text:
I might need a support group. I've finished my fourth? fifth? 241 tote. I might have a small addiction to them. But I can't HELP it. I really do love this bag, and I really really love my most recent iteration too. But not as much as my Melody Miller one, thankfully, since this one isn't staying with me either!
I caught sight of an awesome cool crane block on the Stash Bee blog, and I immediately knew I needed to make one, and for my BFF. I had originally planned to make her a 241 with an EPP'd hot pink Death Star in the center panel, but the dimensions didn't work out well, and I wasn't up to trying to figure out how to shrink it properly. Also, my EPP skillz were non-existent at the time. I'd feel much more comfortable attempting the pattern now that I have some under my belt.
But a paper pieced origami crane is just as awesome. The exterior of the bag is Kona black and a hot pink print that shall remain nameless because I forgot who made it.
And can I just say I hate interfacing? I HATE INTERFACING. No matter the project, no matter the type of interfacing, no matter the type of fabric. It always seems to play tricksies on me. (Evil stuff of evilness.) I will say, it doesn't look nearly so awful in person--how is that?
The interior is a bit more black and a pink polka dot. I did not use the magnetic snap, and I omitted the interior pocket.
I'll say that my BFF loved the bag, and she told me at first that she wouldn't be able to bring herself to use it. When I promised I'd make her another when this one dies, she consented.
This is finish 5 of 14 for my FAL Q2 list, woo! I'm hoping to finish at least one more item on the list before it's link-up time. Five of fourteen doesn't feel like that many, but I've made great progress on a bunch of the other projects, so that's always a positive thing.
Sunday, May 31, 2015
I am a 241 Tote Addict.
Labels: bags, finish-a-long, finished
4 comments:
That origami crane is super awesome! How wonderful that your friend consented to use it and was super happy with it, too! :)ReplyDelete
Love this bag and especially that paper crane, the color palette is (needless to day?) so you :)ReplyDelete
Those cranes are SO much fun! I kind of need a crane quilt now.ReplyDelete
Woah - this is super cool! Love the hot pink and black together and the origami crane is perfect.ReplyDelete
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text:
Message from CEO Eric S. Gordon
Happy New Year!
A well-deserved winter break provided an opportunity for our scholars and staff to enjoy time with their families and loved ones before the start of the second semester at CMSD. As the winter break winded down to a close for students, CMSD educators were already hard at work, preparing to help scholars reach their academic goals for the third quarter of the school year.
The often unpredictable winter weather in Cleveland makes us all more alert for school closings this tie of year. Review how decisions are made during inclement weather conditions and stay connected to your school to be sure you receive school delays or closing alerts.
To receive alerts as they happen, families are reminded to verify and update your phone number and email address on file at your school. Follow CMSD school alerts by connecting with us on Facebook, Twitter and the CMSD website. Families can put this information at their fingertips by downloading the free CMSD app on your Android or IPhone.
The half-way mark in the school year presents an opportunity not only to help our scholars reflect on their progress so far, but also to help them refocus on their goals as they head into the second semester.
It is fitting that January is designated each year as School Board Appreciation month by the National School Boards Association. Throughout the month, we will be expressing our gratitude to our dedicated school board members in a variety of ways on our website, on social media and at board meetings this month. Please join us this month in thanking members of the Cleveland Board of Education for their tireless service to our school community, for their unwavering support of the Cleveland Plan vision for our district, for taking time to understand the complex issues schools face and for charting a course to build on our history and shape our future.
Thank you for staying connected to CMSD. I look forward to sharing more good news on our continued progress as we head into the second half of the school year!
Sincerely,Eric S. GordonChief Executive Officer

subset: commoncrawl


text:
Do you offer tobacco at a Native American wedding?
A good Traditional Spiritual Leader uses a lot of tobacco
(Kinnick ~ Kinnick)
Charges you nothing for the service.
So yes, a good traditional spiritual leader is always in need of the herbs
(Kinnick ~ Kinnick).
One should also remember that a tobacco gift given the correct way is a
Prayer for a blessing to the person receiving your gift, so you can gift this
herb anytime that you feel the need to.
Because a traditional Native American is always giving out this herb.
Receiving this herb is a blessing to the pocket.
Our gift given tobacco is
Kinnick~ Kinnick!
Shechaim Walkingfox with Tah, after wedding ceremony
American Native Wedding Family
Words from a Native American wedding ceremony?
At a time when the couple is ready and the wedding party is set around the prayer alter each in turn may exchange their love and vowels to each other, the female has the choice as to who will start first.
The Spiritual leader performing the blessed event, in our tribe, will first speak to Creator in our tongue, then English for each section of the wedding ceremony.
The words chosen by the couple with the acceptance are not as important as the words by the couple and the tribal sacred words from the Spiritual leader to the couple and Creator, what the words are of course is a very guarded secret sacred ceremony.
The Eastern Woodland American Native Wedding Ceremony, this must be said because this is only speaking about our people.
There are still over 500 tribes in Indian Country
That have permission to be recognized and at least as many that the government is still trying to eliminate by not recognizing.
There are about 500 ways they may have to their native weddings; I have been to many of them.
Our wedding ceremony, a Traditional Wedding, should be something like many of the others however; it is not like the Funeral ceremony, because the public may enjoy the complete ceremony with the permission of the couple.
The beginning and ending prayer, like most sacred prayers should never be recorded, this is the leader and the couples request for marriage to Creator and thanks to Creator after the ceremony.
The prayer can be filmed just not the words. Only the Spiritual leader and the couple need the Creators blessing at the beginning, Creator at the end of the ceremony will bless everyone.
If you are being groomed for our ceremony please understand, this can take from a few days to at least a month.
By studying correctly you will knowing that you will be blessed, remember; only Creator can bless!
Someone, in the favor with the couple, should gift a blanket; this person must also attend at least some of the pre ceremony.
Everyone gifting at the time of and with the permission of the Spiritual leader and the couple should attend at least some of the pre ceremony.
Sometimes the families and/or friends wish to gift a Turtle Rattle, Regalia, Headpiece, Sage, Sweet grass, and/or Tobacco for the ceremony.
As with the funeral ceremony, both families can asked to help with the meal after.
Anyone asked to, can join in the meal and whatever plans after the wedding.
Native American pre marriage ceremonies
The pre marriage meetings for our people is not a requirement for marriage, it is a request from the spiritual leader.
At this meeting the couple and any member of the soon to be wedding, will learn everything that will take place on that blessed day, the couple and any person directly involved will then know what is expected of them by Creator during the wedding.
The couple will learn where to stand and why, will learn about the regalia and why it is used and all of the sacred blessings from Creator through your ancestors.
That said, please remember, whatever happens during the wedding will not be judged, after all it is a fun, loving, first day for the rest of your lives.


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A CAMPAIGN to get young people in North Ayrshire to vote in next year's Scottish Parliament elections is underway with the help of technology.
For the first time, 16 and 17-year-olds have been given the chance to vote in a national election and to ensure that as many young people are registered to vote as possible, North Ayrshire Council are promoting the introduction of the new voting app.
it is hoped that the app will ensure that all those now eligible to vote will grab hold of the opportunity to take part in 2016's vote, with the Scottish Parliament lowering the voting age after the success of giving 16 and 17 year olds the vote in last year's Scottish independence referendum.
Elma Murray, Returning Officer for North Ayrshire, said: "No one should miss out on their legal right to be part of the democratic process and I would encourage those who will be 16 and 17 by next May to activate their legal right to vote by downloading the new voting app." Voters with a Young Scot NEC card can get reward points by downloading the app, at www.moderndemocracy.co.uk/ayrshire_valuation_joint_board.htm


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Family Cruise – User Hall of Fame
We're saaaaaiiiling awaaaaayyyy. Now that looks like a relaxing and happy balcony with a true ocean view good enough to land in the ReallyColor User Hall of Fame!
CLICK HERE to Download Your Own Copy Ready to PRINT and COLOR
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text:
Please use this identifier to cite or link to this item:
|The syntheses and reactivity of four- and five-membered metallacycles of platinum and palladium.
|Mason, Simon
|Award date:
|Presented at:
|University of Leicester
|Chapter 1 reviews the literature concerning the synthesis and reactivity of oxodimethyl- enemethane metal complexes and their applications in organic synthesis. The preparation of metal-ureylene complexes and amino acid complexes of platinum are also discussed. Chapter 2 describes the synthesis of metallaphosphetane-3-oxide complexes of platinum and palladium, [M {lcub}CH(R)P(O)(Ph)CHR{rcub} L2]. Crystallographic and n.m.r. evidence for benzoyl substituted complexes, indicates that the four-membered rings are puckered, with the phosphoryl oxygen adopting an equatorial environment. The ligand substitution reactions of platinum analogues are also discussed. The preparation of new platina-2,4,3-diazaphosphetidine-3-oxide complexes, [Pt{lcub}N(R)P(O)(Ph)NR{rcub}L2] is presented in Chapter 3. An X-ray crystal structure determination on an N,N -diphenyl derivative indicates that the four-membered metalla-cyclic ring is almost planar, the nitrogen atoms of which show sp2 hybrid character. An investigation into the insertion reactions of the N,N'-dihydrogen derivatives with dimethyl acetylenedicarboxylate resulted in the isolation of six-membered platinacyclic products, characterised by n.m.r. and i.r. spectroscopy. Attempts to prepare a similar insertion product using hexafluorobut-2-yne, led only to the formation of an organic polymeric material. The formation of a novel four-membered ring species containing a phosphin-imine functionality [Pt{lcub}SP(=NPh)(Ph)NPh{rcub}L2] is also described in Chapter 3. The phos-phinimine group was shown to have Lewis base capabilities and also underwent Wittig-type reactions with C=O and C=S containing molecules to form [Pt{lcub}SP(O)(Ph)NPh{rcub}L2] and [Pt{lcub}SP(S)(Ph)S)L2] ring systems respectively. The formation and characterisation of phosphonato, phosphato and arsonato complexes of platinum(II) are described in Chapter 4. The molecular structure of a bis(phosphine)phos- phonato complex establishes the presence of a slightly puckered four-membered ring with the phosphoryl oxygen adopting an equatorial position. The decomposition in solution of a bis(benzyldiphenylphosphine) analogue led to the formation of the di-orthometallated product cis-[Pt{lcub}C6H4CH2PPh2{rcub}2], as shown by X-ray crystallography. Chapter 5 describes the synthesis of five-membered platinacycles containing amino acid derivatives, [Pt{lcub}N(R2)-CH(R1)-C(O)O{rcub}L2]. An X-ray crystal structure determination on an [N-acetylglycinato(2-)-N,O] complex, indicated the presence of an almost planar five- membered ring that contains substantial electron delocalisation within the carboxylate and amide functionalities. The reaction of these complexes in ethanol with carbon monoxide or sulphur dioxide led to the formation of bis(ethoxycarbonyl) or bis(ethylsulphonato) metal complexes respectively. The final Chapter investigates the syntheses of several new five-membered metallacyclic species which contain metal bonds to carbon, nitrogen, oxygen or sulphur. The isolation of the metallaoxacyclopentenone ring system [Pt{lcub}CH=C(NHCOMe)C(O)O{rcub}L2], formed via the rearrangement of an initially produced [Pt{lcub}N(COMe)C(=CH2)C(O)O{rcub}L2] species, was confirmed by a single crystal X-ray diffraction study. The natures of the other complexes were examined using n.m.r. and i.r. spectroscopy.
|Copyright © the author. All rights reserved.
|Appears in Collections:
|Theses, Dept. of Chemistry
Leicester Theses
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|Adobe PDF
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text:
The Tillers, a neo-old-time three-piece band from Cincinnati, Ohio, will make a two-week tour (2-15 November 2013) in Britain and Ireland in support of their new album Hand on the plow, which is due for release on 4 November on the Muddy Roots Music Recordings label.
Iris DeMent is quoted as saying: 'The Tillers… I could sit and listen to them all night long!' The band have released several earlier albums, and have won three Cincinnati Entertainment Awards for best Folk and Americana act (2009, 2010, 2013). While in Britain, they will be playing six dates with Pokey LaFarge (USA).


text:
The Position Of Education And Coaching To The Success Of TQM Implementation.
In fact, I'm not in the slightest degree ashamed to admit to you that I am on no account higher than the person who sadly has to have that next drink or essentially the most handsome man and prettiest lady with a Scotch and water in their hand at some swanky cocktail affair on New York's Fifth Avenue. Constitutional monarchy – a system of government wherein a monarch is guided by a constitution whereby his/her rights, duties, and tasks are spelled out in written regulation or by custom. It is a manufacturing facility-mannequin classroom. Impressed partly by the approach Horace Mann saw in Prussia in 1843, it appeared to adequately prepare American youth for the 20th century industrialized economic system. But in 1983, the federal authorities declared in A Nation At Threat that our system was beginning to slide.
ME replies – clearly that did not work within the time before significant lending and the one subsidies have been from scholarship. The rationale there is such a mortgage program within the first place is competitors failed to supply school education to those who couldn't afford the price tag. The result, after all, is a much less educated America and all of the unfavorable consequences that brings on.
The federal Department of Education could be charged with growing alternative units of curricula, in session with all state Division of Educations, that may produce a effectively-rounded, educated pupil who is ready to enter the world even when he or she does not go on to varsity or vocational college. I say alternative curricula as a result of whereas we're altering the world right here, we'd as effectively go entire hog.
Being a wise particular person also requires integration. Having the ability to have a look at the entire image creates a extra … Read More ...


text: A technology study from Intertech-Pira titled "Advances in Nanophotonics" provides an overview of the field, including challenges and emerging trends across a wide variety of industries. It discusses nanophotonics applications, among them amplifiers, biosensors, solar cells, optical switching, quantum computing, data storage, memory devices and flat panel displays. Developments in related materials and devices are addressed, including LEDs, lasers, biomaterials, nanocrystals, surface plasmons, nanophosphors, near-field optics, photonic crystals (2- and 3-D), and quantum dots, wells and wires. A section is devoted to manufacturing techniques such as extrusion, deposition, micromachining, microlithography, stack methods, self-assembly and holographic lithography. A list of nanophotonics suppliers and users is provided. The price of the report is $555.82.


text:
Overweight and obese people who take a high-dose of supplementary Vitamin C daily may get some of the cardiovascular benefits of exercise without the exercise, new research has found.
In a small trial that recruited sedentary adults who were overweight or obese, study participants who took 500 milligrams of Vitamin C daily saw equal improvement in blood vessel tone — a key measure of cardiovascular health — as did those who took up a three-month regimen of brisk walking five to seven times a week, investigators at the University of Colorado at Boulder reported.
The results were presented in Atlanta this week at the American Physiological Society's annual meeting. But they have not yet been published in a peer-reviewed journal and so are considered preliminary.
The study's small size — 15 subjects got the walking treatment, while 20 took the Vitamin C supplements — may also limit the uptake of its findings by public health officials, who have struggled, with limited success, to get sedentary Americans off the couch. Some 4 in 10 American adults are thought to be entirely sedentary.
But the study's invasive measures of "endothelial function" — blood vessels' ability to contract and dilate as needed — suggested that both the benefits of modest aerobic exercise and of Vitamin C were substantial.
At the start of the trial, all of the study's subjects were sedentary and overweight or obese, and all showed levels of vascular tone that were impaired. In a pattern typical for overweight and obese adults who don't get much exercise, their blood vessels did not respond to experimental conditions with the strength and suppleness seen in normal, healthy adults.
Their poor vascular tone sets off a cascade of harmful effects, including inflammation and changes in the blood that favor the formation of clots. As a result, these subjects were at increased risk of developing high blood pressure and suffering heart attacks and strokes.
The average ingoing body-mass index of exercisers was 29.3 and for the Vitamin C group, 31.3 (a BMI between 25 and 29.9 is considered overweight, and obesity is diagnosed at a BMI of 30). During the study's three-month duration, neither group lost any weight.
Both three months of moderate-intensity exercise and three months of Vitamin C supplements drove subjects' vascular tone back into healthy territory. But the Vitamin C did so without the burning of shoe leather or the exertion of walking.
The study's lead author, Caitlin Dow, said the findings were particularly important for people who cannot exercise because of injury or physical limitations.
"This is not 'the exercise pill,' " said Dow, a post-doctoral fellow at Colorado who conducts research on nutrition and vascular biology.
Dow underscored that engaging in regular physical activity appears to have broader effects — lowering "bad" cholesterol, improving metabolic function and boosting mood and cognitive function — than does Vitamin C. For those able to get out and walk, or to hit the gym's cardio equipment, that makes exercise a healthier option, she said.
But if a supplement that is widely taken and is safe for most people can mitigate some of the risks of excess weight, it may have broad benefits, she said. That's especially important because only a very small minority — fewer than 1% by a recent estimate — of those with established obesity succeed in losing and keep off enough weight to return to a normal healthy weight.
"If we can improve different measures of risk for disease without changing weight, it takes a little bit of the pressure off some people," Dow said. While Vitamin C "certainly isn't a new cure," she added, "it's important to know what other lifestyle changes we can offer people who can't exercise."
Jessica Jones-Smith, an expert on human nutrition at Johns Hopkins University's School of Public Health, said the new findings would be welcome if they mitigate obesity's health impacts without a downside.
"At the same time, we should be cautious in interpreting these findings," said Jones-Smith. In addition to the preliminary nature of the results, "it is not clear that improved vascular tone" -- the principal outcome measured in the trial -- "will translate to decreased risk of cardiovascular disease."
Dow said that while the finding may need to be demonstrated in a more diverse population, the current study, which required the insertion of measurement devices into subjects' forearms, was necessarily small. Its subject population was sufficiently large to conclude that the effects seen were not a statistical fluke, she added.
A moderate supplemental intake of Vitamin C is between 30-and-180 mg per day, so 500 mg per day is a relatively high dose. But the tolerable upper limit for adults of Vitamin C is 2,000 milligrams. Because it is a water-soluble vitamin, any Vitamin C that is not used is excreted in urine. The most common complaints with high doses of Vitamin C are diarrhea, nausea, abdominal cramps and other gastrointestinal disturbances.
One study, which has not be replicated, has found that in postmenopausal women with diabetes, taking a daily 300-mg Vitamin C supplement was significantly associated with an increased risk of cardiovascular disease mortality. High vitamin C intakes also may contribute to the formation of kidney stones, especially in individuals with renal disorders.
Follow me on Twitter @LATMelissaHealy and "like" Los Angeles Times Science & Health on Facebook.


text:
I have done little lately, i put some mags on the Battletruck, had some bitch crash into the front of it and decommision the reverse gear in the gearbox. Now I'm waiting on AA Insurance to get their shit together so she's sitting forelornly in the drive way at The Ballroom. I got inspired to make some Ginger Bee. I got the Brewcraft kit,, which is nothing like I remembered and seems like nothing more than a can of malt extract and a flavoursachet. i gues sthe proof will be in the bottle in a month or two. I lack motivation to write. This is all.
Oh yeah, I forgot I went to Beach Hop 2010 at whangamata, so if you want to see pics of awesome hot rods, rat rods, and other V8 stuff, check out my flickr page
Yeah, and I did a stencil of those fantails. And I gave someone the design for a tattoo, pics when it happens.
Sunday, April 11, 2010
On the Go slow
Posted by Mike Shadow at 1:27 PM
Labels: ratrod
1 comment:
- Brumby said...
Don't you wish you had a Nan who makes awesome ginger bee(r) and could get a receipe from her?
- April 11, 2010 at 2:02 PM
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text:
At Yacht Deliveries, we have the ability to place fully assessed and vetted skippers and crew with vessels to ensure a safe and trouble free passage, with minimum wear to the vessel and maximum peace of mind for the owner! Yacht delivery is our business!
At Yacht Deliveries, we have the ability to place fully assessed and vetted skippers and crew with vessels to ensure a safe and trouble free passage, with minimum wear to the vessel and maximum peace of mind for the owner! Yacht delivery is our business!
At Yacht Deliveries.biz we only hire skippers and crew that are willing to represent the company in a professional manner and take pride in their work.
Yacht Deliveries is the first delivery business to use Boat Tracking as standard
Yachting delivery skipper has had a busy time lately, and this month starts his way back from "Beef Island" (Tortola) to Guernsey. Steve started working for Yacht Deliveries last year, working part time for us as well as himself designing as an Artist, who is also currently looking at our web site! However, just lately Steve cant seem to get away from the water as we get ever increasingly busy, the more work we keep piling on him!!! Steve is just about to sail a Nichoson 35 with owner David Stone back from Beef Island to make it his third delivery this year for us in two months!
we gain more support! After teaming up with sailing school "Happy whale", Yacht Deliveries has now made further alliances. "A bay watch" is an online accommodation agency in Cowes. Accommodation can be found for all of the major sailing advents including: Cowes Week, Little Britain, Commodores Cup, Round the Island, Silicon Cup and other regattas in Cowes. Charter a yacht and set sails! "A bay watch" will find you rentals, holiday home rental and short term let accommodation in Cowes from houses, flats and apartments. So if you need accommodation at Cowes.
Yacht Deliveries has had an exciting April, with the ongoing domestic business always increasing, we are working in conjunction with a world wide yacht brokerage.
Now we are moving their show boats around, and there is a huge demand for crew! In response to this Yacht Deliveries has enlisted the help of Happy Wheel. Happy Wheel offer training and assessment for professional certificates of competence from the UK's Maritime & Coastguard Agency (MCA), the Royal Yachting Association (RYA) and Yachting Australia (YA). Their commercial Basic Safety Training course complies with the internationally recognised Standards of Training, Certification and Watch Keeping for Seafarers (STCW 95). They also offer a recruitment service for all its Graduates to help them on their road to employment.


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Van Eck, the New York City-based ETF issuer known for its commodity producing equity ETFs, remains active on the product development front, recently announced plans for a constant maturity commodity ETF. In a recent filing with the SEC, the company released details on the Market Vectors CM Commodity Index ETF, which would track the performance of the UBS Bloomberg Constant Maturity Commodity Total Return Index [read the Ultimate Guide To Agricultural ETFs].
The underlying index is a rules-based, composite benchmark diversified across 26 commodities from the following five sectors: energy, precious metals, industrial metals, agriculture and livestock. The index is comprised of futures contracts with maturities ranging from around three months to over three years for each commodity, depending on liquidity. The overall return will reflect a combination of the returns on the futures contracts and the daily fixed-income return that would be earned on a hypothetical portfolio of 91-day U.S. Treasury bills theoretically deposited as margin for the hypothetical positions in the futures contracts comprising the index.
The selection and relative weightings of the components of the proposed fund are designed to reflect the economic significance and market liquidity of each commodity, as determined based on global economic data, consumption data, commodity futures prices, open interest and volume data [read Ten Commodity ETFs Every Investor Should Know But Most Don't].
If approved, the new fund would likely face stiff competition in the increasingly crowded commodity ETF space where new products seemingly debut every month. Among the competitors would be the United States Commodity Index Fund ( USCI), which selects a total of 14 holdings from a universe of 26 commodities in total [see a Closer Look At The Third Generation Commodity ETF].
Van Eck is a major player in the commodity space, offering a number of funds that focus on equities of commodity intensive equities. In addition to the broad-based Hard Assets Producers ETF ( HAP), the company's lineup includes ETFs focused on gold miners ( GDX, GDXJ), the coal industry ( KOL), agribusiness ( MOO), and rare earth metals ( REMX). The proposed CM Commodity Index ETF would be the first to offer exposure to commodities through futures products.
Earlier this month Van Eck debuted a mutual fund version of the proposed ETF, the Van Eck CM Commodity Index Fund (CMCAX). The recently-launched mutual fund is passive in nature, seeking to replicate the performance of the underlying index [see Mutual Fund To ETF Converter].
[For more news about upcoming ETFs, sign up for our free ETF newsletter.]
Disclosure: No positions at time of writing.
Click here to read the original article on ETFdb.com.


text:
- Commentary
- Open Access
Smurf2 as a novel mitotic regulator: From the spindle assembly checkpoint to tumorigenesis
© Osmundson et al; licensee BioMed Central Ltd. 2009
- Received: 01 June 2009
- Accepted: 07 July 2009
- Published: 07 July 2009
The execution of the mitotic program with high fidelity is dependent upon precise spatiotemporal regulation of posttranslational protein modifications. For example, the timely polyubiquitination of critical mitotic regulators by Anaphase Promoting Complex/Cyclosome (APC/C) is essential for the metaphase to anaphase transition and mitotic exit. The spindle assembly checkpoint prevents unscheduled activity of APC/C-Cdc20 in early mitosis, allowing bipolar attachment of kinetochores to mitotic spindle and facilitating equal segregation of sister chromatids. The critical effector of the spindle checkpoint, Mitotic arrest deficient 2 (Mad2), is recruited to unattached kinetochores forming a complex with other regulatory proteins to efficiently and cooperatively inhibit APC/C-Cdc20. A weakened and/or dysfunctional spindle checkpoint has been linked to the development of genomic instability in both cell culture and animal models, and evidence suggests that aberrant regulation of the spindle checkpoint plays a critical role in human carcinogenesis. Recent studies have illuminated a network of both degradative and non-degradative ubiquitination events that regulate the metaphase to anaphase transition and mitotic exit. Within this context, our recent work showed that the HECT (Homologous to E6-AP C-terminus)-family E3 ligase Smurf2 (Smad specific ubiquitin regulatory factor 2), known as a negative regulator of transforming growth factor-beta (TGF-β) signaling, is required for a functional spindle checkpoint by promoting the functional localization and stability of Mad2. Here we discuss putative models explaining the role of Smurf2 as a new regulator in the spindle checkpoint. The dynamic mitotic localization of Smurf2 to the centrosome and other critical mitotic structures provides implications about mitotic checkpoint control dependent on various ubiquitination events. Finally, deregulated Smurf2 activity may contribute to carcinogenesis by perturbed mitotic control.
- Spindle Assembly Checkpoint
- Spindle Checkpoint
- Mitotic Exit
- Anaphase Onset
- Early Mitosis
The spindle assembly checkpoint
The spindle assembly checkpoint is a complex signal transduction cascade that inhibits the metaphase to anaphase transition in the presence of unattached or untensed kinetochores. It incorporates a molecular surveillance mechanism whereby a single unattached kinetochore is sufficient to initiate a global/cell-wide inhibitory signal to prevent the biochemical events driving anaphase onset. The critical downstream target of the spindle checkpoint is APC/C which, in association with its activator Cdc20, is responsible for the rapid ubiquitin-dependent degradation of mitotic regulatory proteins such as Securin, an inhibitor of sister chromatid segregation, Cyclin B, and Aurora B kinase. In early mitosis, the checkpoint protein Mad2 is recruited to sites of unattached kinetochores in association with Mad1 (Mitotic arrest deficient 1), Bub1 (Budding uninhibited by benzimidazoles 1 homolog) and other components of the Mitotic Checkpoint Complex (MCC). The association of Mad2 with various components of the MCC at the kinetochore is thought to induce a dramatic conformational change of Mad2 allowing for the tight binding between Cdc20 and Mad2 and the inhibition of both kinetochore-associated and cytoplasmic APC/C. This prevents premature APC/C activity which would trigger mitotic exit and the development of numerical chromosomal abnormalities. Implicit in this mechanism is the requirement for reversibility, allowing for the rapid activation of APC/C once all kinetochores are securely attached to spindle microtubules. During spindle checkpoint activation, Mad2 undergoes a dramatic conformational change from an inactive to an active conformer capable of binding to and inhibiting Cdc20-associated APC/C. While the evidence for the two state model of Mad2 is abundant, the spontaneous conversion of Mad2 from an inactive form to an active, inhibitory conformation takes several hours, evoking the need for a catalytic mechanism [1]. The precise mechanisms allowing for both the rapid reversibility and the global nature of the inhibitory signal remain controversial, and leading hypotheses have been recently reviewed [2, 3].
It has been known for some time that rapid APC/C-mediated polyubiquitination and degradation of diverse substrates drives anaphase onset and the segregation of sister chromatids. Recent work, however, has implicated non-canonical roles for ubiquitination in the regulation of the spindle checkpoint. Stegmeier, Reddy and others have provided evidence for an antagonistic cycle of ubiquitination and deubiquitination of coactivator Cdc20 in early mitosis which regulates the assembly of Cdc20-Mad2 complexes, and thereby APC/C activation and spindle checkpoint activity [4, 5]. Available evidence supports that USP44-mediated deubiquitination stabilizes the Cdc20-Mad2 complex by removing ubiquitin conjugates from Cdc20 that would otherwise promote disassembly of Cdc20-Mad2. Importantly, this work strongly implies that the non-degradative ubiquitination of Cdc20 is a prerequisite for the onset of timely APC/C activity. This must be reconciled with recent evidence presented by Pagano and Pines groups who argue that during spindle checkpoint activation, a significant proportion of Cdc20 is rapidly polyubiquitinated and degraded, perhaps in a Mad2-dependent manner, a process which may be essential for spindle checkpoint activation [6, 7]. Taken together, these studies suggest that an intricate network of both degradative and non-degradative ubiquitination events regulates mitotic progression. Adding to this complexity is our recent study indicating the activity of Smurf2, a HECT family E3 ligase, in the stability of Mad2 and the function of the spindle checkpoint [8].
Smurf2 targets and expanding array of diverse substrates
Like all HECT domain-containing ubiquitin ligases, Smurf2 has a catalytic activity as a single polypeptide. It contains an N-terminal C2-calcium phospholipid binding domain, three WW domains within a flexible linker region, followed by a C-terminal HECT domain responsible for its catalytic activity. Smurf2 was originally characterized as a negative regulator of the TGF-β signaling pathway by targeting receptors, signaling intermediates, and other pathway-specific transcription factors for degradation [9–11]. Recent studies have uncovered new roles and substrates for this E3 beyond the canonical TGF-β signaling pathway. For example, Smurf2 targets the Guanine-Trinucleotide Phosphate hydrolase Rap1B [12], the RING (Really Interesting New Gene- domain) protein RNF11 [13], the Runt domain transcription factors Runx2 [14] and Runx3 [15], Beta-catenin [16], and most recently reported, its paralog Smurf1 [17]. Through its role as a regulator of TGF-β mediated transcriptional events, Smurf2 has been tangentially implicated in the control of the cell cycle, but direct evidence implicating Smurf2 in cell cycle control was lacking until recently.
Smurf2 is a novel mitotic regulator
The first clue that Smurf2 could play a more direct role in cell cycle control came with the evidence that Smurf2 itself is a cell cycle regulated protein. In synchronized HeLa cells, Smurf2 protein levels are lower in late G1 and early S and peak in late G2 and early mitosis. Whereas previous studies had localized Smurf2 to non-clathrin containing, caveolin- and EEA1-positive endosomes [18], our subsequent analyses localized Smurf2 to the centrosome by both immunocytochemical [8] and biochemical means (E. Osmundson, H. Kiyokawa unpublished data). Furthermore, Smurf2 exhibits a highly dynamic localization pattern throughout mitosis, moving from centrosomes in late prophase and metaphase, to the mitotic midzone in anaphase, and ultimately to the midbody in telophase. This localization pattern is reminiscent of, though not identical to, chromosomal passenger proteins (i.e. survivin and Aurora B) which have well established roles in mitotic regulation [19]. Consistent with this notion, our experiments have shown that Smurf2 is required for normal mitotic progression, with acute depletion of Smurf2 in mammalian cells leading to multinucleation and cytokinesis failure. Smurf2-depleted cells often initiate anaphase in the presence of unaligned chromosomes. Further, following chromatin condensation in prophase, Smurf2-depleted cells frequently fail to form a discernable metaphase plate (i.e. chromosomal congression defects) and exit mitosis as a bi- or multi-nucleated cell (i.e. mitotic failure). These phenotypes suggest that Smurf2 plays a role in ensuring proper alignment of chromosomes at metaphase, a process controlled by the spindle assembly checkpoint.
Cells depleted of spindle checkpoint proteins such as BubR1 (Bub1-related kinase), Mad2, or USP44 demonstrate mitotic defects, and fail to arrest in early mitosis in response to spindle toxins like nocodazole or taxol. Similarly, Smurf2-depleted cells also fail to arrest in prometaphase when exposed to nocodazole, displaying premature degradation of the APC/C-Cdc20 substrates, i.e., Securin, Cyclin B, and Aurora B. Co-depletion of Smurf2 and Cdc20 can restore protein levels of these substrates, confirming premature activation of APC/C. Therefore, Smurf2 is required for the spindle assembly checkpoint-mediated APC/C inhibition. Anaphase onset is accelerated in Smurf2-depleted cells, which is analogous to Mad2- or BubR1-depleted cells. Importantly, Mad2 protein levels are significantly decreased and kinetochore localization of Mad2 is virtually undetectable in Smurf2-depleted cells. In contrast, levels and localization of BubR1 are essentially unaffected by Smurf2 depletion. These data suggested that Smurf2 functions upstream of Mad2 in spindle checkpoint control.
Smurf2-mediated control of Mad2 stability
The regulation of cellular Mad2 levels has been described primarily in terms of transcriptional control, with recent studies demonstrating that Mad2 is a transcriptional target of E2F, BRCA1, Myc, and most recently REST [20–23]. While Mad2 has been shown to be regulated by phosphorylation [24], other potential forms of post-transcriptional modification and regulation of Mad2 have not been thoroughly characterized. Smurf2-mediated control of Mad2 appears to occur at the level of Mad2 protein stability [8]. While there is no change in Mad2 mRNA levels, an increase in polyubiquitin-conjugated Mad2 protein is observed in Smurf2-depleted cells, which is further increased by proteasome inhibition. These observations suggest that Smurf2 normally functions as a suppressor of ubiquitin-dependent degradation of Mad2. Interestingly, Smurf2 may also influence the kinetochore localization of Mad2, since forced overexpression of Mad2 in Smurf2-depleted cells results in a failure of exogenous Mad2 in localizing to kinetochores in the presence of nocodazole.
The role of Smurf2 in the spindle checkpoint appears to be mediated, at least partly, through its activity as an E3 ubiquitin ligase. Cells expressing a catalytically inactive Smurf2 mutant (Smurf2-C716A) also exhibit mitotic defects similar to Smurf2-depleted cells, together with premature activation of APC/C, indicating spindle checkpoint dysfunction.
Two models of Smurf2-mediated control of Mad2 and the Spindle Assembly Checkpoint
In the second model, hereafter referred to as the indirect model, Smurf2 catalyzes the ubiquitin-dependent degradation of an unidentified E3 ligase (or its critical cofactor) that promotes consititutive polyubiquitination of Mad2. In this way, mitotic Smurf2 activity would antagonize the action of this unknown E3 ligase, thereby allowing for stability and proper localization of Mad2 and a functional spindle checkpoint. Conditions leading to decreased levels or activity of Smurf2 would upregulate the activity of this E3 ligase, targeting Mad2 for polyubiquitination and degradation. The implications of the indirect model are best appreciated in context of what is known about the kinetics of Mad2 conformational interconversion. The spontaneous reverse transition from active (inhibitory) to inactive(non-inhibitory) Mad2 conformation is six-fold slower than the forward reaction (which is already unusually slow at ~9 hrs), owing partly to the thermodynamically favored inhibitory conformation [1]. While p31comet-dependent mechanisms exist to block the conversion of inactive to active Mad2 in aggregate [29–31], to our knowledge no mechanisms have been described to catalyze the conversion of the active conformer of Mad2 back to inactive conformer, an energetically costly process. Alternatively, it may be more efficient for the cell to simply bypass this problem through rapid ubiquitin-dependent degradation of the inhibitory Mad2 conformer once the spindle checkpoint has been satisfied, allowing for swift and decisive anaphase onset. Given that kinetochore-microtubule interaction is a stochastic process, this would occur locally on a kinetochore by kinetochore basis. In support of this view, most Mad2 exists in the non-inhibitory conformation in interphase cells [1], and the inhibitory conformation of Mad2 is unlikely to exist as a monomeric form uncomplexed with Mad2, Cdc20, or Mad1 [32]. Viewed in this light, Smurf2 would target the activity of this E3 ligase in early mitosis at unattached kinetochores. As kinetochores become securely attached to mitotic spindle, Smurf2 activity could be locally downregulated or it could be sequestered from the vicinity, which would allow for the local ubiquitin-dependent degradation of the inhibitory conformer of Mad2.
It will be interesting to determine if a direct causal relationship exists between the apparent mislocalization and instability of Mad2 in Smurf2-depleted cells. Recent work has emphasized the importance of localization-dependent activity of ubiquitin ligases (i.e. APC/C) and other participants of the ubiquitin proteasome system [33]. It is plausible that the destiny of Mad2, either degradation or APC/C inhibition, could be entirely dependent upon matching subcellular localization with mitotic state/phase, and that Mad2 is simply degraded when it is mislocalized. Thus the enhanced ubiquitin-dependent degradation of Mad2 observed in Smurf2-depleted cells could be entirely a result of being in the wrong place at the wrong time. The common thread linking these two models is the unknown E3 ligase regulating the degradation of Mad2, whose identity should be determined by future studies.
A broader role for Smurf2 in mitosis
While defective spindle checkpoint function is likely the major contributor to the mitotic defects in Smurf2 depleted cells, the localization pattern of Smurf2 throughout mitosis suggests that Smurf2 plays a role downstream of the metaphase to anaphase transition. A number of centrosomal proteins, including centriolin and survivin, in association with other members of the chromosomal passenger complex, undergo traffic to the mitotic midzone during anaphase and the midbody at telophase, executing unique roles presumably at each of their successive destinations. Furthermore, the individual depletion of many of these proteins results in a failure of cytokinesis and multi-nucleation possibly in spindle checkpoint-independent manners. Thus, it is likely that post-translational modification of Smurf2 or its association with different cellular factors orchestrates the complex trafficking of Smurf2 to various mitotic structures during mitosis. Current studies are underway to examine the possibility of mitosis-specific, perhaps spindle checkpoint-independent roles of Smurf2.
The centrosome acts as a physical platform for the integration of multicomponent signaling cascades throughout various phases of the cell cycle. It is noteworthy that Smurf2 is detected at the centrosome throughout the cell cycle, and studies thus far have only tangentially addressed a possible role for Smurf2 at the centrosome. Smurf2 depleted cells frequently display both numerical and structural centrosomal abnormalities although this could be explained by mitotic failure after normal centrosomal duplication cycles. Furthermore, several players in the spindle assembly checkpoint (e.g. BubR1, Cdc20, Mad2, and now Smurf2) convene at the centrosome in early mitosis, the significance of which remains obscure.
It is also of interest that Smurf1 controls cell polarity by targeting RhoA for proteasomal degradation [34], and the critical role for RhoA in cytokinesis has been established [35]. A recent paper by Fukunaga et. al reports that Smurf2 can promote the degradation of Smurf1 to increase RhoA signaling and promote metastatic progression [17]. While most previous studies have shown that Smurf1 regulates RhoA activity locally at cellular protrusions, it is plausible that Smurf1 participates in control of RhoA signaling during cytokinesis. Although our group did not observe any appreciable effect of Smurf1 depletion on mitosis or cytokinesis, these experiments do not rule out the possibility that Smurf2-mediated control of Smurf1 regulates RhoA activity during mitotic exit. It remains to be determined whether Smurf2 is involved, either directly or indirectly, in the regulation of RhoA during cytokinesis.
Implications for deregulation of Smurf2 during tumorigenesis
Genomic instability and aneuploidy are well established properties of cancer, which are often associated with poor prognosis of patients. It is clear that a defective spindle checkpoint can promote genomic instability and aneuploidy at the cellular level. Moreover, recent in vivo studies have examined whether aneuploidy secondary to mitotic checkpoint dysfunction is a predisposing event in cancer development [36]. For example, Mad2 haploinsufficiency causes premature anaphase onset and chromosomal instability, which is consistent with the higher susceptibility of Mad2-heterozygous mice to lung tumorigenesis [37]. On the other hand, transgenic mice with inducible Mad2 overexpression also develop a variety of tumors [38], which is consistent with Mad2 overexpression observed in a wide range of human cancers [39]. Furthermore, mouse models with Bub1 hypomorphism [40] or Mad1 haploinsufficiency [41] provide further evidence that misregulation of the spindle assembly checkpoint promotes in vivo tumorigenesis through the development of chromosomal instability. Similarly, deregulated Smurf2 activity beyond functionally optimal ranges may promote cancer development with genomic instability. Consistent with this notion, we have recently observed that not only Smurf2 depletion but also forced expression of wild-type Smurf2 to exceedingly high levels can perturb the spindle checkpoint and ultimately cause multinucleation (E. Osmundson and H. Kiyokawa, unpublished observations). This is analogous to the phenotypes of forced overexpression of Mad2 both in vitro and in vivo.
Previously, Smurf2 has been functionally implicated in tumorigenesis through its role as a negative regulator of growth inhibitory TGF-β signaling. Smurf2 has been shown to be upregulated in esophageal carcinomas [42], and a recent study by Jin et. al, employing a breast cancer tissue array, showed that Smurf2 is upregulated in many breast cancer tissues [43]. Based on their functional analyses they concluded that Smurf2 activity contributes to metastatic progression, yet likely in a manner independent of TGF-β signaling. The Oncomine database of gene expression profiles http://www.oncomine.org also show increased expression of Smurf2 is observed in breast, ovary, brain and some other cancers, analogous to increased Mad2 expression. Our recent work highlighting the role of Smurf2 upstream of Mad2 stability control provides new insight into roles for Smurf2 in human carcinogenesis. Viewed in this light, the overexpression of Smurf2 could provide a double-hit to cells undergoing the process of carcinogenesis; by rendering cells unresponsive to the tumor suppressive TGF-β signals, and by promoting spindle checkpoint dysfunction and the genomic instability characteristic of malignant phenotypes. More mechanistic studies are needed to establish the role of deregulated Smurf2 actions in carcinogenesis.
We appreciate Qingshen Gao, Gerald Thomsen, Gina Kirsammer for collaboration and helpful discussions. Research in Kiyokawa laboratory has been supported in part by the National Institutes of Health (CA112282, CA100204, and HD38085), H-Foundation, Searle Leadership Fund and Zell Fund.
Authors' Affiliations
- Luo X, Tang Z, Xia G, Wassmann K, Matsumoto T, Rizo J, Yu H: The Mad2 spindle checkpoint protein has two distinct natively folded states. Nat Struct Mol Biol 2004, 11: 338–345. 10.1038/nsmb748View ArticlePubMedGoogle Scholar
- Yu H: Structural activation of Mad2 in the mitotic spindle checkpoint: the two-state Mad2 model versus the Mad2 template model. J Cell Biol 2006, 173: 153–157. 10.1083/jcb.200601172PubMed CentralView ArticlePubMedGoogle Scholar
- Skinner JJ, Wood S, Shorter J, Englander SW, Black BE: The Mad2 partial unfolding model: regulating mitosis through Mad2 conformational switching. J Cell Biol 2008, 183: 761–768. 10.1083/jcb.200808122PubMed CentralView ArticlePubMedGoogle Scholar
- Reddy SK, Rape M, Margansky WA, Kirschner MW: Ubiquitination by the anaphase-promoting complex drives spindle checkpoint inactivation. Nature 2007, 446: 921–925. 10.1038/nature05734View ArticlePubMedGoogle Scholar
- Stegmeier F, Rape M, Draviam VM, Nalepa G, Sowa ME, Ang XL, McDonald ER 3rd, Li MZ, Hannon GJ, Sorger PK, et al.: Anaphase initiation is regulated by antagonistic ubiquitination and deubiquitination activities. Nature 2007, 446: 876–881. 10.1038/nature05694View ArticlePubMedGoogle Scholar
- Nilsson J, Yekezare M, Minshull J, Pines J: The APC/C maintains the spindle assembly checkpoint by targeting Cdc20 for destruction. Nat Cell Biol 2008, 10: 1411–1420. 10.1038/ncb1799PubMed CentralView ArticlePubMedGoogle Scholar
- Ge S, Skaar JR, Pagano M: APC/C- and Mad2-mediated degradation of Cdc20 during spindle checkpoint activation. Cell Cycle 2009, 8: 167–171.PubMed CentralView ArticlePubMedGoogle Scholar
- Osmundson EC, Ray D, Moore FE, Gao Q, Thomsen GH, Kiyokawa H: The HECT E3 ligase Smurf2 is required for Mad2-dependent spindle assembly checkpoint. J Cell Biol 2008, 183: 267–277. 10.1083/jcb.200801049PubMed CentralView ArticlePubMedGoogle Scholar
- Bonni S, Wang HR, Causing CG, Kavsak P, Stroschein SL, Luo K, Wrana JL: TGF-beta induces assembly of a Smad2-Smurf2 ubiquitin ligase complex that targets SnoN for degradation. Nat Cell Biol 2001, 3: 587–595. 10.1038/35078562View ArticlePubMedGoogle Scholar
- Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH, Wrana JL: Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGF beta receptor for degradation. Mol Cell 2000, 6: 1365–1375. 10.1016/S1097-2765(00)00134-9View ArticlePubMedGoogle Scholar
- Lin X, Liang M, Feng XH: Smurf2 is a ubiquitin E3 ligase mediating proteasome-dependent degradation of Smad2 in transforming growth factor-beta signaling. J Biol Chem 2000, 275: 36818–36822. 10.1074/jbc.C000580200View ArticlePubMedGoogle Scholar
- Schwamborn JC, Muller M, Becker AH, Puschel AW: Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity. EMBO J 2007, 26: 1410–1422. 10.1038/sj.emboj.7601580PubMed CentralView ArticlePubMedGoogle Scholar
- Subramaniam V, Li H, Wong M, Kitching R, Attisano L, Wrana J, Zubovits J, Burger AM, Seth A: The RING-H2 protein RNF11 is overexpressed in breast cancer and is a target of Smurf2 E3 ligase. Br J Cancer 2003, 89: 1538–1544. 10.1038/sj.bjc.6601301PubMed CentralView ArticlePubMedGoogle Scholar
- Kaneki H, Guo R, Chen D, Yao Z, Schwarz EM, Zhang YE, Boyce BF, Xing L: Tumor necrosis factor promotes Runx2 degradation through up-regulation of Smurf1 and Smurf2 in osteoblasts. J Biol Chem 2006, 281: 4326–4333. 10.1074/jbc.M509430200PubMed CentralView ArticlePubMedGoogle Scholar
- Jin YH, Jeon EJ, Li QL, Lee YH, Choi JK, Kim WJ, Lee KY, Bae SC: Transforming growth factor-beta stimulates p300-dependent RUNX3 acetylation, which inhibits ubiquitination-mediated degradation. J Biol Chem 2004, 279: 29409–29417. 10.1074/jbc.M313120200View ArticlePubMedGoogle Scholar
- Han G, Li AG, Liang YY, Owens P, He W, Lu S, Yoshimatsu Y, Wang D, Ten Dijke P, Lin X, Wang XJ: Smad7-induced beta-catenin degradation alters epidermal appendage development. Dev Cell 2006, 11: 301–312. 10.1016/j.devcel.2006.06.014View ArticlePubMedGoogle Scholar
- Fukunaga E, Inoue Y, Komiya S, Horiguchi K, Goto K, Saitoh M, Miyazawa K, Koinuma D, Hanyu A, Imamura T: Smurf2 induces ubiquitin-dependent degradation of Smurf1 to prevent migration of breast cancer cells. J Biol Chem 2008, 283: 35660–35667. 10.1074/jbc.M710496200View ArticlePubMedGoogle Scholar
- Di Guglielmo GM, Le Roy C, Goodfellow AF, Wrana JL: Distinct endocytic pathways regulate TGF-beta receptor signalling and turnover. Nat Cell Biol 2003, 5: 410–421. 10.1038/ncb975View ArticlePubMedGoogle Scholar
- Ruchaud S, Carmena M, Earnshaw WC: Chromosomal passengers: conducting cell division. Nat Rev Mol Cell Biol 2007, 8: 798–812. 10.1038/nrm2257View ArticlePubMedGoogle Scholar
- Guardavaccaro D, Frescas D, Dorrello NV, Peschiaroli A, Multani AS, Cardozo T, Lasorella A, Iavarone A, Chang S, Hernando E, Pagano M: Control of chromosome stability by the beta-TrCP-REST-Mad2 axis. Nature 2008, 452: 365–369. 10.1038/nature06641PubMed CentralView ArticlePubMedGoogle Scholar
- Hernando E, Nahle Z, Juan G, Diaz-Rodriguez E, Alaminos M, Hemann M, Michel L, Mittal V, Gerald W, Benezra R, et al.: Rb inactivation promotes genomic instability by uncoupling cell cycle progression from mitotic control. Nature 2004, 430: 797–802. 10.1038/nature02820View ArticlePubMedGoogle Scholar
- Menssen A, Epanchintsev A, Lodygin D, Rezaei N, Jung P, Verdoodt B, Diebold J, Hermeking H: c-MYC delays prometaphase by direct transactivation of MAD2 and BubR1: identification of mechanisms underlying c-MYC-induced DNA damage and chromosomal instability. Cell Cycle 2007, 6: 339–352.View ArticlePubMedGoogle Scholar
- Wang RH, Yu H, Deng CX: A requirement for breast-cancer-associated gene 1 (BRCA1) in the spindle checkpoint. Proc Natl Acad Sci USA 2004, 101: 17108–17113. 10.1073/pnas.0407585101PubMed CentralView ArticlePubMedGoogle Scholar
- Wassmann K, Liberal V, Benezra R: Mad2 phosphorylation regulates its association with Mad1 and the APC/C. EMBO J 2003, 22: 797–806. 10.1093/emboj/cdg071PubMed CentralView ArticlePubMedGoogle Scholar
- Mapelli M, Massimiliano L, Santaguida S, Musacchio A: The Mad2 conformational dimer: structure and implications for the spindle assembly checkpoint. Cell 2007, 131: 730–743. 10.1016/j.cell.2007.08.049View ArticlePubMedGoogle Scholar
- Mikhailov A, Cole RW, Rieder CL: DNA damage during mitosis in human cells delays the metaphase/anaphase transition via the spindle-assembly checkpoint. Curr Biol 2002, 12: 1797–1806. 10.1016/S0960-9822(02)01226-5View ArticlePubMedGoogle Scholar
- Shannon KB, Canman JC, Salmon ED: Mad2 and BubR1 function in a single checkpoint pathway that responds to a loss of tension. Mol Biol Cell 2002, 13: 3706–3719. 10.1091/mbc.E02-03-0137PubMed CentralView ArticlePubMedGoogle Scholar
- Vong QP, Cao K, Li HY, Iglesias PA, Zheng Y: Chromosome alignment and segregation regulated by ubiquitination of survivin. Science 2005, 310: 1499–1504. 10.1126/science.1120160View ArticlePubMedGoogle Scholar
- Mapelli M, Filipp FV, Rancati G, Massimiliano L, Nezi L, Stier G, Hagan RS, Confalonieri S, Piatti S, Sattler M, Musacchio A: Determinants of conformational dimerization of Mad2 and its inhibition by p31comet. EMBO J 2006, 25: 1273–1284. 10.1038/sj.emboj.7601033PubMed CentralView ArticlePubMedGoogle Scholar
- Xia G, Luo X, Habu T, Rizo J, Matsumoto T, Yu H: Conformation-specific binding of p31(comet) antagonizes the function of Mad2 in the spindle checkpoint. EMBO J 2004, 23: 3133–3143. 10.1038/sj.emboj.7600322PubMed CentralView ArticlePubMedGoogle Scholar
- Yang M, Li B, Tomchick DR, Machius M, Rizo J, Yu H, Luo X: p31comet blocks Mad2 activation through structural mimicry. Cell 2007, 131: 744–755. 10.1016/j.cell.2007.08.048PubMed CentralView ArticlePubMedGoogle Scholar
- Luo X, Yu H: Protein Metamorphosis: The Two-State Behavior of Mad2. Structure 2008, 16: 1616–1625. 10.1016/j.str.2008.10.002PubMed CentralView ArticlePubMedGoogle Scholar
- Ban KH, Torres JZ, Miller JJ, Mikhailov A, Nachury MV, Tung JJ, Rieder CL, Jackson PK: The END network couples spindle pole assembly to inhibition of the anaphase-promoting complex/cyclosome in early mitosis. Dev Cell 2007, 13: 29–42. 10.1016/j.devcel.2007.04.017View ArticlePubMedGoogle Scholar
- Wang HR, Zhang Y, Ozdamar B, Ogunjimi AA, Alexandrova E, Thomsen GH, Wrana JL: Regulation of cell polarity and protrusion formation by targeting RhoA for degradation. Science 2003, 302: 1775–1779. 10.1126/science.1090772View ArticlePubMedGoogle Scholar
- Glotzer M: The molecular requirements for cytokinesis. Science 2005, 307: 1735–1739. 10.1126/science.1096896View ArticlePubMedGoogle Scholar
- Pellman D: Cell biology: aneuploidy and cancer. Nature 2007, 446: 38–39. 10.1038/446038aView ArticlePubMedGoogle Scholar
- Michel LS, Liberal V, Chatterjee A, Kirchwegger R, Pasche B, Gerald W, Dobles M, Sorger PK, Murty VV, Benezra R: MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells. Nature 2001, 409: 355–359. 10.1038/35053094View ArticlePubMedGoogle Scholar
- Sotillo R, Hernando E, Diaz-Rodriguez E, Teruya-Feldstein J, Cordon-Cardo C, Lowe SW, Benezra R: Mad2 overexpression promotes aneuploidy and tumorigenesis in mice. Cancer Cell 2007, 11: 9–23. 10.1016/j.ccr.2006.10.019PubMed CentralView ArticlePubMedGoogle Scholar
- Michel L, Benezra R, Diaz-Rodriguez E: MAD2 dependent mitotic checkpoint defects in tumorigenesis and tumor cell death: a double edged sword. Cell Cycle 2004, 3: 990–992.View ArticlePubMedGoogle Scholar
- Jeganathan K, Malureanu L, Baker DJ, Abraham SC, van Deursen JM: Bub1 mediates cell death in response to chromosome missegregation and acts to suppress spontaneous tumorigenesis. J Cell Biol 2007, 179: 255–267. 10.1083/jcb.200706015PubMed CentralView ArticlePubMedGoogle Scholar
- Iwanaga Y, Chi YH, Miyazato A, Sheleg S, Haller K, Peloponese JM Jr, Li Y, Ward JM, Benezra R, Jeang KT: Heterozygous deletion of mitotic arrest-deficient protein 1 (MAD1) increases the incidence of tumors in mice. Cancer Res 2007, 67: 160–166. 10.1158/0008-5472.CAN-06-3326View ArticlePubMedGoogle Scholar
- Fukuchi M, Fukai Y, Masuda N, Miyazaki T, Nakajima M, Sohda M, Manda R, Tsukada K, Kato H, Kuwano H: High-level expression of the Smad ubiquitin ligase Smurf2 correlates with poor prognosis in patients with esophageal squamous cell carcinoma. Cancer Res 2002, 62: 7162–7165.PubMedGoogle Scholar
- Jin C, Yang YA, Anver MR, Morris N, Wang X, Zhang YE: Smad ubiquitination regulatory factor 2 promotes metastasis of breast cancer cells by enhancing migration and invasiveness. Cancer Res 2009, 69: 735–740. 10.1158/0008-5472.CAN-08-1463PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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ajagur wrote:
it says 4hrs on mine!!!
The countdown on Elite is counting down to the 28th not the release time of the map pack.
elite doesn't cost anything...just sign up!
He's messing with me.
Mine says 12 hours... It's nearly 9pm! Really?! I expected it to be ready for midnight
is there also not usually an update... in BO1 they would have a playlist update before a DLC drop...
Could be wrong though
© 2019 Activision Publishing, Inc. ACTIVISION, CALL OF DUTY, MODERN WARFARE, CALL OF DUTY MODERN WARFARE, CALL OF DUTY BLACK OPS, CALL OF DUTY GHOSTS, CALL OF DUTY ADVANCED WARFARE, CALL OF DUTY INFINITE WARFARE, and the CALL OF DUTY WORLD LEAGUE Logo are trademarks of Activision Publishing, Inc. All other trademarks and trade names are property of their respective owners.


text:
For most adolescents, sexual activity begins when physical growth and emotional development are accompanied by sexual maturation – which are often accompanied by sexual exploration and intimate relationships. These changes happen at different times for different people, and they are dependent on many individual, social and cultural factors. Whether or not they are living with HIV, adolescents have a right to a healthy, enjoyable and safe sex life. Health providers should affirm and encourage this in age-appropriate ways that are also sensitive to the personal beliefs of individual clients.
The recent WHO guidance Ensuring human rights in the provision of contraceptive information and services: guidance and recommendations supports this.
All adolescents need to understand the physical changes occurring in their bodies and how to responsibly enjoy their emerging sexuality. This period of physical change and sexual exploration is often marked by emotional immaturity and a lack of information, services and commodities for disease prevention and contraception. For adolescents living with HIV, these issues are compounded by the pressing need to protect themselves from additional harm and to prevent transmission of HIV to others. In addition, social norms that condone gender inequity and power imbalances pose major difficulties for those adolescents coerced into sexual relationships. As a consequence of all of these combined factors, some adolescents do not practice safe sex.
Sexual and reproductive health (SRH) information and services are important for all adolescents, including those living with HIV, most of who do not lose their desire for sex or their hopes to have children, but whose needs are often not addressed. Adolescents with perinatally acquired HIV may not yet be sexually active but they may have questions related to having sex. People who acquired HIV during adolescence may already be sexually active and are now considering the implications of the diagnosis on their sex lives; they may have concerns about how they can have intimate relationships and families in the future, fears related to disclosing their status to sexual partners and as well as concerns about HIV transmission.
Adolescents who acquired HIV perinatally may have additional SRH concerns due to HIV-related complications such as slow skeletal growth and delayed sexual maturation. This is due to the effect that HIV has on metabolic and endocrine functions. This may also have an impact on the psychosocial development, resulting in strong feelings of frustration and anger because they look or feel different from their HIV-negative peers.
The greatest challenge facing health providers who work with adolescents is communicating effectively, particularly when discussing sex. Workloads are heavy, which can lead to hurried consultations and avoidance of difficult topics. Providers of adolescent SRH services can also be influenced by their own views about adolescent sexual activity, which are shaped by personal values, societal and cultural norms and taboos. Unfortunately these views often create a barrier to open discussions around sex, relationships and other issues important to adolescents, resulting in missed opportunities for thorough SRH assessments and effective provision of information to promote healthy and safer sexual practices. It is important that all health providers who work with adolescents feel comfortable talking about sexuality and SRH issues with their young clients.


text:
More Pictures from WWII New Caledonia
from the scrapbook of Anthony J. Drongowski
Contributed by his son, Robert Drongowski
Pat Loan
A.J. Drongowski, second row on the left with white cap
Other names on the back of the picture are, Logan, Ball, Baggy,
Fuchs, Atkins, Twork, Garcia, Benwicz, Beaghan.
Bill Stiller
Bill Stiller in the middle
The French prison,in the background was between the Section Base and the Seaplane Base.
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Pictures-Copyright� 2001-Robert Drongowski-All rights reserved.
Used with permission


text:
Bradley R Smith
PO Box 439016
San Ysidro CA 92143
Telephone: 209 682 5327
Email: email@example.com
Web: www.codoh.com
For Publication
19 November 2010
The Holocaust Education Trust of Ireland has held what was supposedly a public conference on "Anti-Semitism and Holocaust Denial" on November 18th and 19th at Trinity College, Dublin. Not only did the organizers not invite any "Deniers" to participate in the conference on "Denial," but they effectively banned Revisionists from attending the Conference. This from an assortment of individuals who claim to advocate "tolerance."
This Conference appears to have been what other such get-togethers have proven to be, platforms for advocating the blacklisting and censorship of Revisionists. Revisionist views are consistently distorted and misrepresented in objectionable ways, but not those of Revisionists alone. Arabs, Islam, and Iranians are all sermonized about without a single representative of any of those groups being invited to speak.
To understand the tenor of this "Conference," consider a couple of the speakers:
Mark Weitzman of the Simon Wiesenthal Center recently testified that "In Holland, the home of Anne Frank, a ceremony commemorating the Second World War was disrupted by students who chanted "Hamas, Hamas, Jews to the gas" http://tinyurl.com/2e6zy3h . Weitzman cannot demonstrate that this charge is true. The Anne Frank House denies that it is true.
Professor Meir Litvak, famous for advocating an attack on Iraq in 2003 is quoted: "Litvak said a short war with and the quick removal of Saddam Hussein could greatly improve the peace process." http://tinyurl.com/2aw4kz7 . There have been some 1,400,000 Iraqi war dead since the beginning of Litvak's "short war and peace process." Is Litvak going to advise us about a "short war" with Iran?
There were interesting and important topics to be discussed at this Conference, but an honest discussion of those topics was not invited, and one was not wanted, as the exclusion of Revisionist attendees on principle is a forthright example. This Conference appears to have been little more than a sacred Dog and Pony Show being carried out to demonize others, with Revisionism treated as a new blasphemy.
The organizers sought governmental involvement and scheduled the Minister for Foreign Affairs Micheál Martin T.D., to speak. If the Minister intended to act in good faith and in support of the ostensibly laudable purposes of the Conference, why would he cooperate with the banning of a free exchange of ideas on a historical question, rather than cooperate with those who support intellectual freedom on such matters?
Important issues were at stake at this International Conference on Anti-Semitism and Holocaust Denial. Please, we all need to speak out to the Irish government to promote peace and a truthful, multi-sided discussion of these historical and political questions.
"CODOH" – Where everything is.
SMITH'S TALK IN TEHRAN at Iranian Holocaust Conference in 2008
Saturday, November 20, 2010
Letter sent to Irish press following the HETI conference on "Anti-Semitism and Holocaust Denial"
Posted by Bradley R. Smith at 5:24 PM
Labels: HETI
1 comment:
It's not a conference, it's a mind program in Holocaustianity. The religion of the holocaust requires massive amounts of faith to believe it so as such can not withstand debate and question or else the whole house of cards tumbles. One should ask "if the events were really true, they only happened in one country, Germany. Why does the entire list of White nations have to undergoe this massive rebuke and shaming for an event they themselves never participated in but rather fought against, offering their own sons and daughters?"
- November 22, 2010 at 8:45 AM
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While we are enjoying our stay at the beach, I hadn't on being crafty..
Then we found out this store is within walking distance to our house. Actually it's right next door lol!
You can't be next to a yarn store and not buy anything!!!
So I came home with these goodies for me and two craft kits for Emma which I'm sure will come with pictures later 😉


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The Rev. Dr. Richard Turnbull, the Principal (think Dean) of Oxford University's Wycliffe Hall seminary spoke encouraging words to Northern California Anglicans at the St. Francis Yacht Club in San Francisco this last Sunday evening, July 5th.
Dr. Trubull+ says that we must understand the difference between first order issues and second order issues. He says there are really only two first order issues, issues worth "dying in the ditch for":
1) authority of scripture, and
2) salvation/ uniqueness of Jesus Christ.
Dr. Trubull+ explained that what seemed to be a second order issue, sexuality, was really a first order issue masquerading as a second order issue because God's plan for human sexuality is clearly presented in the Bible. To challenge God's plan for human sexuality as presented in the Bible is to challenge the authority of scripture.
Dr. Trubull+ is an Evangelical and author of Anglican and Evangelical? Audience members not familiar with him were not sure how bold and simple these two first order issues were for him. In the question and answer, he was provided opportunities to expand on and nuance his understanding of these two primary issues.
During his talk, Dr. Trubull+ had stated that "God wrote the Bible". In the question and answer, he clarified that he believed that God inspired humans to write the Bible, humans embedded in their social contexts.
Also in the question and answer after the talk, he was asked how his understanding of salvation fit with those of the famous Anglican C. S. Lewis. Lewis believed in salvation through Christ alone, but in a way that is beyond our understanding and may include those who did not embrace Christ in this life. In The Last Battle, Lewis presented a pagan Calormene soldier who was credited with worshiping Aslan all along, even though he didn't know what he was doing. It was not clear from his response whether Dr. Trubull+ subscribes to Lewis' generous view on salvation.
The audience was eager to learn more about the thinking of Dr. Trubull+. The fifteen copies of Anglican and Evangelical? were snapped up. Additional copies would have been sold had they been available.
A generous parishioner of St James' San Jose hosted the event. A recording will be available at the New Anglican Church website.
Monday, July 6, 2009
Richard Turnbull on First Order Issues for Anglicans
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text: Add Tracing To WCF Messages 10. September 2014 Heath Programming Comments (0) It sometimes becomes useful to trace messages coming into and out of a WCF service for debugging. I find when I am doing soap integration's it is especially useful to be able to trace the soap messages for debugging. The message isn't obviously stored, however there is a trace that you can attach to to get it though the system.diagnostics library. <system.diagnostics> <sources> <source name="System.ServiceModel.MessageLogging"> <listeners> <add name="messages" type="System.Diagnostics.XmlWriterTraceListener" initializeData="c:\logs\messages.svclog" /> </listeners> </source> </sources> </system.diagnostics> <system.serviceModel> <diagnostics> <messageLogging logEntireMessage="true" logMalformedMessages="false" logMessagesAtServiceLevel="true" logMessagesAtTransportLevel="false" maxMessagesToLog="3000" maxSizeOfMessageToLog="2000"/> </diagnostics> </system.serviceModel> Simple enough and now you will have a log file with your requests.


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Brilliant Energy's "Summer50" offer is valid through March 01, 2019, for residential customers who enroll for service under any of Brilliant Energy's fixed rate residential products with a term of 12 months or more ("Qualifying Product"). This offer is not available to customers who enroll for service through an aggregator, broker, or consultant. To qualify for receipt of your gift card, you must comply with Brilliant Energy's Terms of Service and pay the first three bills for your Qualifying Product on-time and in-full. This offer cannot be combined with any other offers, discounts, or other promotions, and use of the promotional code associated with this offer will render null and void any other such offers, discounts, and other promotions. Please allow up to 30 days after final payment for delivery of your gift card.
The Bullseye Design, Target and Target GiftCard are registered trademarks of Target Brands, Inc.
Terms and conditions are applied to gift cards. Target is not a participating partner in or sponsor of
this offer.
El Diseño de tiro al blanco (Bullseye), Target y Target GiftCard son marcas registradas de
Target Brands, Inc. Las tarjetas gift cards están sujetas a términos y condiciones. Target no
está asociado ni es patrocinador de esta oferta.
*Amazon.com is not a sponsor of this promotion. Except as required by law, Amazon.com Gift Cards ("GCs") cannot be transferred for value or redeemed for cash. GCs may be used only for purchases of eligible goods on Amazon.com or certain of its affiliated websites. For complete terms and conditions, see www.amazon.com/gc-legal. GCs are issued by ACI Gift Cards, Inc., a Washington corporation. All Amazon ®, ™ & © are IP of Amazon.com, Inc. or its affiliates. No expiration date or service fees.


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The one-third tubular plate, which is placed posterolaterally on the fibula in an antiglide position, indirectly reduces the fracture and acts as a buttress to resist the posterior and proximal displacement of the distal fragment.
Additionally, the main fracture can be compressed with a lag screw, inserted through the plate.
The third fragment, if large enough, can be fixed to the main lateral malleolar fragment with a cancellous lag screw. This technique is used for the three-part type of transsyndesmotic multifragmentary fracture, in which an oblique fracture of the fibula has occurred through the transsyndesmotic zone, and the tip of the proximal fragment ("ski tip") has fractured off.


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In laboratories around the world, genetic researchers using tools that are ever more sophisticated to peer into the DNA of cells are increasingly finding things they were not looking for, including information that could make a big difference to an anonymous donor.
The question of how, when and whether to return genetic results to study subjects or their families "is one of the thorniest current challenges in clinical research," said Dr. Francis Collins, the director of the National Institutes of Health. "We are living in an awkward interval where our ability to capture the information often exceeds our ability to know what to do with it."
The federal government is hurrying to develop policy options. It has made the issue a priority, holding meetings and workshops and spending millions of dollars on research on how to deal with questions unique to this new genomics era.
The quandaries arise from the conditions that medical research studies typically set out. Volunteers usually sign forms saying that they agree only to provide tissue samples, and that they will not be contacted. Only now have some studies started asking the participants whether they want to be contacted, but that leads to more questions: What sort of information should they get? What if the person dies before the study is completed?
The complications are procedural as well as ethical. Often, the research labs that make the surprise discoveries are not certified to provide clinical information to patients. The consent forms the patients signed were approved by ethics boards, which would have to approve any changes to the agreements — if the patients could even be found.
..... One of the first cases came a decade ago, just as the new age of genetics was beginning. A young woman with a strong family history of breast and ovarian cancer enrolled in a study trying to find cancer genes that, when mutated, greatly increase the risk of breast cancer. But the woman, terrified by her family history, also intended to have her breasts removed prophylactically.
Her consent form said she would not be contacted by the researchers. Consent forms are typically written this way because the purpose of such studies is not to provide medical care but to gain new insights. The researchers are not the patients' doctors.
But in this case, the researchers happened to know about the woman's plan, and they also knew that their study indicated that she did not have her family's breast cancer gene. They were horrified.
"We couldn't sit back and let this woman have her healthy breasts cut off," said Barbara B. Biesecker, the director of the genetic counseling program at the National Human Genome Research Institute, part of the National Institutes of Health.


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Visit LEO Pharma headquarters
Here you can find information on how to get to the LEO Pharma headquarters in Ballerup outside Copenhagen in Denmark.
By car
- From Copenhagen Airport follow E20 towards Odense - 13.7 km
- Follow E47/E55 towards Helsingør (Elsinore) - 1.2 km
- Exit E47/E55 to 21 towards Roskilde - 10 km
- Exit 21 to 04 towards Ballerup - 7.5 km
- At the first light, turn right down Industriparken. You will find LEO Pharma at the far end - 1.8 km
By train
- At Copenhagen Airport go to the train platform. Take the first train to Københavns Hovedbanegård (Copenhagen Main Central station)
- Exit the train at Københavns Hovedbanegård
- Go to platform 11/12 and take the either the H+ (dest. Frederikssund) or C (dest. Ballerup) S-train (make sure that the train stops at Malmparken Station before you enter)
- Exit the train at Malmparken Station
- Follow Malmparken towards the North (and towards Ballerup Byvej) - 0.2 km
- At the first light, turn right and you have arrived at LEO Pharma
Useful links
Krak (maps and route descriptions): In English or in Danish
Copenhagen Airport: In English or in Danish
Rejseplanen (journey planner - public transportation): In English or in Danish
DSB (information on trains): In English or in Danish
HT (information on buses): In English or in Danish
AOK (information on Copenhagen): In English or in Danish


text:
The Celtic
Art Coracle Volume 1 Issue 3
B.C. CELTS IN BC? - Aidan Meehan
Fig. 25: Ogham from British Columbia
The ogham,"
S.S.L", is accompanied by a line of points. The translation "rain" has been
offered and this may be so. Or it could also he read as "iS SáiLe é", meaning,
"it is salty", a warning, perhaps, of brackish water.
Moira Farrow of the Vancouver Sun wrote about the work of
John Corner in her feature, "The Ogham Clue", March 18, 1983.
Legend: T_F_N , TaFaiN = Running (Irish)
The Celtic Art Coracle Vol 1
Contents © Coracle Press 1983
All Rights Reserved
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The Rita Banks Studio
|About me
I am an environmentalist who relates to the rural and the wilderness.
A walker, runner, climber and caver I have always been interested in the painted image.
Alongside my love of the landscape is my love of colour.
Painting and sharing my joy with others is now my main preoccupation.
|Help Days
Come and have an enjoyable day painting in beautiful surroundings.
We can paint outside weather permitting, or in my studio.
I am happy to pass on my knowledge and love of painting and to paint with friends.
Tea, coffee and biscuits are always available.
Either bring your own lunch or I can provide some food and wine.
Tel: 01889 505386


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Unsere Meldungen
Spacieuse propriété de plain pied avec piscine et 3200 m2 de terrain.
FRANCE - Villa - Cagnes sur mer
villa néo provençal individual of renowned architect 6 rooms 315 m ² on 2 levels with a splendid sight sea and castle of Cagnes
Cagnes sur mer, very nice recent villa of 5 rooms with a very beautiful sea view
On the commune of Nice, very nice flat of 4 rooms of corner located in one of the most beautiful rehabilitations of the Lanterne.
FRANCE - House - La Colle sur Loup
Magnificent Provencal Mas of 300m2 of the 18th century in stones, located in the middle of a landscaped park of 2000 m ².
FRANCE - Villa - Villeneuve Loubet
Fantastic 290 m2 luxury villa , on a dominating position , in absolut calm , very close to all conveniences and the sea
Very nice 3 rooms apartmùent , in calm , situated in the center town between the Republique boulevard and Carnot
FRANCE - Apartment - Cagnes sur Mer
Very nice 3 rooms apartment of 71 m2 at calm , in the heart of Cagnes sur Mer , and at 200 metres from the sea
FRANCE - Apartment - Villeneuve-loubet
Nice 3 rooms apartment in the heart of Villeneuve-loubet, situated in the Bouche du Loup , perfect for investment or young family
FRANCE - Villa - Cagnes sur Mer
Wonderful 220 square meters villa in the heart of the St Véran's disctrict in Cagnes sur Mer
Very nice 3 rooms apartment of 66 m2 , made up recently by an inside architect , in the center of Mandelieu
Very nice 2 rooms apartment at 300 m from the beach and with a very good locative performance
FRANCE - Apartment - Villeneuve-loubet
Nice 4 rooms apartment on a surface of 75 m2 perfect for families
Nice atypical 2/3 rooms apartment in duplex Biot at 5 minutes from the sea
FRANCE - Apartment - Villeneuve-loubet
Pretty 2 rooms apartment in Villeneuve loubet with a nice sea view


text: Any Yorkshire based readers out there? Two of my favourite artists – Emily Sutton and Angie Lewin – are exhibiting watercolours and prints at Godfrey & Watt in Harrogate until 2 December. If you love Emily's work as much as me but your purse says 'no', she has designed a Christmas range for Betty's tea rooms including a tea caddy and mug in her lovely nostalgic style.


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Egyptian protesters return to Tahrir
Sept. 9 - Thousands gather in Cairo's Tahrir Square demanding a faster pace of reform in Egypt under the billing, ''Correcting the Path'' of the revolution. Nick Rowlands reports.
TV AND WEB RESTRICTIONS~**NONE**~ Thousands of protesters gather in Cairo's Tahrir Square after Friday prayers to demand a faster pace of reform. After a lull in protests during the holy month of Ramadan, people have taken to the streets calling for a clearer road map to democracy and an end to military trials for civilians. This woman chants, "Hold your head high, you are Egyptian, I would die for Egypt to prevail." The police and military - who have recently been occupying the square - were nowhere to be seen. (SOUNDBITE) (Arabic) PROTESTER, ASHRAF GABER: ''Today is called the Friday to correct the revolution's path. In the past few months we have all noticed that life in Egypt has not changed since before January 25th. So, the Egyptian people have decided, after Ramadan, to reassert themselves on the streets, in order to correct the path of the revolution, which is a path of reform that the revolution should never waver from.'' Egyptians are angry at the Supreme Council of Armed Forces, which took power after Mubarak fell, over the lack of reform. Some believe they are secretly plotting behind the scenes to remain in control after the upcoming parliamentary and presidential elections. Field Marshal Mohamed Hussein Tantawi, who heads the Supreme Council, has been called to testify on Sunday in the case of former president Hosni Mubarak. Around 850 people died during the uprising which ousted Mubarak, and he is charged with ordering the killing of protesters. Nick Rowlands, Reuters.


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Know more about this business than we do? Cool! Please submit any corrections or missing details you may have.Help us make it right
Be the first MLive.com user to add photos or videos of Someplace Else
Try the new place where this was. It is called either Macs or Max but in same location. It is like the roaring twentys in there and is really kool. They have many difrrent cool drinks to choose from.
I've had most of their menu, and it's all great.
Someplace Else is located at 118 N Michigan Ave, Saginaw, MI..
Someplace Else can be found at N Michigan Ave 118. The following is offered: Bars & Pubs. The entry is present with us since Sep 9, 2010 and was last updated on Nov 14, 2013. In Saginaw there are 29 other Bars & Pubs. An overview can be found here.


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1. Plan Ahead: When planning parties it really does help to plan ahead especially when you are party planning with young kids. Planning ahead helps relieve unwanted stress and helps keep things organized.
Childhood 101 created this fun and bright party plan printable to help you plan your next party.
2. Research: Once you have picked a theme go crazy searching for ideas. Use Pintrest, Google, party planning blogs and ask family & friends for ideas. Look for fun decoration ideas, treats, games and anything else you might want to have at your party. I really go crazy with this step...I tell myself I have 1 hour for this step and then it's time to start working. If I don't set a time limit I waste a lot of time.
3. Involve your Kids: This step can be really hard to do but it can also add a lot of fun memories to the occasion. Some of my son's favorite birthday memories are the little things I let him help me with like putting icing on the cake or teaching him how to blow up a balloon.
4. Have Fun: Party planning may not be your thing, if that's the case keep it simple. If you are like me and start thinking about party ideas weeks in advance have fun but don't let all the planning and putting things together get in the way of having fun and enjoying the party.
For more party fun check out our Pintrest board.
For more party fun check out our Pintrest board.


text: Elegance comes from a strength or power in equipoise. It is the balance of understated beauty. It rises from within not from frills, diamonds or money. It surfaces into an aesthetic of gestures, many of which are merely implied, and focused with unselfconscious simplicity. When we see real elegance, when a dancer reminds us how to move in space, or a singer to inflect or lilt, or a writer lands a phrase lightly, we remember how to soar, wing, to alight, and to pause. And rather than exotic it seems strangely familiar, a déja vu, the freedom that need not writhe to realize that our invisible breath from our soul is mere — air. It is the secret of a caress, kindness before sentiment, at times the child's and the very old's white flag before conflict. It is patterns of raindrops on a windowpane, snowflakes tumbling in faint starlight. It is the precision of perception not things.


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This section contains 469 words
(approx. 2 pages at 400 words per page)
Spring 1532 Summary
George experiences firsthand the public's rejection of Anne when they are refused service at a restaurant. They leave and dine in a monastery, where the king is now an object of terror, given his claim to power over the country's entire religious system.
The women of the country feel that if the King of England can put his loyal wife aside because he wants a change, then no woman is safe in her marriage. The people are calling Anne a witch and a murderess, and are accusing her of supernaturally causing the queen's barrenness.
William Stafford suggests that if Mary wanted to marry a simple man with a little manor then she should do so before her sister's wedding. Mary flirts and says no one has asked her yet. William disappears for two weeks, telling Mary's uncle that he has gone to prepare...
(read more from the Spring 1532 Summary)
This section contains 469 words
(approx. 2 pages at 400 words per page)


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Women In Life Sciences
Meet women driving change in Life Sciences
We are proud to collaborate with leading women in life sciences in their quest to advance science and patient care.
Women In Life Sciences
We are proud to collaborate with leading women in life sciences in their quest to advance science and patient care.
"That is the key for me to learn and understand, being able to ask the right questions to the people I work with, my clients and to myself."
– JESSICA NAGAR, Manager – Applied Life Sciences
We asked inspiring women within the Life Sciences industry to reflect on their career journey and to share the work they do to improve lives every day. These are their stories…
"I learned how to discover what drives people and how we can collaborate towards a common goal."
– CLAUDIA TILLI, Novartis
Women in Life Sciences
Claire Holmes, Associate Director of EU Regulatory Operations, discusses her breadth of experience in Life Sciences.
Women in Life Sciences
Yoko Saiki, executive director of strategic business management at Astellas, discusses her journey through the life sciences industry.
Women in Life Sciences
Joanne Hackett, Chief Commercial Officer at Genomics England, discusses her career and the work developing Genomics England's industry strategy.
Follow us for the latest trends in Life Sciences
Connect with us for our latest research & insights