphingolipids) in regulating caveolar endocytosis in human skin fibroblasts. Pretreatment of cells with endoglycoceramidase (cleaves glycosphingolipids) or sialidase (modifies cell surface gangliosides and glycoproteins) selectively inhibited caveolar endocytosis by >70%, inhibited the formation of plasma membrane domains enriched in sphingolipids and cholesterol ('lipid rafts'), reduced caveolae and caveolin-1 at the plasma membrane by approximately 80%, and blunted activation of beta1-integrin, a protein required for caveolar endocytosis in these cells. These effects could be reversed by a brief incubation with gangliosides (but not with asialo-gangliosides or other sphingolipids) at 10 degrees C, suggesting that sialo-lipids are critical in supporting caveolar endocytosis. Endoglycoceramidase treatment also caused a redistribution of focal adhesion kinase, paxillin, talin, and PIP Kinase Igamma away from focal adhesions. The effects of sialidase or endoglycoceramidase on membrane domains and the distribution of caveolin-1 could be recapitulated by beta1-integrin knockdown. These results suggest that both gangliosides and beta1-integrin are required for maintenance of caveolae and plasma membrane domains.Traffic 03/2010; 11(3):348-60. DOI:10.1111/j.1600-0854.2009.01022.x · 4.71 Impact Factor
Article: Co-regulation of caveolar and Cdc42-dependent fluid phase endocytosis by phosphocaveolin-1.[Show abstract] [Hide abstract]
ABSTRACT: Several clathrin-independent endocytosis mechanisms have been identified that can be distinguished by specific requirements for certain proteins, such as caveolin-1 (Cav1) and the Rho GTPases, RhoA and Cdc42, as well as by specific cargo. Some endocytic pathways may be co-regulated such that disruption of one pathway leads to the up-regulation of another; however, the underlying mechanisms for this are unclear. Cav1 has been reported to function as a guanine nucleotide dissociation inhibitor (GDI), which inhibits Cdc42 activation. We tested the hypothesis that Cav1 can regulate Cdc42-dependent, fluid phase endocytosis. We demonstrate that Cav1 overexpression decreases fluid phase endocytosis, whereas silencing of Cav1 enhances this pathway. Enhancement of Cav1 phosphorylation using a phosphatase inhibitor reduces Cdc42-regulated pinocytosis while stimulating caveolar endocytosis. Fluid phase endocytosis was inhibited by expression of a putative phosphomimetic mutant, Cav1-Y14E, but not by the phospho-deficient mutant, Cav1-Y14F. Overexpression of Cav2, or a Cav1 mutant in which the GDI region was altered to the corresponding sequence in Cav2, did not suppress fluid phase endocytosis. These results suggest that the Cav1 expression level and phosphorylation state regulates fluid phase endocytosis via the interaction between the Cav1 GDI region and Cdc42. These data define a novel molecular mechanism for co-regulation of two distinct clathrin-independent endocytic pathways.Journal of Biological Chemistry 03/2010; 285(20):15119-25. DOI:10.1074/jbc.M109.069427 · 4.60 Impact Factor
Article: Development of a Rab9 transgenic mouse and its ability to increase the lifespan of a murine model of Niemann-Pick type C disease.[Show abstract] [Hide abstract]
ABSTRACT: Niemann-Pick, type C (NP-C) disease is an autosomal recessive neurovisceral storage disorder in which cholesterol and sphingolipids accumulate. There is no specific treatment for this disease, which is characterized by progressive neurological deterioration, sometimes accompanied by hepatosplenomegaly. We and others have shown that overexpression of certain Rab GTPases corrects defective membrane trafficking and reduces lipid storage in cultured NP-C fibroblasts. Here, we tested the possibility that Rab protein overexpression might also have beneficial effects in vivo using a murine model of NP-C. We first generated several lines of transgenic mice that ubiquitously overexpress Rab9 up to approximately 30-fold more than endogenous levels and found that the transgene expression had no obvious effects on fertility, behavior, or lifespan in normal mice. These transgenic strains were then crossed with NP-C mutant mice to produce NP-C homozygous recessive mice with and without the Rab9 transgene. Life expectancy of the NPC1 homozygous recessive animals was extended up to 22% depending on gender and the transgenic strain that was used. Histological studies and lipid analysis of brain sections indicated that the NP-C mice carrying the Rab9 transgene had dramatically reduced storage of GM(2) and GM(3) gangliosides relative to NP-C animals lacking the transgene. These results demonstrate that Rab9 overexpression has the potential to reduce stored lipids and prolong lifespan in vivo.American Journal Of Pathology 01/2009; 174(1):14-20. DOI:10.2353/ajpath.2009.080660 · 4.60 Impact Factor
Article: Inhibition of caveolar uptake, SV40 infection, and β1-integrin signaling by a nonnatural glycosphingolipid stereoisomer[Show abstract] [Hide abstract]
ABSTRACT: Caveolar endocytosis is an important mechanism for the uptake of certain pathogens and toxins and also plays a role in the internalization of some plasma membrane (PM) lipids and proteins. However, the regulation of caveolar endocytosis is not well understood. We previously demonstrated that caveolar endocytosis and beta1-integrin signaling are stimulated by exogenous glycosphingolipids (GSLs). In this study, we show that a synthetic GSL with nonnatural stereochemistry, beta-D-lactosyl-N-octanoyl-L-threo-sphingosine, (1) selectively inhibits caveolar endocytosis and SV40 virus infection, (2) blocks the clustering of lipids and proteins into GSLs and cholesterol-enriched microdomains (rafts) at the PM, and (3) inhibits beta1-integrin activation and downstream signaling. Finally, we show that small interfering RNA knockdown of beta1 integrin in human skin fibroblasts blocks caveolar endocytosis and the stimulation of signaling by a GSL with natural stereochemistry. These experiments identify a new compound that can interfere with biological processes by inhibiting microdomain formation and also identify beta1 integrin as a potential mediator of signaling by GSLs.The Journal of Cell Biology 04/2007; 176(7):895-901. DOI:10.1083/jcb.200609149 · 9.69 Impact Factor
Article: Caveolar Endocytosis and Microdomain Association of a Glycosphingolipid Analog Is Dependent on Its Sphingosine Stereochemistry[Show abstract] [Hide abstract]
ABSTRACT: We have previously shown that glycosphingolipid analogs are internalized primarily via caveolae in various cell types. This selective internalization was not dependent on particular carbohydrate headgroups or sphingosine chain length. Here, we examine the role of sphingosine structure in the endocytosis of BODIPYtrade mark-tagged lactosylceramide (LacCer) analogs via caveolae. We found that whereas the LacCer analog with the natural (D-erythro) sphingosine stereochemistry is internalized mainly via caveolae, the non-natural (L-threo) LacCer analog is taken up via clathrin-, RhoA-, and Cdc42-dependent mechanisms and largely excluded from uptake via caveolae. Unlike the D-erythro-LacCer analog, the L-threo analog did not cluster in membrane microdomains when added at higher concentrations (5-20 microm). In vitro studies using small unilamellar vesicles and giant unilamellar vesicles demonstrated that L-threo-LacCer did not undergo a concentration-dependent excimer shift in fluorescence emission such as that seen with BODIPYtrade mark-sphingolipids with natural stereochemistry. Molecular modeling studies suggest that in d-erythro-LacCer, the disaccharide moiety extends above and in the same plane as the sphingosine hydrocarbon chain, while in L-threo-LacCer the carbohydrate group is nearly perpendicular to the hydrocarbon chain. Together, these results suggest that the altered stereochemistry of the sphingosine group in L-threo-LacCer results in a perturbed structure, which is unable to pack closely with natural membrane lipids, leading to a reduced inclusion in plasma membrane microdomains and decreased uptake by caveolar endocytosis. These findings demonstrate the importance of the sphingolipid stereochemistry in the formation of membrane microdomains.Journal of Biological Chemistry 11/2006; 281(41):30660-8. DOI:10.1074/jbc.M606194200 · 4.60 Impact Factor
Article: Distinct mechanisms of clathrin-independent endocytosis have unique sphingolipid requirements[Show abstract] [Hide abstract]
ABSTRACT: Sphingolipids (SLs) play important roles in membrane structure and cell function. Here, we examine the SL requirements of various endocytic mechanisms using a mutant cell line and pharmacological inhibitors to disrupt SL biosynthesis. First, we demonstrated that in Chinese hamster ovary cells we could distinguish three distinct mechanisms of clathrin-independent endocytosis (caveolar, RhoA, and Cdc42 dependent) which differed in cargo, sensitivity to pharmacological agents, and dominant negative proteins. General depletion of SLs inhibited endocytosis by each clathrin-independent mechanism, whereas clathrin-dependent uptake was unaffected. Depletion of glycosphingolipids (GSLs; a subgroup of SLs) selectively blocked caveolar endocytosis and decreased caveolin-1 and caveolae at the plasma membrane. Caveolar endocytosis and PM caveolae could be restored in GSL-depleted cells by acute addition of exogenous GSLs. Disruption of RhoA- and Cdc42-regulated endocytosis by SL depletion was shown to be related to decreased targeting of these Rho proteins to the plasma membrane and could be partially restored by exogenous sphingomyelin but not GSLs. Both the in vivo membrane targeting and in vitro binding to artificial lipid vesicles of RhoA and Cdc42 were shown to be dependent upon sphingomyelin. These results provide the first evidence that SLs are differentially required for distinct mechanisms of clathrin-independent endocytosis.Molecular Biology of the Cell 08/2006; 17(7):3197-210. DOI:10.1091/mbc.E05-12-1101 · 4.55 Impact Factor
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ABSTRACT: Glycosphingolipids are known to play roles in integrin-mediated cell adhesion and migration; however, the mechanisms by which glycosphingolipids affect integrins are unknown. Here, we show that addition of the glycosphingolipid, C8-lactosylceramide (C8-LacCer), or free cholesterol to human fibroblasts at 10 degrees C causes the formation of glycosphingolipid-enriched plasma membrane domains as shown by visualizing a fluorescent glycosphingolipid probe, BODIPY-LacCer, incorporated into the plasma membrane of living cells. Addition of C8-LacCer or cholesterol to cells initiated the clustering of beta1-integrins within these glycosphingolipid-enriched domains and the activation of the beta1-integrins as assessed using a HUTS antibody that only binds activated integrin. On warming to 37 degrees C, beta1-integrins were rapidly internalized via caveolar endocytosis in cells treated with C8-LacCer or cholesterol, whereas little beta1-integrin was endocytosed in untreated fibroblasts. Incubation of cells with C8-LacCer or cholesterol followed by warm-up caused src activation, a reorganization of the actin cytoskeleton, translocation of RhoA GTPase away from the plasma membrane as visualized using total internal reflection fluorescence microscopy, and transient cell detachment. These studies show that LacCer can regulate integrin function both by modulating integrin clustering in microdomains and by regulating integrin endocytosis via caveolae. Our findings suggest the possibility that aberrant levels of glycosphingolipids found in cancer cells may influence cell attachment events by direct effects on integrin clustering and internalization.Cancer Research 10/2005; 65(18):8233-41. DOI:10.1158/0008-5472.CAN-05-0803 · 9.28 Impact Factor
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ABSTRACT: Niemann-Pick disease type C (NPC) is a genetic disorder in which patient cells exhibit lysosomal accumulation of cholesterol and sphingolipids (SLs) caused by defects in either NPC1 or NPC2 proteins. We previously demonstrated that NPC1 human skin fibroblasts overexpressing endosomal Rab proteins (Rab7 or Rab9) showed a correction in the storage disease phenotype. In the current study, we used protein transduction to further investigate Rab9-mediated reduction of stored lipids in NPC cells. Recombinant human Rab9 fused with the herpes simplex virus VP22 protein fragment was overexpressed, purified, and added to culture medium to induce protein transduction. When VP22-Rab9 was transduced into NPC1 fibroblasts, nearly all cells showed significant reduction in cellular free cholesterol levels, with no cytotoxicity up to 5 microM. A fraction of the VP22-Rab9 that was transduced into the cells was shown to bind to rab GDP dissociation inhibitor, suggesting that this pool of VP22-Rab9 had become prenylated. The reduction in cellular free cholesterol was associated with correction of abnormal intracellular trafficking of BODIPY-lactosylceramide and an increase of sterols in the culture media. The clearance of lysosomal free cholesterol was also associated with a decrease in LDL-receptor levels. In addition, we demonstrated reduction of intracellular cholesterol by VP22-Rab9 transduction in NPC2 fibroblasts and in cultured mouse NPC1 neurons. These observations provide important new information about the correction of membrane traffic in NPC cells by Rab9 overexpression and may lead to new therapeutic approaches for treatment of this disease.The FASEB Journal 10/2005; 19(11):1558-60. DOI:10.1096/fj.04-2714fje · 5.48 Impact Factor
Article: Analysis of the cellular and molecular mechanisms of trophic action of a misspliced form of the type B cholecystokinin receptor present in colon and pancreatic cancer.[Show abstract] [Hide abstract]
ABSTRACT: Gastrin and cholecystokinin (CCK) have trophic action on cells expressing wild type A or B CCK receptors. Potential relevance to pancreatic and colonic cancers was raised by the demonstration of a misspliced type B CCK receptor that, when expressed in Balb3T3 cells, had constitutive activity to stimulate intracellular calcium. We attempted to confirm and extend this observation in CHO cells by establishing lines expressing similar densities of variant or wild type B CCK receptor. While both were capable of normal binding and agonist-induced signaling, neither expressed constitutive signaling and both had similar basal growth. Agonist stimulation of cells expressing misspliced receptor had greater increases in calcium and greater growth rates than control cells despite similar MAP kinase phosphorylation responses. Thus, this variant receptor can potentiate peptide-stimulated signaling and trophic action and may contribute to the proliferation of neoplasms expressing it.Cancer Letters 06/2005; 222(1):95-105. DOI:10.1016/j.canlet.2004.09.008 · 5.02 Impact Factor
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ABSTRACT: Internalization of some plasma membrane constituents, bacterial toxins, and viruses occurs via caveolae; however, the factors that regulate caveolar internalization are still unclear. Here, we demonstrate that a brief treatment of cultured cells with natural or synthetic glycosphingolipids (GSLs) or elevation of cholesterol (either by acute treatment with mbeta-cyclodextrin/cholesterol or by alteration of growth conditions) dramatically stimulates caveolar endocytosis with little or no effect on other endocytic mechanisms. These treatments also stimulated the movement of GFP-labeled vesicles in cells transfected with caveolin-1-GFP and reduced the number of surface-connected caveolae seen by electron microscopy. In contrast, overexpression of caveolin-1 decreased caveolar uptake, but treatment with GSLs reversed this effect and stimulated caveolar endocytosis. Stimulation of caveolar endocytosis did not occur using ceramide or phosphatidylcholine and was not due to GSL degradation because similar results were obtained using a nonhydrolyzable GSL analog. Stimulated caveolar endocytosis required src kinase and PKC-alpha activity as shown by i) use of pharmacological inhibitors, ii) expression of kinase inactive src or dominant negative PKCalpha, and iii) stimulation of src kinase activity upon addition of GSLs or cholesterol. These results suggest that caveolar endocytosis is regulated by a balance of caveolin-1, cholesterol, and GSLs at the plasma membrane.Molecular Biology of the Cell 08/2004; 15(7):3114-22. DOI:10.1091/mbc.E04-03-0189 · 4.55 Impact Factor
Article: Heterodimerization of type A and B cholecystokinin receptors enhance signaling and promote cell growth[Show abstract] [Hide abstract]
ABSTRACT: Dimerization of several G protein-coupled receptors has recently been described, but little is known about its clinical and functional relevance. Cholecystokinin (CCK) and gastrin are structurally related gastrointestinal and neuronal peptides whose functions are mediated by two structurally related receptors in this superfamily, the type A and B CCK receptors. We previously demonstrated spontaneous homodimerization of type A CCK receptors and the dissociation of those complexes by agonist occupation (Cheng, Z. J., and Miller, L. J. (2001) J. Biol. Chem. 276, 48040-48047). Here, for the first time, we also demonstrate spontaneous homodimerization of type B CCK receptors, as well as heterodimerization of that receptor with the type A CCK receptor. Unlike type A CCK receptor dimers, the homodimerization of type B CCK receptors was not affected by ligand occupation. However, although heterodimers of type A and B CCK receptors bound natural agonists normally, they exhibited unusual functional and regulatory characteristics. Such complexes demonstrated enhanced agonist-stimulated cellular signaling and delayed agonist-induced receptor internalization. As a likely consequence, agonist-stimulated cell growth was markedly enhanced in cells simultaneously expressing both of these receptors. Our results provide the first evidence that heterodimerization of G protein-coupled receptors can form a more "powerful" signaling unit, which has potential clinical significance in promoting cell growth.Journal of Biological Chemistry 01/2004; 278(52):52972-9. DOI:10.1074/jbc.M310090200 · 4.60 Impact Factor
Article: Forskolin suppresses insulin gene transcription in islet beta-cells through a protein kinase A-independent pathway.[Show abstract] [Hide abstract]
ABSTRACT: This work was designed to evaluate the effect of cAMP on insulin gene regulation. We studied the effects of forskolin on insulin gene transcription in the INS-1 beta-cell line, confirming key results in primary cultures of human islet cells. Forskolin increased intracellular cAMP and cAMP-responsive element-binding activity. Insulin gene transcription was studied using a reporter construct in which the human insulin promoter was fused to luciferase. When cells were treated with forskolin for 12 h, insulin promoter activity was decreased 2- to 3-fold, whereas islet amyloid polypeptide promoter activity was significantly increased. This effect of forskolin on the insulin gene was time- and concentration-dependent, and was mimicked by 8-bromo-cAMP. Mutagenesis of the CRE-like elements in the insulin promoter had no effect on the forskolin-induced suppression, but dramatically decreased basal insulin promoter activity. Inhibition of PKA with H-89 also did not reverse the forskolin-induced suppression of insulin transcription. However, this effect was completely reversed by inhibition of cellular MAP kinase activity with PD98059 or U0126. These results demonstrate that forskolin suppresses insulin transcription in INS-1 cells through a PKA-independent mechanism that probably involves MAP kinase signalling.Cellular Signalling 02/2003; 15(1):27-35. DOI:10.1016/S0898-6568(02)00051-7 · 4.47 Impact Factor
Article: Glucose and forskolin regulate IAPP gene expression through different signal transduction pathways.[Show abstract] [Hide abstract]
ABSTRACT: Molecular mechanisms for the regulation of islet amyloid polypeptide (IAPP) gene expression remain unclear. In the present study, we investigated the effects of glucose and forskolin on IAPP gene regulation in the INS-1 islet beta-cell line. Both glucose and forskolin increased the level of expression of this gene, as measured by Northern blot analysis, and increased IAPP gene transcription in a time- and concentration-dependent manner, as demonstrated in a reporter gene assay. Although inhibition of protein kinase A activity with H-89 eliminated the effect of forskolin on this gene, the glucose effect was unaffected. This supported the predominant use of a protein kinase A-independent signaling pathway for glucose regulation of the IAPP gene. Electrophoretic mobility shift assay further indicated that glucose and forskolin regulated expression of this gene by targeting different elements of the promoter. Mutation of the cAMP regulatory element flanking the IAPP coding region resulted in the loss of most of the forskolin-stimulated IAPP gene promoter activity, whereas glucose-enhanced IAPP gene transcription was unaffected. These results demonstrate parallel and distinct regulatory pathways involved in glucose- and forskolin-induced IAPP gene expression in this model beta-cell system.AJP Endocrinology and Metabolism 12/2001; 281(5):E938-45. · 4.09 Impact Factor
Article: In vivo and in vitro studies of cytosolic phospholipase A2 expression in Helicobacter pylori infection.[Show abstract] [Hide abstract]
ABSTRACT: Modifications of mucosal phospholipids have been detected in samples from patients with Helicobacter pylori-positive gastritis. These alterations appear secondary to increased phospholipase A2 activity (PLA2). The cytosolic form of this enzyme (cPLA2), normally involved in cellular signaling and growth, has been implicated in cancer pathogenesis. The aim of this study was to investigate cPLA2 expression and PLA2 activity in the gastric mucosae of patients with and without H. pylori infection. In gastric biopsies from 10 H. pylori-positive patients, cPLA2 levels, levels of mRNA as determined by reverse transcriptase PCR, levels of protein as determined by immunohistochemistry, and total PLA2 activity were higher than in 10 H. pylori-negative gastritis patients. To clarify whether H. pylori had a direct effect on the cellular expression of cPLA2, we studied cPLA2 expression in vitro with different human epithelial cell lines, one from a patient with larynx carcinoma (i.e., HEp-2 cells) and two from patients with gastric adenocarcinoma (i.e., AGS and MKN 28 cells), incubated with different H. pylori strains. The levels of cPLA2, mRNA, and protein expression were unchanged in Hep-2 cells independently of cellular adhesion or invasion of the bacteria. Moreover, no change in cPLA2 protein expression was observed in AGS or MKN 28 cells treated with wild-type H. pylori. In conclusion, our study shows increased cPLA2 expression and PLA2 activity in the gastric mucosae of patients with H. pylori infection and no change in epithelial cell lines exposed to H. pylori.Infection and Immunity 10/2001; 69(9):5857-63. DOI:10.1128/IAI.69.9.5857-5863.2001 · 4.16 Impact Factor
Article: Molecular characterization and organ distribution of type A and B cholecystokinin receptors in cynomolgus monkey.[Show abstract] [Hide abstract]
ABSTRACT: Differences in the molecular structure or organ distribution of receptors can limit the usefulness of a given species for drug studies. In this work, we have studied cholecystokinin (CCK) receptors in cynomolgus monkey, an animal model useful for preclinical testing. The type A CCK receptor cDNA was cloned and predicted to encode a 428 amino acid peptide that was 98% identical to the human receptor. Only 2 of the 10 residues that were distinct from the human receptor were not present in other cloned CCK receptor species. A Chinese hamster ovary cell line that stably expressed this receptor was developed. The cynomolgus receptor expressed in this environment was functionally indistinguishable from the human receptor, binding CCK with high affinity [inhibition constant (K(I)) = 1.8 +/- 0.5 nM] and exhibiting a potent intracellular calcium signaling response to this hormone (EC(50) = 6.6 +/- 2.1 pM). Like the human type A CCK receptor, this receptor was expressed prominently in monkey gallbladder and stomach and was expressed in low levels in brain and pancreas. The type B CCK receptor cDNA was cloned from stomach and brain (450 residue receptor that is 96% identical to the human receptor), where it was highly expressed yet was undetectable in gallbladder or pancreas. This work confirms the relevance of the cynomolgus species for preclinical testing of drugs acting on the type A CCK receptor.AJP Gastrointestinal and Liver Physiology 09/2001; 281(2):G507-14. · 3.74 Impact Factor
Article: Refinement of the structure of the ligand-occupied cholecystokinin receptor using a photolabile amino-terminaI probe[Show abstract] [Hide abstract]
ABSTRACT: Affinity labeling is a powerful tool to establish spatial approximations between photolabile residues within a ligand and its receptor. Here, we have utilized a cholecystokinin (CCK) analogue with a photolabile benzoylphenylalanine (Bpa) sited in position 24, adjacent to the pharmacophoric domain of this hormone (positions 27-33). This probe was a fully efficacious agonist that bound to the CCK receptor saturably and with high affinity (K(i) = 8.9 +/- 1.1 nm). It covalently labeled the CCK receptor either within the amino terminus (between Asn(10) and Lys(37)) or within the third extracellular loop (Glu(345)), as demonstrated by proteolytic peptide mapping, deglycosylation, micropurification, and Edman degradation sequencing. Truncation of the receptor to eliminate residues 1-30 had no detrimental effect on CCK binding, stimulated signaling, or affinity labeling through a residue within the pharmacophore (Bpa(29)) but resulted in elimination of the covalent attachment of the Bpa(24) probe to the receptor. Thus, the distal amino terminus of the CCK receptor resides above the docked ligand, compressing the portion of the peptide extending beyond its pharmacophore toward the receptor core. Exposure of wild type and truncated receptor constructs to extracellular trypsin damaged the truncated construct but not the wild type receptor, suggesting that this domain also may play a protective role. Use of these additional insights into molecular approximations provided key constraints for molecular modeling of the peptide-receptor complex, supporting the counterclockwise organization of the transmembrane helical domains.Journal of Biological Chemistry 03/2001; 276(6):4236-44. DOI:10.1074/jbc.M003798200 · 4.60 Impact Factor
Top Journals
Mayo Clinic - RochesterРочестер, Minnesota, United States
University of Minnesota DuluthDuluth, Minnesota, United States
University of Alberta
Edmonton, Alberta, Canada
- Centre for Neuroscience
National Institute of Infectious Diseases, TokyoEdo, Tōkyō, Japan
Albert Einstein College of MedicineNew York, New York, United States
Mayo Clinic - ScottsdaleScottsdale, Arizona, United States
University of Naples Federico IINapoli, Campania, Italy
Vanderbilt University
Нашвилл, Michigan, United States
- Department of Chemistry
University of Washington SeattleSeattle, Washington, United States
The American Society for Biochemistry and Molecular BiologyRochester, New York, United States


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Latest from The Spokesman-Review
Sprague Lake offers anglers rare opportunity to catch healthy-size hatchery steelhead
April 23, 2015 in Outdoors on Page O3 The one-time bounty of steelhead stocked in Sprague Lake last year is catching on with anglers. "They're doing really well and are certainly contributing to the fishery," said Randall Osborne, …
Hatchery trucks dumping steelhead into Sprague Lake
May 25, 2014 in Outdoors on Page C11 About 369,000 steelhead smolts are being stocked into Sprague Lake to avoid wasting hatchery fish that landed in limbo as a result of a Wild Fish Conservancy lawsuit. "We have …
Out & About: Spectacle bluegills released in Sprague Lake
Oct. 20, 2013 in Outdoors, Sports on Page C12 OUTFISH – Sprague Lake recently received a plant of about 2,000 adult bluegills netted from Spectacle Lake in Okanogan County. Marc Divens, Washington Fish and Wildlife Department warmwater fisheries biologist, …
Newlyweds searching for lost dog near Sprague, Wash.
July 25, 2013 in City on Page A5 A pair of Seattle newlyweds recently married in Spokane are searching frantically for their dog, lost after a rollover accident near Sprague Lake last week. Sarah Cressey, 21, had just … 9
Out & About: Free fishing offered in Idaho, Washington
June 2, 2013 in Outdoors on Page C9 OUTDO – Washington and Idaho are among the many states offering free fishing – no fishing license required – next weekend.
Man dies in Sprague Lake boating accident
May 21, 2013 in Region A man has drowned in a boating accident Tuesday afternoon in Sprague Lake, the Lincoln County Sheriff's office reported. 12
Bluegills arrive at Sprague Lake
April 11, 2013 in Outdoors on Page K4 Sprague Lake is in a transition this year as it's weaned from a lunker trout fishery and emerging as a hot spot for bass and panfish. Bluegills that were in … 1
Landers: Contest gives anglers incentive to hit the water
May 17, 2012 in Outdoors, Sports on Page B1 Anglers have extra incentive to go fishing at a few choice waters this season. Several contests have the potential to pad wallets along with boosting egos.
Derby taps free-fishing
April 12, 2012 in Sports on Page K3 A prize totaling $500 awaits the angler who catches the biggest trout on June 9 during the first Sprague Lake Trout Derby. Fishermen have boated some huge rainbows out of …
Creating warmwater fisheries takes time at Sprague Lake
Oct. 17, 2010 in Outdoors on Page C14 Three years after Washington's largest fisheries rehabilitation project, Sprague Lake is just barely kicking into gear. As predicted. 1
Officials identify drowned Sprague Lake fishermen
April 20, 2010 in City on Page A6 Two Spokane fishermen who drowned in Sprague Lake last week were identified Monday as 72-year-old James Kindlespire and 53-year-old Virgil Phillips. 1
2 men who drowned in Sprague Lake identified
April 19, 2010 in City The Spokane fishermen who drowned in Sprague Lake have been identified as 72-year-old James Kindlespire and 53-year-old Virgil Phillips. 4
2 Spokane men dead after boat capsizes in Sprague Lake
April 16, 2010 in City, Region Two Spokane men were found dead in Sprague Lake today after their boat capsized. 1
Sprague's west end restricted
April 15, 2010 in Sports on Page K10 Anglers will have new rules to observe after May 1 as they pursue the still-developing fishery at Sprague Lake. Surviving rainbow trout stocked after the 2007 lake rehabilitation have grown …
Sprague Lake issue stirs debate
Jan. 28, 2010 in Outdoors on Page B1 Sprague Lake's value as a fishery and a wildlife sanctuary will be scrutinized next week when the Washington Fish and Wildlife Commission votes on fishing rule changes. State wildlife biologists … 2
Sprague proposals irk anglers
Jan. 14, 2010 in Outdoors on Page B1 A proposal to protect shorebirds and waterfowl by changing a wildlife reserve boundary at Sprague Lake has caused consternation among fishermen. Anglers are not the only ones confused about a …


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Small Hotels in London: 41
December 7, 2005
By: Mary Winston Nicklin
Enter through the residents-only entrance to discover London's exclusive, intimate retreat. From the marble and wood-paneled lobby on the 5th floor, there are 16 deluxe rooms and 4 split-level suites—including the Conservatory suite with its glass ceiling. All are elegantly decorated with mahogany furniture, black leather details, marble bathrooms, and equipped with the latest technology. A few rooms also offer views overlooking The Royal Mews at Buckingham Palace, where the horses are exercised daily. Awarded the Silver award for "Best Small Hotel in London" by VisitLondon, 41 prides itself on truly five star service. The hotel's best feature? The Lounge, where you can enjoy a cup of coffee or martini by the fire.
Christmas on the Cape at the Chatham Bars Inn
Space available at the inn for Christmas?! Could it be? Indeed, New England's premier oceanfront resort and historic landmark is all spruced up for the holidays, with a few rooms available for a last-minute getaway. In addition to the 205 luxurious guestrooms, there are 34 Cape-style cottages situated around the 25-acres of gardens. Heated pool, full-service spa, heaps of children's activities: this is the perfect spot for a family retreat. The halls are decked, and full of good cheer; enjoy afternoon tea, holiday music, and lots of hot chocolate and cookies by a cozy fire. Christmas day itself is marked by a stunning feast, ice carvings, wine tastings and culinary demonstrations, and pastries from an award-winning French chef.
Chatham Bars Inn, Official Site
Chatham Bars Inn, Five Star Alliance
Say Hello to the New Hotel Place d'Armes in Montreal
Hotel Place d'Armes has recently added 39 new rooms and 48 suites, as well as a chic spa with four treatment rooms. Housed in an historic building, the boutique hotel sits in the heart of Old Montreal. The 83 rooms and 42 suites are the essence of elegance, some with jetted baths, fireplaces, home theater systems, original brick walls and city views. The new full-service Rain Spa—with private atrium and Vichy shower room—boasts Montreal's first hammam. Additionally, the hotel just opened the bar Suite 701, the newest destination for the city's trendsetters.
Hotel Place d'Armes, Official Site
Hotel Place d'Armes, Five Star Alliance
San Francisco Eats: The Ultimate Walking Tour
The best way to see the city's unique and colorful hoods? Why, eat your way around town! Close to the country's most prized and productive farm land, the organic-minded San Francisco is brimming with tasty delights. A mecca for restaurateurs who know their quality cuisine, the city is jam-packed with gems in every distinctive neighborhood.
Rise and shine, with a California sky that blue, it's impossible to sleep the day away.
For the perfect morning coffee, head to Noe Valley's Martha and Bros., a local Latina-owned cooperative that boasts daily delicious roasts. With its boutiques and neighborhood charm, Noe Valley is picture-perfect-cute. Stroll past Noe's colorful Victorians (and charge up the city's famous inclines) for the next stop in the Mission. Got to feed that growling stomach! Not far from the sloping green of Dolores Park, with the famous mission glowing white in the California sun, Tartine beckons with its exquisite crossaints (oozing chocolate) and beautiful pastries. The line curling out the door and around the block advertise that this is absolutely the best bakery in the city. While in line-- as the aroma of hot bread wafts out of the kitchen-- try not to eat your arm off waiting for the shortbread, bread pudding or Mexican wedding cookies.
Stuffed with bread, head out the door to enjoy a Mission morning. Walk by walls covered in brilliant murals, or artistic graffiti, storefronts plastered with political profanity. And there's people-watching aplenty: from hipsters, to funkified artists, to dog-walkers, to Mexican futbolistas, and beautiful couples from the vibrant gay community of the neighboring Castro. Tired already? Nothing like a quick pick-me-up in the Lower Haight to lure you on. rnm is a paradox of sorts: outrageously hip, yet mellow and laid-back, like its Lower Haight environs. Like most major metropolises, San Francisco succumbed to the "little plates" invasion a few years ago, and rnm has perfected the trend, with plates-to-share like truffle oil pizza. Just to die for. They're not open this early? Knock, knock. I bet you can get take-out. Beg, plead. These guys are cool—after all, this is the Lower Haight. If you can't score some wanna-be tapas, head to Thep Phenom, the best Thai restaurant in town, just two blocks away, for a small bowl of pad thai.
Continue your hike to Hayes Valley, the recently revamped stretch of blocks that all the mags are talking about these days. The tiny little neighborhood somehow emblematic of a "San Francisco renaissance." As if San Fran has ever been uncool? Though right now, Hayes is the height of hip. Boutiques are full of fashion: from shoes to vintage French posters. Your lunch destination? Absinthe, of course, on the corner of Hayes and Gough. In addition to gourmet burgers with Niman Ranch ground beef, gorgonzola, sauteed mushrooms and onions, the weekend brunch is one of the best in the city. Another option is the glass-walled lunch-destination of Zuni Cafe, for its famous raw bar. Enjoy the signature roast chicken for two (spilling delicious stuffing) and buzzing atmosphere, at this prime spot overlooking Market Street.
Full? Too bad. There's too much good stuff in this town! Afternoon delights await! Continue your walking tour to the top of Fillmore and Broadway in Pacific Heights, for a breathtaking view of the bay, golden gate, and small white-houses of the Marina. The land and seascape are almost Mediterranean. Get your caffeine fix at the Coffee Bean and Tea Leaf, and then stroll through one of the city's finest shopping streets.
Continue down the hill to Union Street, for more great shopping amongst the yuppies of Cow Hollow. A fabulous walk commences at Fillmore, continues on Union Street over Russian Hill, then down into the land of Italian bistros and cozy cafes in North Beach. Gawk at another vista point, atop Telegraph Hill with the flock of wild parrots which has made the Coit Tower environs its home. Another afternoon coffee break awaits at the famous Caffe Trieste, where the Beat Generation used to wax poetical. Rest your weary feet and daydream about your dinner options: the exquisite Gary Danko, or long-time city favorite, Boulevard, located on the waterfront in the historic Audiffred Building. Ahhhh, San Francisco treats.
Auberge Does It Again, With Southern Charm
December 5, 2005
By: Guest Writer
Text and photo by Alex Rose
The Inn at Palmetto Bluff is Auberge's newest addition to their family of luxury resorts. It fits in quite nicely with the Southern charm and hospitality of the people and the region. It's located on 20,000 acres of Carolina Lowcountry in Bluffton, South Carolina. The residence cottages come with a beautiful view of the May River and its dolphins. There's a wide variety of activities including an 18-hole Jack Nicklaus signature golf course and the Spa, known for its Relaxing Bath and the Pumpkin Peach Body Peel packages.
The tradition of Auberge cuisine excellence continues with the River House Restaurant; the stand-out menu includes She-Crab Bisque, the Butter Poached Lobster, and the Crème Brulee Trinity (with chocolate-Grand Marnier) for dessert. Be sure to get a golf cart and take in the resort's marsh and wetland area, which includes alligators and abundant wildlife.
The Inn at Palmetto Bluff, Official Site
The Inn at Palmetto Bluff, Five Star Alliance
By: Guest Writer
Angkor What? The Allure of Cambodia's Khmer World Heritage Site
Monkeys giggle above in the trees. The sun is scorching hot overhead. From the road, the jungle overgrowth suddenly parts to reveal the majestic domes of ancient Angkor Wat. Fragrant orange blossoms hang from the trees, matching the brilliant robes of the Buddhist monks who are seated around the temples. Welcome to the most important archaeological site in Southeast Asia. Spread out over 400 square kilometers, Angkor's Archaeological Park includes hundreds of temples of the Khmer Empire, dating from the 9th to the 15th century. Watch the sun set (or rise) over the magnificent Angkor Wat (the largest and most celebrated of the temples), gaze at the huge stone heads at Bayon, and walk through the mysterious calm of Ta Prohm, where trees' gnarled root systems are slowly overtaking the temples. (And after all, this was where Angelina Jolie's Laura Croft toted those big-- um-- guns on the set for Tomb Raider!!! Sweet.) Where to stay? Raffles Grand Hotel D'Angkor, of course. With 60,000 sq meters of tranquil gardens, Cambodian art and architecture, and superb restaurants and spa.
Raffles Grand Hotel D'Angkor, Official Site
Raffles Grand Hotel D'Angkor, Five Star Alliance
Jamaica Hangs the (Half) Moon
Half Moon, Montego Bay is celebrating the big 5-0 and has thus come up with some pretty sweet packages. The sun is shining, birds are singing, and space is available for the winter holidays, so why not book the "Take Me To The Moon" package? From $589 a night, includes swank accommodations, sumptuous food and—could it be?—unlimited beverage, unlimited use of the fitness center and tennis courts, a welcome gift with champagne, and round trip airport transfers. Chill on the palm-dotted beaches or in your choice of 50 freshwater pools, unwind at the spa, partake in the water sports, or challenge yourself on the world-class tennis courts and golf course. The dining options? For a self-contained little paradise, the restaurant choices are almost (surprisingly) limitless.
Half Moon, Official Site
Half Moon, Five Star Alliance
Daily Candy Jets to Paris
We're loving today's candy, with lots of recs for the City of Light. Perfectly mahvelous boutique hotels, more palatial pads, and shopping, of course. (What would a trip to Par-ee be without picking up some pretty paper and ass-squeezing designer jeans?)
Spotlight On: THEhotel at Mandalay Bay, Las Vegas
December 2, 2005
By: Mary Winston Nicklin
Though it's beyond gimmicky (who was the big brain behind this name?), THEhotel is anything but corny. In 43 stories rising above the Strip, it's got the largest standard rooms in Vegas (a measly 750 square feet). The place is a playground packed with cosmopolitan fun: the 1,117 one-bedroom suites with wet bar, marble bathroom, plasma TV; the Bathhouse Spa with its pools of different temperatures, baths and flowing waterfall; and the swank Lounge (with delish cocktail concoctions) on the very top floor. Don't be fooled by December's ridiculously low rates; THEhotel is a sizzling Vegas destination.
THEhotel at Mandalay Bay, Official Site
THEhotel at Mandalay Bay, Five Star Alliance
Special Offers: Casa Del Mar Beach Golf and Spa Resort, Los Cabos
December 1, 2005
By: Mary Winston Nicklin
Think Mexico for pre- or post-holiday recuperation! With 56 ocean view rooms, Casa del Mar is a hacienda-style resort set in lush gardens overlooking the Sea of Cortez. Play a round of golf at the Robert Trent Jones II designed championship course. Head to the spa for an outstanding signature treatment like the Tropical Exfoliation, where the skin is buffed with fine milled coffee and dried coconut, and then massaged with coconut massage oil. In the evening, dine under a poolside palapa. With the Relax 33 special package, save 33% off regular rates, starting as low as $269 a night for a Deluxe Oceanview Room. Offer good December 1-20, 2005, and January 2-15, 2006. Minimum 2 night stay required.


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Carolyn Samit Dec 14, 2010 10:12 PM
Re: Video playing in response to Rex NgHi,
Not sure about a video clip but you can download and install the Pandora app, listen to music in Sleep mode that way. It works for me.
Make sure Auto-Lock is set to Never.
no_jazz Dec 29, 2010 6:06 AM
Re: Video playing in response to Rex NgI'm wondering the same thing. I seem to remember this being possible on the iPhone but no longer. Would like this feature on iPad.
rc137 Dec 29, 2010 7:56 AM
Re: Video playing in response to Rex NgJust purchased an iPad wi-fi 3G 64G on eBay. Synced with iTunes. I have a bunch of music videos (MP4) which got sent to the Music section of iTunes by Realplayer which had done the conversion. When I synced, it sent the videos to the Movie section on my iPad. I wanted to make some playlists like I have on my iPhone. I haven't figured out how to get my videos into the "Music Videos" section on my iPad. I created some playlists in iTunes which got synced to my iPad.
Problem 1: When I go to iPod and select a playlist and then select one of the videos it plays just fine. But only that video. When I play from a music album, it'll play all the songs. The problem is ... when I select SHUTTLE, it'll only play audio (on my iPhone, it'll play the audio and video). *What do I need to do to create a playlist that will play video in shuttle mode?*
Problem 2: I have my auto-lock set to 2 minutes (the screen is supposed to lock after 2 minutes of inactivity). On my iPhone, when playing a video in shuttle mode, the auto-lock will be disabled. But on my iPad, when playing a video in shuttle mode, it'll play the audio and auto-lock after 2 minutes and shut down the video (when playing music, the screen will go dark but the music will continue playing). *Where do I find the "setting" to disable auto-lock when playing a video in shuttle mode?*
Amritpal Singh Apr 16, 2012 8:26 AM
Re: Video playing in response to Rex Ng
To listen to music videos, whilst the idevice is locked...
Go on the music video via the ipod music section, and then pause it. Then, click the home button to get to the home screen. After this, double click the home button to get the small multitasking bar up at the bottom. Keep swiping right, so that you get to the furthest left. There should be a music play 'menu'. Click play, and then you can listen to the music shilst the ipad is sleeping. When you unlock it, the lock screen will show the beginning of the video as artwork.
To convert videos to music videos...
What you have to do is:
1. Put the Video on the films sectoin of ITunes
2. Then right click on the video and click on "Get Info"
3. Click on the options tab of the dialog box
4. Then on the drop down menu title "Media Kind", select "Music Video"
5. Deselect the tick box below that says "Skip when shuffling"
6. Click OK
The video wil now be in the music section, and also listed as a musci video on the video dection of your ipod. You can create a playlist titled "Musci Videos" and then put the music videos in that.
Hope this helps...
palumboseverance Sep 20, 2012 10:47 AM
Re: Video playing in response to Amritpal Singh
Has anybody gotten the video (audio) playback while the screen is off to work with the IOS 6 update? I cannot seem to get this to work anymore.


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I would suspect that this book would be of most value to Catholics. All of us have heard that unlike the Protestants, Catholics do not rely solely on Scripture but on Tradition. Read morePublished 7 months ago by Charles Lewis
This book is an outstanding work on the historical, theological, and Biblical basis of tradition, including apostolic tradition, in the 2000-year-old Catholic Church. Read morePublished on March 21, 2013 by rjjrm
This book is awesome. Yves Congar is brilliant... His thorough explanation of tradition is truly a gift to his readers.Published on January 8, 2013 by Veronica Torres
I often heard that Congar was a dissenter, but I didn't get that impression at all from this book. His understanding of tradition is profound. Very insightful, short read.Published on September 19, 2008 by Bobby Bambino


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Oregon Over-incentifies Renewable Energy, Critics Say
Running counter to Oregon's incentify-it-and-they-will-come strategy for renewable energy, critics say that the state is literally and figuratively throwing money into the wind.
At the center of the argument is the Oregon Business Energy Tax Credit, reports OregonLive. The tax credit, which encourages investment in alternative energy, recycling and energy conservation, is estimated to cost the state $168 million over the next two years, which is about $100 million more than it cost the state in the last two-year budget cycle. Such high figures have prompted state legislators to consider limiting the tax credit.
During the past eight years, the state incentive has drawn $300 million in applications. But critics say that the credit, which provides up to 50 percent of a project's cost (up to $11 million, including cost overruns), is unnecessarily generous.
Oregon has the nation's fifth-best renewable energy incentives, according to Ernst & Young.
Oregon has 812 megawatts worth of wind farms under proposal, and another 1,265 MW in the permitting process, according to a chart at OregonLive. There is already 1,585 MW worth of wind farm capacity in operation.
Oregon has said that its utilities must serve up 25 percent of their power via renewables by 2025.
Oregon has better wind resources than other Western states, so developers would come anyway, the critics say.
Yet evidence shows that incentives do matter. States with strong renewable energy portfolio standards or goals tend to outperform others when it comes to adding solar, wind, biomass and other emerging renewable energy forms, according to new research from the National Renewable Energy Laboratory.
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