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Corby's legal team under fire
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A Perth QC enlisted by the Australian Government to help Schapelle Corby has launched a stinging attack on her legal team, saying it was unprepared for her appeal and had treated him like "window dressing".
Mark Trowell said yesterday that he had not spoken to the head of Corby's defence team, Vasu Rasiah, since the Bali-based legal co-ordinator's flying visit to Perth on Friday.
Asked if he had been frozen out, he said: "I don't think we were ever brought in."
Mr Trowell's comments came as the prosecutors in the Corby case lodged an appeal in the Bali High Court yesterday to increase her prison sentence from 20 years to life.
Corby's legal team has until today to file their own appeal against her sentence. Mr Trowell, who was enlisted to help in its preparation, said yesterday that he had still not seen a draft of the appeal grounds or been given any indication what arguments might be presented.
"They've never really given us any part to play in their appeal other than being a conduit to the Government," he said.
"I'm disappointed for Schapelle Corby. I never assumed in any way we would interfere in the preparation of the appeal by the Bali lawyers but given our experience, expertise and contacts, we though that they would have given us some role to play.
"There is an expectation in the Australian community that Australian lawyers would have some part to play. And that was the Government's expectation as well. That's obviously why they approached us."
Mr Trowell and fellow Perth QC Tom Percy had offered to work on Corby's case pro bono after being asked to lend their expertise on the appeal. But Mr Trowell questioned what more they could do when they weren't being included in the legal discussions.
He said they had still not seen any transcript of the proceedings in English or Indonesian.
Mr Trowell criticised the legal team's handling of its request last Friday for information from the Australian Government to help her case, saying it was made at the last minute and was a rehash of a former request that her lawyers knew the Government was unable to deliver on.
"My criticism is of not being prepared," he said.
"They should be spending more time preparing the appeal than holding press conferences in Jakarta with soapie starlets."
On Sunday, the defence recruited an Indonesian soap star, Anisa Tri Hapsari, to act as an information officer to persuade ordinary Indonesians of Corby's innocence and help influence Indonesian judges.
"How insulting is it to suggest that public pressure would in any way influence Indonesian judges in their decision," Mr Trowell said.
Prosecutors yesterday argued that Corby had been involved in a transnational crime and needed to be punished more severely.
'In a draft of Corby's appeal, her lawyers insist the prosecutors did not prove Corby imported the 4.1 kilograms of marijuana. While the drugs were in her possession, they did not "explain and prove" how they came to be there.
- with Matthew Moore
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Based on a 2,000 calorie dietSee full nutrition
Ready In
My Mom made this and she used blue cheese dressing instead of the mayo. she said it had more flavor than it did with just the mayo..
I loved it- and my guests! I never use exact measurements and I never peel anything (potatoes/apples) and it still turned out delicious! I mashed the potatoes with the blue cheese to help mix it...
I made this and really liked it. Next time I will use a little less blue cheese as I thought it was very strong. I will also use a little less apple and a little more potato. I saved a little of...
This was pretty good. I would mix the blue cheese into the dressing though so the blue cheese flavor is more evenly distributed. The apples add a nice crunch and bright flavor to the salad.

subset: commoncrawl


text: Home > How To > Insulation > Q&A: Unvented Roof Problems Insulation Q&A: Unvented Roof Problems Tying Into Block By Hank Spies Login or Register to download the PDF version of this article. (177.65 kB) A.Moisture problems and heat buildup are possible in this construction. While polyisocyanurate or extruded polystyrene insulation is essentially a vapor retarder, moisture migrating with air through the cracks in the insulation might pose a problem. To prevent the possibility of moisture moving into the roof assembly, install a polyethylene vapor retarder over the ceiling decking and under the insulation as shown in the illustration at left. This will serve as both a vapor retarder and an air barrier.In addition to potential moisture problems, this type of roof has no ventilation to cool the back of the sheathing. As a result, the surface temperature of the roof could get very high, which might reduce the life of the shingles. Login or Register to continue reading


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'There's none so blind as them that will not see' was the insightful, if ungrammatical, comment of a childhood mentor about those who refuse to admit adverse reality.
The line sprang to my mind when speaking to James Hatchley, a managing director of Freeman & Co, an M&A advisory consultancy. On most other topics, Mr Hatchley expressed reasonable and sensible opinions, but when it came to the subject of funds of hedge funds, an area his firm earns a lot of revenue from, he seemed to be in a different world.
"We see funds of [hedge] funds as a net beneficiary of the current crisis," he said. "The market is entering into a winners and losers phase."
While many might agree with the second statement, I would have put funds of hedge funds generally firmly into the losers' basket. When questioned more closely about what the benefit might be, he predicted "fewer, bigger, better funds of funds".
This may be a win for the end-investors, those that still have any money to invest and have the nerve to entrust it to funds of hedge funds, but it is presumably bad news for the many funds of hedge funds not fitting this description.


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NAMI Southwestern Illinois
- find help
- find hope
contact us
- Excecutive Director, Jessica Gruneich, JD
- email@example.com
- President, Dr. Beverley Watkins, PhD, LCSW
- email@example.com
- Webmaster, Mary Gauen
- firstname.lastname@example.com
NAMI Southwestern Illinois Office
- Gateway Regional Medical Center
- 2100 Madison Ave. 4th Floor
- Granite City, IL 62040
- Office Phone: 618-798-9788
- Office Fax: 866-332-5338
- Office E-mail:
- email@example.com
FY18 Budget Briefings
Feb 15, 2017
Governor Rauner gave his FY18 Budget address on Feb 15th. The governor's proposed budget has been published.
The FY18 Budget briefings for the Department of Human Services, the Department of Healthcare and Family Services, the Department on Aging, the Department of Public Health, and the Department of Child and Family Services. All briefings can be found in one document.
NAMI Illinois Action Alert
NAMI Illinois is fighting hard to make our voices heard. NAMI Illinois' position and actions to be taken will be found on NAMI Illinois' website at http://namiillinois.org/advocacy-legislation/. We urge you to visit that resource frequently to find additional information on important issues that are under consideration.
Take Action!
We need strong and persistent messages urging Congress to act. Please help advance mental health care by promoting Comprehensive Mental Health Reform Legislation.
Congress decimating mental health care during Mental Health Month
May 2, 2017
May is Mental Health Month and how is Congress celebrating? By trying to decimate mental health coverage in America.
This week, there is a vote expected in the House on the amended American Health Care Act (AHCA). If this bill passes, millions of Americans will lose mental health coverage or be charged more simply because they have a mental health condition.
NAMI Family Support Group
NAMI Family Support Group is a peer-led support group for family members, caregivers and loved ones of individuals living with mental illness. Groups generally meet on a monthly basis but may meet weekly. The hallmark of a NAMI support group is leveraging the collective knowledge and experience of the other participants.
NAMI Connection
A peer-led support group, following 12 principles of support, open to all individuals living with any type of mental health condition. NAMI Connection groups are discreet and absolutely confidential, an ideal setting to connect with other individuals in recovery who are learning to cope with issues related to mental illness.
NAMI Parent Support Group
For parents and caregivers of children and adolescents living with a mental illness. This support group offers a safe, non-judgmental and confidential outlet for sharing with other parents and caregivers who have experiences similar to yours. There is hope for your child and for you. You don't have to face this struggle on your own.
RACE • WALK - May 13, 2017
Thanks to all who came out to run, walk, or just socialize. And a special thanks to our 2017 sponsors! It's through your generosity and continued support that NAMI SWI can carry on its mission of helping those with a mental illness along with their loved ones.
Peter Dodge and David Noble traveled to Monteagle, Tennessee in June, 2016 to be trained as NAMI Homefront facilitators. Homefront is similar to Family-to-Family, but specially designed for military-connected families. We will be launching this program soon. Click here for more info.
¿Por qué luchar por su cuenta contra la enfermedad mental y el estigma que esta produce? ¡Apóyense mutuamente en una reunión del grupo de apoyo, Conexión de NAMI! Aprenda y comparta técnicas que la gente usa para luchar contra estas condiciones. NAMI SWI ha iniciado un nuevo Grupo de Apoyo de Conexión en la Fairmont City Library en Fairmont City, IL (St. Clair County). Haga clic aquí para más info.
Latest News
Jan 2016
A J French • Threshold's Hero Award
Congratulations AJ!!!
In Mid-November 2015, former NAMI SWI Board Member, AJ French, attended the Kennedy Gala and received Threshold's Hero Award. The Kennedy Gala event involved two nights of glitz and glamour in Chicago. The purpose of this gala was to draw attention to the civil rights struggle for persons with psychiatric disabilities and elevating the conversation about community mental health.
Mark Ishaug, CEO of Thresholds, presented AJ French with the Threshold's Hero Award
AJ said, "I was honored to be recognized for my advocacy efforts and humbled to be a hero among heroes; surrounded by incredible people who are all connected in the fight to make this world a better place for persons with mental health conditions."
News Archive
- Dec 2016
The Senate passed HR 34, which includes Mental Health Reform!
- Nov 2016
No Family Left Behind • Helping Families Cope with the Invisible Wounds of War.
- Oct 2016
NAMI Illinois State Conference • We Are Stronger When We Speak With One Voice.
- Mar 2016
Thank you, Tom Johnson, CIT Coordinator, for your involvement with this very worthy project.
- Jan 2016
A J French • Threshold's Hero Award Congratulations AJ!
- Nov 2015
Share your support of United Way and why you're helping …
- Oct 2015
Recent announcement by the FDA
- Sept 2015
READ Allsup's blog by Guest Blogger Jessica Gruneich, NAMI SWI Executive Director
- Aug 2015
Are you looking for a place where you can speak freely, find support and encourage others?
- July 2015
The 2015 NAMI SWI 5K Race for Recovery, 1Mile Walk for Awareness was held
- Dec 2014
Opportunity Knocked … and together we opened the doors!
- Nov 2014
NAMI SWI expresses a huge "THANK YOU" to community partners
- Sept 2014
Great News for NAMI IL and Our Affiliate
- Aug 2014
Mental Health Cops Help Reweave Social Safety Net In San Antonio
- July 2014
NAMI FaithNet is an information resource and network for NAMI members, clergy and people of faith
- June 2014
NAMI SWI Annual Membership Meeting • Guest Speakers
- Apr 2014
A Day of Giving and Remembering • NAMI Illinois Remembers …
- Feb 2014
No Family Left Behind • Conference and Connection Fair
- Jan 2014
Affordable Care Act • FREE Informational Workshop
Check out our News Archive for important stories you may have missed.
About Us
NAMI Southwestern IL
Gateway Regional Medical Center
2100 Madison Ave. 4th Floor
Granite City, IL 62040
Email: firstname.lastname@example.com
Phone: 618-798-9788
Fax: 866-332-5338
Copyright © 2017 namiswi.org


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Pussy Riot, the Russian all-girl punk group that saw two of its members jailed in their homeland for their protest music and guerilla performances, now has a film.
"Pussy Riot – A Punk Prayer," just debuted at the Sundance Film Festival.
Directors Mike Lerner and Maxim Pozdorovkin followed the group from their well-publicised trial to the jailing of three members (two of them, Nadya and Masha, remain in prison, while a third, Katya, is out on probation).
"As you're going along you just don't know what kind of footage you're going to get so it's hard to plan on the film," Pozdorovkin told the LA Times. But he and Lerner told the Times they were compelled by the idea that the group had brought punk rock and performance art to Russia, neither of which had ever had much of a presence in the country.
"They've designed an image and idea that's very simple to grasp even if people don't understand what it quite means, because if they did — I don't think Madonna and all these people are quite as radical in their thinking as these women," he said. "They're not liberals; they're Marxist feminist revolutionaries. That's putting it mildly."
Rolling Stone reports that the documentary has just been bought by HBO Films.


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We recommend using a modern web browser such as Google Chrome or Microsoft Edge with their default settings.
At the yearly gathering of booklovers held in Chicago's McCormick Place convention center June 22 – 27, Wordsworth the Better World Bookmobile is...
Jordan Hanssen
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Mary Phipps
From the first dreams of race planning to heaving through ocean waves, Rowing Into the Son: Four Young Men Crossing the North Atlantic takes the reader along with team Outdoor Adventure Racing (OAR) Northwest as they head out from New York Harbor, catch the Gulf Stream current, and make the final dramatic push for the finish line, a narrow 50-mile wide "gate" at Bishop's Rock Lighthouse off the coast of Cornwall. Hurricane-level winds, giant eddies, passing freighters, flying fish, and sharks are all elements of the journey, and the race comes to a tense head on day 17 with another 55 days to go as the crew realizes their food supplies are running out and they must drastically restrict their eating.
This is lead rower Jordan Hanssen's intimate account of team OAR Northwest's journey, set against the backdrop of Hanssen's reflections on the teachings of both his stepfather and his biological father, who passed away many years previously. How Hanssen and his teammates cope within the confines of their tiny boat and their determination to push their limits will keep readers enthralled in this remarkable true tale of coming-of-age and adventure.
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CHV: Kawasaki Hydrographic Painting
We recently toured the cavernous Kawasaki Motors plant in Lincoln, Nebraska. Within the endless production lines—making products ranging from ATVs to subway cars—we found the company uses several fascinating industrial processes. This is the first...
Artist Jake Gillespie
Nebraska-based artist Jake Gillespie makes huge graphite-and-chalk drawings and black and white murals. His sparse lines (often just gestural) and dark, smudgy fields of color make for expressive, impermanent-seeming images that read like thoughts...


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Community Organization
Written by: Russell P. Dawn
Anglican community is experienced at its most basic level in the parish. Long before the Church of England's independence from Rome, the Roman Catholic Church in England (and elsewhere) was divided into geographical dioceses and parishes. After the break from Rome, this system was retained. Each parish consisted of a geographical area that was, in most cases, contiguous with the local township (a town and the surrounding countryside). Within the geographical area of the parish, all residents were entitled to the pastoral care of the parish clergy, who represented and were under the authority of the diocesan bishop. Within the geographical area of the parish, all residents were entitled to the pastoral care of the parish clergy.
The parish system in England is still basically the same today, yet modern transportation networks allow many English Anglicans to choose to attend a church other than their local parish church. A particular church's worship style or theological bent is likely to be the basis of one's choice to attend that church, especially in the cities.
In most areas outside England, the parochial system is not civically defined. Of course there is an effort to disperse churches geographically, and there are administrative functions that are tied to geography (i.e., the diocese), but there is no civic connection between a church and its locality, and Anglicans are not viewed as part of a given parish for the mere reason of living close to the church. "Parish" in these contexts refers not to the area around a church, but to a church and its members, wherever they might reside.
A collection of parishes within a defined geographical area constitutes a diocese, the fundamental ecclesiastical and administrative unit of Anglican organization. A diocese is governed by a bishop, under whose authority the parish clergy minister to parishioners. The bishop's official seat is known as the episcopal see, and is normally in the cathedral of the diocese. The term "see" also refers to the geographical location of the cathedral or diocese--for example the see of Winchester.
A group of contiguous dioceses constitutes a province. This can be a term of some confusion. In The Episcopal Church (TEC, also known as the Protestant Episcopal Church in the United States of America or PECUSA, and often informally dropping the "P" for "Protestant"), for example, there are nine geographical subdivisions known as provinces, within each of which are a number of dioceses. Simultaneously, TEC is a province of the Anglican Communion. The latter usage is the more salient. A province of the Anglican Communion is a group of dioceses having a head bishop (for example, the Presiding Bishop of TEC) or archbishop (like the Archbishop of York). An archbishop's see is known as an archiepiscopal see, such as the see of York. The head bishop or archbishop of a province is also called the primate of the province.


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From: "Molle Bestefich" <molle dot bestefich at gmail dot com>
> How do you guys setup anti-spoofing?
> It seems to me like I have to make anti spoofing rules manually, and
> on each individual interface?
> I would like to tell m0n0wall that eg. these are my networks:
> * foo 192.168.1.0/24
> * bar 192.168.2.0/24
> And then multi-home one of the adapters, that is in effect tell
> m0n0wall that "foo" sits behind fxp0, and so does "bar", and please
> automatically generate anti-spoofing rules.
> I can't find any feature like this, although some of the interfaces
> does have a "static IP" option. I wouldn't mind if the firewall had a
> static IP in each of the above mentioned networks, so I guess it would
> be nice if I could create a network definition including a static IP
> address and use that for anti-spoofing. But there's only one static
> IP field, so I guess that's not the solution either.
> Is anti-spoofing really a manual process?
It is built in. Dead at the bottom of http://gateway/interfaces_wan.php is
"Block private networks"


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CONTACT: Justin Hoyt, (518) 629-7898, firstname.lastname@example.com
FOR RELEASE: Immediate, Monday, April 17, 2011
The Hudson Valley Community College softball team (13-5) won both games of a doubleheader over Adirondack Community College (1-8) 11-3 and 12-1 on Monday afternoon.
In game one, Molly McDonough (Lansingburgh/Lansingburgh) went 3-4 with two doubles, a triple and an RBI. Megan Mulholland (Lansingburgh/Lansingburgh) called a great game behind the plate while going 2-3 with a double and RBI.
Mulholland continued to stay hot in game two, going 2-2 at the plate and McDonough went 1-1 with three walks. The Vikings' first 15 batters reached base safely producing 10 runs in the first inning.
The women travel to SUNY Delhi on Friday, April 22 for a doubleheader beginning at 3 p.m.


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(based on 4 reviews)
Ratings Distribution
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of respondents would recommend this to a friend.
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Reviewed by 4 customers
Displaying reviews 1-4
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Great Product, Great Color
By API Constructio
from Northern Virginia
About Me Professional
Comments about 7.5 LFT Blacksburg Barn Laminate Stair Nose:
Recommend Lumber Liquidators to my client and found this product which was much better quality and less expensive than her quotes from other flooring companies.
Bottom Line Yes, I would recommend this to a friend
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Love it!
By Alicia
from Long Island NY
It looks beautiful!
Do tread on me!
By Revrun
from Topeka, KS
About Me Casual Do-It-Yourselfer
We had it professionally installed by one of your recommended installers who did a beautiful job. I am glad we did because the little touches made all the difference. They loved the barn board pattern and took pictures of the finished job. My wife and I love it and are so glad we saw your ad before paying much more at local flooring stores. You are THE place for flooring. Thanks.
Go ahead, walk on me.
My wife and I had hardwood floors in one of the parsonages we lived in 40 years ago. Now that we are retired, we have dumped the carpet in our home and love the laminate that was installed throughout the house except for entry and bathrooms. [...] Very professional product [...]. And your price beat local stores completely. [...]
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10 Frozen Ice Carving Ideas for Home
This swan ice sculpture is perfect for dinner table centerpiece. You can also place them on coffee table. This can also suit as New Year beautification. You may even choose this for your kid's room. You can also select this for tabletop.
LED Cubes
Ice LED cubes can look awesome for room decoration. You can use them in parties or festivals. This can provide soft glow in room. You can even render romantic feel in your room with these lightings. You can even decorate floors and furniture with them.
You can also use this abstract patterned ice carving for home beautification. You can use them on fireplace mantel this look great in home bar. You can simply adjust on refrigerator. You may also get them for your living room.
This ice carving can look lovely as centerpiece for tables and other areas. You can even use them for major festivals and occasions. You can utilize them for birthday parties. You can also put them on table like that in dining room. You may even place them on side table in bedroom.
If you are music fanatic, then you can get your favorite instrument shape carved on ice. Here you can see a set of drums sculpted from pure ice. This can work well in home decoration. You can place them in man cave or recreation room.
You can use ice sculptures and miniatures for bedroom decoration. You may buy couples sculpted on ice to grant romantic appearance to your bedroom. You can also use these items as decorative accents in other areas.
You can shift to oriental or Asian decoration for home interiors. You can use dragon ice sculpture for your home. You can place them in any corner of a room. This will surely make your space look outstanding.
Frozen Flowers
You can also purchase frozen ice sculpts that has flowers inside. This gives an enchanting appearance to your home surrounding. This can also look cool in your dining room and kitchen. You can adjust them on window sills or ledges as well.
Candle Holders
You can buy candle holders made from ice you can do this yourself as well. You can cut out slabs of ice and place candles on them. You can get dry ice cube for this purpose. It will look striking as outdoor decoration accent.
Flower Vase
You may purchase ice sculpt flower vase for your room. This can look entertaining for home environment. You can color the ice with paint to make it look much more adorable. You can settle them in garden and other spaces like living room coffee table.
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frozen smiles ice cube tray
Ahahahaha granny teeth!
Funny and cute!! Cakewich baking pan is shaped like 2 big hunks of white bread — just bake and slice to make double-decker sandwich cakes with yummy fillings. Everyone loves a good sandwich, now you can have one for dessert too!
so pretty sure the boyfriend would DEF get a kick outta this one. Just sayin...not too mention, I'm actually quite fascinated by how it looks. hehe.
People are natural party animals, and here are the perfect cups to let them express their inner beast! Drinking from these strong, paper cups turns anyone's cute button nose into something WILDTags: kids, humor, office supplies, kitchen, childrens, glass, entertaining, bbq, animalsAdded 8 Years Ago from Perpetualkid
Such a clever and cute idea for a toothpick holder!


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Trianon multi strand necklace, crafted with frosted crystal beads and ruby gold spacers. 18k yellow gold clasp with crystal ball, also decorated with ruby cabochons and diamonds
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ber is arming teams of independent contractors with burner phones and credit cards as part of its sophisticated effort to undermine Lyft and other competitors. Interviews with current and former contractors, along with internal documents obtained by The Verge, outline the company's evolving methods. Using contractors it calls "brand ambassadors," Uber requests rides from Lyft and other competitors, recruits their drivers, and takes multiple precautions to avoid detection. The effort, which Uber appears to be rolling out nationally, has already resulted in thousands of canceled Lyft rides and made it more difficult for its rival to gain a foothold in new markets. Uber calls the program "SLOG," and it's a previously unreported aspect of the company's ruthless efforts to undermine its competitors.
Together, the interviews and documents show the lengths to which Uber will go to halt its rivals' momentum. The San Francisco startup has raised $1.5 billion in venture capital, giving it an enormous war chest with which to battle Lyft and others. While the company's cutthroat nature is well documented, emails from Uber managers offer new insight into the shifting tactics it uses to siphon drivers away from competitors without getting caught. It also demonstrates the strong interest Uber has taken in crushing Lyft, its biggest rival in ridesharing, which is in the midst of a national expansion.
After The Verge asked Uber for comment on its report, the company stalled for time until they could write this blog post introducing Operation SLOG to the world. "We never use marketing tactics that prevent a driver from making their living — and that includes never intentionally canceling rides," the company said.
Click here to continue reading.


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Mt. Hood makes it 11 in a row with win at Clackamas
OREGON CITY The Mt. Hood CC volleyball team stretched its win streak to 11 matches Friday night with a 25-23, 25-18, 25-11 sweep over rival Clackamas.
The Saints climbed out of a late three-point hole to take the opening set. Kylie Kitzmiller brought the Saints within striking distance with a powerful kill that went straight down on the other side. She also converted set point when the Cougars floated a pass over the middle of the net, and Kitzmiller was the first player off her feet to tip a winner over a pair of Clackamas blockers.
We didnt want to come out here and make it a struggle, so getting that first one was important Kitzmiller said. We really stuck together as a team. We never gave up on a ball, and we never gave up on each other.
Barlow High graduate Lihau Perreira served out the last four points of the set.
Mt. Hood (28-9) can finish a perfect run through the South Region with a win at Chemeketa on Wednesday.
Look for extended match coverage in the Tuesday, Nov. 6, print edition.
View a photo gallery of Fridays match at


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Tweets from @TBHomeTeam/writers
MORE from our HomeTeam writers.
Fri. January 14, 2011 | Bryan Burns
2010 St. Petersburg Times' North Suncoast baseball player of the year Ian Townsend will sign on Tuesday with St. Johns River Community College according to his father Phil Townsend.
Townsend, a two-sport athlete, batted .473 with 44 hits, 35 runs, 26 RBIs and ten doubles as a junior to help Hernando reach the Class 4A region finals. He decided to forgo football this season to concentrate on baseball.
Townsend plans to spend two years at St. Johns River, where he will meet up with former Hernando head coach Donnie Whitehead, who is currently an assistant coach for the Vikings. Townsend, a key senior this season for what is anticipated to be another strong Hernando squad, is hoping to get selected in the Major League Baseball Draft during his time at St. Johns River.


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Up until now we have not sold books directly - but have just added 2 beautiful hardback sewing books to the website because they are a direct fit with Liberty fabrics and Colette patterns. They are - The Liberty Book of Home Sewing (2011)and the Colette Sewing Handbook (Dec 2011 release)
We also have a list below of favourite books with are available on Amazon. If you click on the links it will take you to the book details on the Amazon website.


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...more >>
Chicken, Chicken Meal (Source of Glucosamine and Chondroitin Sulfate), Whole Brown Rice, Ground Rice, Chicken Fat (Preserved with Mixed Tocopherols), Dried Plain Beet Pulp, Pea Protein, Potato Protein, Natural Flavors, Lamb Meal (Source of Glucosamine and Chondroitin Sulfate), Salmon Meal, Sunflower Oil (Preserved with Mixed Tocopherols), Rolled Oats, Potassium Chloride, Salt, Flaxseed, Fish Oil (Preserved with Mixed Tocopherols), Egg Product, Tomato Pomace, Choline Chloride, Dried Pomegranate, Dried Blueberry, Dried Cranberry, Dried Pumpkin, Dried Spinach, Dried Carrot, Vitamin E Supplement, Zinc Sulfate, Zinc Proteinate, Ferrous Sulfate, L-Ascorbyl-2-Polyphosphate (Source of Vitamin C), Biotin, Niacin Supplement, Potassium Iodide, Copper Proteinate, Calcium Pantothenate, Vitamin B12 Supplement, Riboflavin Supplement (Source of Vitamin B2), Vitamin A Supplement, Pyridoxine Hydrochloride (Source of Vitamin B6), Thiamine Mononitrate (Source of Vitamin B1), Sodium Selenite, Beta Carotene, Manganese Proteinate, Manganous Oxide, Vitamin D3 Supplement, Folic Acid, Rosemary Extract.
Feeding Guidelines These are the recommended feeding ranges for small breed puppies. These guidelines should be adjusted as needed to obtain optimum weight. Puppies: Feed the suggested amount in three meals per day until 6 months of age, then twice daily until 12 months. May also be fed to Adult Dogs: Feed at least 80% of the amount shown for puppies 29-52 weeks of ages. Pregnant Bitches: During pregnancy, offer 50% more than the amount shown for puppies 29-52 weeks of ages. Lactating Bitches: Offer at least two to three times the amount shown for puppies 29-52 weeks of age. NUTRO® Dog Food Body Chart Underweight Increase feeding amount by one activity level to achieve ideal weight. Ideal Weight Maintain feeding at current activity level. Overweight Decrease feeding amount to lower range of target weight within the age category. If feeding NUTRO® ULTRA™ Food for Dogs for the first time, we suggest you blend increasing amounts of NUTRO® ULTRA™ Small Breed Puppy Food for Puppies with your old food for 6 days. Keep fresh drinking water available at all times, provide plenty of exercise and see your veterinarian regularly. Serve dry or lightly moistened. To help maintain freshness, we recommend sealing the bag tightly and storing in a cool, dry location.
Always refer to the actual package for the most accurate information


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Micronova Universal Stainless-Steel Mop Handles
Entire handle can be autoclaved
Manufacturer: Micronova SSU9
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March 12, 2014
Nevada Game Notes
Fresno State Game Notes
#3 Nevada Wolf Pack (18-12, 12-6 MW)
#2 Fresno State Bulldogs (20-10, 13-5 MW)
March 14, 2014
Thomas & Mack Center
Las Vegas, Nev.
2:30 p.m. PT
INTERNET BROADCAST: The game will be streamed live on the Mountain West Network via NevadaWolfPack.tv (web/mobile). An audio-only broadcast, is also available at www.nevadawolfpack.com/audio.
RADIO: Ryan Radtke (play-by-play) has the call in Northern Nevada on NBC
Sports Radio 1060 AM . Pregame show starts 15 minutes before tip-off. The
broadcast is available online at NevadaWolfPack.com/audio.
SERIES: The Wolf Pack and Bulldogs have previously met 43 times, in a rather one-sided all-time series. Fresno State leads the lengthy series 32-11, but the two teams have never met on a neutral court in their history. During the regular season, Nevada and Fresno State split the season series, each team claiming a win at home. The two teams have split the season series in each of the past two years.
LAST MEETING: The Bulldogs posted a 73-48 home win back in mid-February
THE SKINNY: Nevada, picked 10th in this year's preseason poll, earned rights to the No. 3 seed after posting a 12-win conference season, the most conference wins in program history ... After receiving its first MW tournament bye, the Wolf Pack are headed to its first MW semifinals game ... Senior Danika Sharp passed Tahnee Robinson Tuesday night with her 12-point effort to become Nevada's 10th all-time leading scorer with 1,073 career points ... Junior Mimi Mungedi set a new Mountain West Tournament record Tuesday when she posted seven blocks, also a new career-high for her ... Head coach Jane Albright is 13 victories shy of 500 for her career and is looking for her 10th trip to the NCAA Tournament
LAYUPS: One of Nevada's biggest strengths is its work on the glass, having outrebounded its opponents in 19 games this season … The Wolf Pack leads the league in offensive rebounds (15.8 orpg) and is second in defensive rebounds (28.1 drpg) … Mungedi's 55 blocks this season rank her first in the conference, nine ahead of Sam Martin (Colorado State) ... Mungedi also ranks highly in the league in field goal percentage, currently second (.542) ... When Nevada leads at the half, its odds for a victory are very high (93 percent) ... The only game this season the Wolf Pack lost after being up at the half, came on the road at Colorado State (led 31-30 at halftime, lost 71-64)
'SHARP' CAREER: Senior guard Danika Sharp continues to etch her name into the Nevada career record book. She has moved into a sole possession of third place in career 3-pointers at Nevada, having drained 159 in her career. Nevada's record for career three-pointers is 212, held by Ashley Bastian (1999-2003).
Sharp is also moving up the list of career free throws (264) at Nevada. She is sixth entering this game. With 12 points during Tuesday's quarterfinals game against San Diego State, Sharp passed Tahnee Robinson in career points, to become Nevada's 10th all-time leading scorer with 1,073 points.
BLOCK PARTY: Juniors Mimi Mungedi and Emily Burns have proven to be two of the better shot-blockers in Nevada history during their careers. You'll find both players on Nevada's single-season and career charts as Burns is coming off a 37-block season in 2012-13 and Mungedi has tallied 55 blocks this year.
CONFERENCE HONORS: Junior center Mimi Mungedi was named the Mountain West Co-Defensive Player of the Year, sharing the title with senior Taylor Thompson of Fresno State. Mungedi also earned a spot on the league's all-defensive team. Senior Danika Sharp received All-MW second team honors, while classmate Arielle Wideman secured honorable mention accolades. This marks Sharp's second Mountain West honor, as she received an honorable mention last year, and is the first for Mungedi and Wideman.
Mungedi leads the league in blocks and posted at least one block in 22 games this season. Sharp hit a career milestone when she notched her 1,000th point against New Mexico and ranks fifth in the conference with 62 made three-pointers. Wideman produced a career-best offensive season, averaging 10.4 points per game. Her 129 assists (4.3 apg) rank her sixth in the league.
HISTORY IN THE MOUNTAIN WEST TOURNAMENT: Friday night's matchup against Fresno State will be the first trip for the Wolf Pack to the semifinals of the Mountain West Tournament. Last year, Nevada's inaugural season in the Mountain West, the Pack defeated Air Force 80-66 in the tournament play-in-game and earned the rights to face San Diego State in the next round. The Aztecs' defense led them to a 67-39 win over the Wolf Pack. Danika Sharp led all Nevada scorers in the two games, posting 35 points, including 25 against Air Force. Mimi Mungedi chipped in 28 points and collected a team-best 16 rebounds and three blocks.


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Weekly Highlights N°4
Leg 1 of Volvo Ocean Race 2014-2015 is coming to a close. After more than 20 days of tough sailing, the fleet is less than 1500 miles to Cape Town and will arrive before the end of the week.
The fleet rounded Fernando de Noronha, the last compulsory waypoint before heading into the South Atlantic.
The half-way stage reached, it was time to hook south avoiding the graveyard conditions of the St Helena High and hunt down the legendary low-pressure weather systems that will power the fleet east into Cape Town.
This first leg has been longer than expected, for some food supplies were starting to run low. With only 24 days worth of food on board the need to ration meant portions were getting smaller.
So big decisions faced the fleet - how long must they continue their southerly trek avoiding the high pressure before safely turning their bows east, and making their dash towards the Cape Town finish.
As the fleet ploughed south, Volvo Race Control reported a deadly hazard ahead, a 200-metre iceberg sitting directly in their path. Without hesitation an exclusion zone was put in place, for the fleet an unexpected course correction.
After 20 days on the ocean the fleet were still racing as a pack as they encountered the legendary roaring 40s. With the boats recording speeds of up to 24 knots, the battle for first position was on with Dongfeng Race Team, Abu Dhabi Ocean Racing, Team Vestas Wind and Team Brunel all exchanging positions, less than 20 miles between them.
Fast but uncomfortable, the roaring 40s are a hard place to be. Cold weather, big waves and wind speeds of up to 30 knots, a huge contrast to the situation only one week before.
So with the fleet due over the next few days anticipation is building in Cape Town. The Race Village is alive, and ready to give what will be a warm South African reception to the 7 boats and 66 sailors of the Volvo Ocean Race.
Marie LaurensVolvo Ocean Race News Distribution firstname.lastname@example.com+34668103908


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NYBROOKLYN-L ArchivesArchiver > NYBROOKLYN > 2002-01 > 1012245721
Subject: [Bklyn] Brooklyn Union May 9, 1882
Date: Mon, 28 Jan 2002 14:22:01 EST
Brooklyn Union May 2, 1882
DAVID MEAD, aged 75 years and living ay No. 652 Madison street, left
home yesterday morning to purchase some slothes polls at a planing mill
corner of Bushwick avenue and Losciiusko street. he made the purchase and
started for home, but since that time has been seen. He wore a black suit.
FRANCIS B. AMES and his wife MARY L. AMES, were found dead last
night in the front parlor ofn the first floor of the boarding house No. 307
West 14th. street, New York, kept by Mrs. E.T.HAIGHT. A brief examination
which was made by the police satisfied them that during the previous night
AMES murdered his wife and afterward committed suicide. Mrs. AMES was 48 and
Mr. AMES was 3 years her senior. They were both natives of Bangor Me., from
his youth, followed the sea, and at the time of his death was the commander
of the ship Llewellyn J. Morse, in which he possessed a quarter interest.
trans by Anna
This thread:


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TxDOT wants to Shame Toll Violators
About 28,000 Texans have a hundred or so toll violations and TxDOT has come up with an idea to do something about it: shame. The scofflaws who didn't pay up by the deadline yesterday are on a web site this morning.
TxDOT's Veronica Beyer says these drivers owe the state $27-million.
"There has been constant communication with these people through letters and through phone calls but they just refused to pay. So now it's time to pay up and we have to take a hard line."
Beyer says publishing the names will get action.
"We publish their name so that everyone knows who these people are. We can ban their vehicles from using TxDOT toll roads and we can also potentially block the renewal of their vehicle's registration."
The deadline to have paid up was Noon yesterday.
"We're taking a hard line; this is serious. The state should not be owed $27-million; we need that money to pay debt; we need that money to fund operation of these roads. So we're giving these people one last chance to do the right thing and pay up or their names are going to be published."


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Episode 201: Roses, Roses, Roses
Everything's coming up roses! This symbol of love, friendship and joy is the one flower everyone who decorates wants to perfect. We'll show you how! And we feature the flower on cakes, cupcakes and even candy projects that are amazingly easy to make.
Episode 202: Sports
No matter the sport, whether you're a participant or spectator, we have cakes, cupcakes, even sandwich and appetizer ideas perfect for the celebrating … the perfect game, a hole-in-one, the end of season, any occasion!
Episode 203: Tarts, Cheesecakes, Appetizers
Signature recipes that will wow the guests without taxing the host. These projects emphasize the baking, showing you how easy it is to make tarts, cheesecakes and several appetizers.
Episode 204: Hearts Galore
Hearts for the special person and special occasion. From a crown of hearts cake to a heart-shaped candy big enough to share, we offer a variety of heart-shaped projects perfect for saying "I love you."
Episode 205: Patriotic
Raise the flag on a host of projects featuring patriotic designs decorating cookie pops, cakes, gelatin treats and cupcakes. We've even enlisted Uncle Sam!
Episode 206: Children's Birthday
There's nothing more fun than matching the perfect cake to that special child in your life! We've also included ideas for party invitations and favors to make your event perfect!
Episode 207: Big Celebrations
Every celebration deserves a special cake. Whether it's a large anniversary party, the annual family reunion, or an intimate family gathering, we have inspiring cake and cupcake ideas anyone can achieve.
Episode 208: Beach/Pool Party
Cakes, candy, and other treats perfect for summer parties or adding a touch of sunshine to any gathering any time or year!
Episode 209: Quick Desserts
Even when time is limited, a few key ingredients on hand mean impressive desserts in no time at all. We're featuring remarkable desserts meant to inspire and impress that no one will guess took very little effort at all to create.
Episode 210: Gingerbread
Gingerbread isn't just for the holidays. In addition to traditional houses, we share a springtime variation, cookies perfect any time, and spicy truffles and muffins you'll love throughout the year.
Episode 211: Shaped Pans
Shaped pans are an easy way to achieve intricate design without baking and cutting up multiple cakes. They're also so easy to decorate, even novices look like experts.
Episode 212: Easy Pretty Cakes
A bevy of beautiful cakes that won't tax the baker. From a delicate multi-hued pastel cake, to a warm treat for the chocolate lover, we'll show you how simple these cakes are to make with specialty pans – anyone can look like an expert!
Episode 213: Showers
Big events – babies, engagements, weddings and more – call for big celebrations and a shower is the perfect way to honor these occasions. Big celebrations, of course, call for spectacular, delicious desserts and special favors. We show you how easy both are to make homemade – even a novice can make them special!


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2 Min Read
(Reuters) - Visa Inc (V.N) invested about 2.1 million pounds in British technology company Monitise Plc (MONI.L) through the purchase of 7.6 million shares.
Visa Europe also agreed to buy 45.3 million Monitise shares, which would take its stake in the British mobile banking technology and services company to 10.2 percent and make it the largest shareholder. It owned 6.8 percent as on July 4.
The world's largest credit- and debit-card network Visa Inc, which was Monitise's largest shareholder, will own about 9.4 percent after the offering.
Visa Inc and Visa Europe are separate, independently operating companies, according to Visa Inc's website.
Monitise expects to raise about 24 million pounds ($38.13 million) by issuing 81 million new shares at 28.25 pence per share.
The company, which also counts Norway's Norges Bank and private equity firm 3i Group (III.L) as major shareholders, said it was also selling 28.1 million shares to certain institutional investors.
Monitise shares were up 3 percent at 29.5 pence at 0709 GMT on Friday on the London Stock Exchange.
($1 = 0.6294 British pounds)
Reporting by Monika Shinghal and Brenton Cordeiro in Bangalore; Editing by Joyjeet Das


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text:
Abstract Index
Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
p21 Suppression of Inflammatory Arthritis Requires the PCNA Domain and Inhibition of p38.
Pandemic H1N1 Influenza Vaccination Responses in Rheumatid Arthritis and Systemic Lupus Erythematosus Patients: An Association with Serum IL17 and CXCL13 Level.
Paradoxical Decrease in Collagen Induced Arthritis Severity in Gadd45 Deficient Mice.
Parenteral MTX as an Initial Treatment Strategy for Early Rheumatoid Arthritis: Results from a Nationwide Cohort.
PARP-1 Deficiency Leads to More Severe Glomerulonephritis and Increased Mortality in an Inducible Mouse Model of SLE.
Parvovirus B19 Non-Structural Protein NS1 Forms Adducts with Cellular DNA, Induces Apoptosis, and Is Condensed in Apoptotic Bodies: A Model for Viral Induction of Autoantibodies and Systemic Lupus Erythematosus.
Patellofemoral Osteoarthritis in Middle-Aged Adults: What Are the Best Measures of Physical Performance and Pain for Use in the Clinic and in Research?
Pathogenesis of Idiopathic Recurrent Pericarditis and Role of the TNFRSF1A Gene Mutations.
Pathogenic Consequences of Mutations of NLRP12 Gene. A New Cold-Induced Autoinflammatory Disease.
Patient Age, Ethnicity and Wait Times Determine the Likelihood of Non-Attendance at a First Specialist Rheumatology Assessment.
Patient Global Impression of Change Results from a 1-Year Open-Label Extension Study of Tapentadol Extended Release in Patients with Chronic Osteoarthritis or Low Back Pain.
Patient Knowledge and Beliefs Concerning Gout and Its Treatment.
Patient Perceptions and Access to Resources Influence Patient Decisions To Attend Rheumatology Appointments.
Patient Preferences for Biologic Agents in Rheumatoid Arthritis: A Discrete Choice Experiment.
Patient Questionnaire Scores for Physical Function and Pain Are More Likely Than Erythrocyte Sedimentation Rate (ESR) To Document a Quantitative Abnormality in New Patients with Rheumatoid Arthritis (RA).
Patient Risk Perception of Teratogenicity of Disease Modifying Anti-Rheumatic Drugs.
Patient-Reported Outcome Measures in Patients with Polymyalgia Rheumatica (PMR): Results from an International, Prospective, Multi-Centre Study. ACR EULAR Study Group for Development of Classification Criteria for PMR.
Patients' Complaints Depend on Systemic Status in Patient with Primary Sjgren s Syndrome: Concordant Results from 2 Independant Cohorts.
Patients Not Responding to Etanercept Obtain Lower Trough Etanercept Concentrations Compared to Responding Patients.
Patients with Gout May Have a Decreased Risk of Colonic Polyps Relative to Patients with Osteoarthritis (OA): Insights from the NY VA Gout Database.
Patients with Systemic Sclerosis and Anti-Centromere Antibodies Are Affected with Accelerated Atherosclerosis.
Patterns of MRI Bone Erosion in Rheumatoid ArthritisWhich Bones Are Most Frequently Involved and Show Most Change?
Patulous Eustachian Tube: A Novel Form of Damage in Wegener's Granulomatosis.
Paucity of PD-L1 Expression on Monocytes during Active Systemic Lupus Erythematosus Is Regulated by IL-10, TNF- and TGF-.
PCI-45292, a Novel Btk Inhibitor with Optimized Pharmaceutical Properties, Demonstrates Potent Activities in Mouse Models of Arthritis.
PDGF Receptor as Therapeutic and Diagnostic Target in Systemic Sclerosis.
Pediatric Behet's Disease, PED-BD: An International Cohort Study of 110 Patients. One-Year Follow-Up Data.
Pediatric Rheumatic Disease in the Intensive Care Unit: Lessons Learned from 15 Years Experience in a Tertiary Care Pediatric Hospital.
Peptide & NMR Spectroscopy Studies of Recombinant Domain I Confirm Conformationally Correct Domain I and Non-Linear Epitope Binding to Anti-Domain I Antiphospholipid Antibodies.
Perceived Helplessness as a Mediator between Household Income and Health Status in People with Self-Report Arthritis.
Perception of RA Disease Activity by Patients and Physicians: Reasons for and Estimators of Discrepancies.
Performance of Anti-Nucleosome, Anti-C1q and Anti-dsDNA Antibodies for the Diagnosis of Concurrent Disease Activity of Systemic Lupus Erythematosus.
Performance of Different Criteria Sets for Inflammatory Back Pain in Patients with Axial Spondyloarthritis with and without Radiographic Sacroiliitis.
Periarticular Bone Changes in Psoriatic and Rheumatoid Arthritis Patients Following Anti-TNF-alpha Therapy.
Peri-Articular Bone Density Is Strongly Correlated with Static Alignment and Varus Thrust.
Periodontal Disease Hampers Anti-TNF Treatment Response in Rheumatoid Arthritis
Peripheral Blood Expression Signatures Reflect Current Lupus Activity and Likelihood of Future Flare.
Peripheral Blood Mononuclear Cells and Plasmacytoid Dendritic Cells from Healthy Human Females Exhibit Altered TLR7-Mediated Immune Responses Compared to Males.
Peripheral Joint Ankylosis in the Spontaneous Model of Arthritis in DBA/1 Mice Is Associated with a Locus on Chromosome 3 That Contains the BMP Receptor Type 1b.
Peripheral Neuropathy in Patients with Systemic Lupus Erythematosus.
Peripheral Vascular Disease in Systemic Lupus Patients.
Permanent Working Disability Caused by Rheumatoid Arthritis Is Declining, Partly Due to Use of TNF-InhibitorsResults from a Nationwide Finnish Register in 20002007.
Peroxisome Proliferator-Activated Receptor and Agonists Together with TGF- Convert Human CD4CD25 T Cells into Functional Foxp3 Regulatory T Cells.
Perturbed VEGF Signalling within the Pulmonary Vasculature of a TGF Dependent Mouse Model of Systemic Sclerosis.
Phase 1 Clinical Safety, Pharmacokinetic and Pharmacodynamic Evaluation of the Novel C5aR Antagonist CCX168, a Potential Therapeutic for ANCA-Vasculitis.
Phenotype and Functional Stability of TGF--Induced CD4Foxp3 Regulatory T Cells in Steady and Inflammatory States.
Phenotypic, Functional and Transcriptomic Analysis of Monocyte-Derived Dendritic Cells from SpA Patients Revealed Their Hypo-Stimulatory Capacity and Specific Molecular Response to LPS Compared to Healthy Controls.
P-Homocysteine Levels Are Independently Correlated to S-Urate but Not to Urate Lowering Treatment. Results of an Observational Study of 112 Patients with Gout.
Phone Administration Compared to Self-Administration on Paper of the Main Instruments Used To Evaluate Ankylosing Spondylitis Patients.
Phosphoinositide 3-Kinase Delta (PI3K) Regulation and Function in RA.
Physical Activity Assessed by Accelerometry in Persons with Knee OA Compared to National Guidelines: The Osteoarthritis Initiative (OAI).
Physical Activity Level and Poor Disability Profile: A Population-Based Study of US Adults with Arthritis.
Physical Exercise Improves Endothelial Function in Patients with Systemic Lupus Erythematosus.
Physician Opinion of Variables That Differentiate Disease Activity and Damage in Systemic Sclerosis.
Physiotherapy Management of Children with Hypermobility: A Review of an Out-Patient Self Management Exercise Programme.
PiHDL and High Plasma Leptin Levels Are Predictors of Longitudinal Progression of Subclincal Atherosclerosis in SLE.
Plasma Cytokine Profles in Ankylosing Spondylitis.
Plasma Endogenous Met- and Leu-Enkephalin Levels Are Decreased and Associated with Clinical and Laboratory Parameters in Early Systemic Sclerosis.
Plasma Fibrinogen Is More Specific Than Either ESR or CRP for Confirmation of Response to Treatment in Patients with Active Polymyalgia Rheumatica.
Plasma Osteopontin as a Marker for Damage in Pediatric Systemic Lupus Erythematosus.
Plasmacytoid Dendritic Cells Control Peripheral Treg Conversion to the RNA-Binding Nuclear Self Antigen La/SS-B.
Platelet Activation and Paradoxical Inhibition of ADP Induced Aggregation by Antiphospholipid Antibodies.
Platelet C4d Is Associated with All-Cause Mortality in Patients with Systemic Lupus Erythematosus.
Platelet Microparticle Proteome: Insight into Role of Microparticles under Different Stimulatory Conditions.
Polyautoimmunity and Autoimmune Aggregation in Rheumatoid Arthritis.
Polymorphisms in the Folate Metabolism Gene MTHFR (C677T and A1298C) Are Not Associated with Methotrexate Adherence: Findings from the Veteran's Affairs Rheumatoid Arthritis (VARA) Registry.
Pooled Analysis of Observational Studies on Lymphoma Incidence among Rheumatoid Arthritis (RA) Patients Initiating Etanercept Therapy.
Population-Based Estimates of Common Comorbidities and Cardiovascular Disease in Ankylosing Spondylitis.
Positivity for Anti-RNP Antibody Is a Risk Factor for Adverse Effects by Trimethoprim-Sulphamethoxazole, a Prophylaxis Agent of P. jiroveci Pneumonia, in Patients with Collagen-Vasular Diseases.
Post-Marketing Surveillance Program of Tocilizumab for RA in Japan Interim Analyses of 3,881 Patients.
Post-Transcriptional Regulation of IL-6 Production by Zc3h12a in Fibroblast-Like Synovial Cells.
Post-Translational Control Mechanisms Regulate Dendritic Cell Activation of T Cell Responses.
Post-Treatment Changes in Serum C-Reactive Protein Levels and Clinical Response in Rheumatoid Arthritis.
Potential Gender Effect on the Association between Knee Osteoarthritis and Risk of Indoor and Outdoor Falls in Elderly Men and Women.
Potential Protein Targets for the Treatment of the Antiphospholipid Syndrome with Statins and Hydroxychloroquine.
Potential Risk Factors for Lupus Nephritis.
Potential Role of the LKB1-AMPK and CaMKKb-AMPK Pathways in Controlling the Progression of OA.
Potential Use of Matrix Metalloproteinase-13 Fluorogenic Probe for Imaging Osteoarthritis Development In Vivo.
Practice Patterns of US Rheumatologists Related to Diagnosis and Assessment of Disease Activity as Well as Switching Biologic Therapies in Rheumatoid Arthritis.
Pre Analytical Effects of Serum Collection and Handling in Quantitative Immunoassays for Rheumatoid Arthritis.
Preclinical Development of Autologous, Autoantigen-Loaded Dendritic Cells Modified with Bay117082 for Tolerizing Immunotherapy in Anti-Citrullinated Peptide Antibody Positive Rheumatoid Arthritis Patients Bearing the HLA-DR Shared Epitope.
Preclinical Evaluation of Cardiac Involvement in Systemic Sclerosis Patients by Speckle Tracking Strain Analysis.
Prediction of 10-Year Cardiovascular and All-Cause Mortality in Rheumatoid Arthritis Using the Ankle-Brachial Index.
Prediction of Early Response to Anti-TNF Therapy and Disease Activity State Using the Ankylosing Spondylitis Disease Activity Score (ASDAS).
Prediction of One-Year Response to Etanercept and Methotrexate in Rheumatoid Arthritis Patients in TEMPO.
Prediction of Total Knee Replacement in a Two-Year Multi-Centre Clinical Trial in Knee Osteoarthritis: Results from a 46 Year Observation.
Predictive Factors of Hand Radiographic Lesions in Systemic Sclerosis: A Prospective Study.
Predictive Risk Factors of Severe Infections in RA Patients Treated with Abatacept in Real Life: Results from the Orencia and Rheumatoid Arthritis (ORA) Registry.
Predictive Validity of the New Preliminary ACR/EULAR Definitions for Remission in Rheumatoid Arthritis.
Predictive Value of High Levels of Antinuclear Antibodies in People without Other Feature of Autoinmunity. A Prospective Study.
Predictive Value of Non-Invasive Tests for the Diagnosis of Scleroderma-Associated Pulmonary Hypertension: PHAROS Registry.
Predictors of 12 Year Revision Risk Following Primary THR for Osteoarthritis in the US Medicare Population.
Predictors of Clinical Outcome in Fibromyalgia: Single Center Experience of a Brief Interdisciplinary Fibromyalgia Treatment Program.
Predictors of Interstitial Lung Disease in Early Systemic Sclerosis: A Prospective Longitudinal Study.
Predictors of Mortality in Diffuse Alveolar Haemorrhage (DAH) Associated with Systemic Lupus Erythematosus.
Predictors of Outcome in Juvenile Polyarteritis Nodosa: A Multicenter Study.
Predictors of Radiographic Progression in Adalimumab-Treated Patients with Ankylosing Spondylitis.
Predictors of Rate of Progression in Organ Damage in SLE.
Predictors of Response to B Cell Depleting Therapy in Adult and Juvenile Myositis.
Predictors of Response to Rituximab in Patients with Active Rheumatoid Arthritis and Inadequate Response to Anti-TNF Agents or Traditional DMARD.
Predictors of Successful Cessation of TNF Blockers in Patients with RA.
Predictors of Survival in Patients with Anti-Synthetase Autoantibodies.
Predictors of Vitamin D Deficiency among Veterans.
Predominance of Complement Components C1q and C4 Bound to Circulating Immune Complexes (CICs) in Juvenile Idiopathic Arthritis (JIA): Support for Classical Pathway Activation.
Predominant Suppression of Plasmablasts by Cyclophosphamide in Patients with Systemic Lupus Erythematosus: A Possible Therapeutic Mechanism.
Prefrontal Lobe Volume Could Reveal Working Memory Function in Patients with System Lupus Erythematosus.
Pregnancies in Systemic Necrotizing Vasculitides: Report on 12 Women and Their 20 Pregnancies.
Pregnancy in Ankylosing Spondylitis Is Associated with Fluctuation in Back Pain but Return to Baseline Postpartum: A Case Control Study.
Pregnancy Outcomes among African American Patients with Systemic Lupus Erythematosus (SLE) Compared to Controls.
Pregnancy Outcomes in Patients with Autoimmune Diseases Treated with Rituximab.
Pregnancy Related Morbidity and Mortality in Patients with Systemic VasculitisA Single Centre Controlled Study.
Preliminary Classification Criteria for the Cryoglobulinemic Syndrome.
Preliminary Comparison of Health-Related Quality of Life in Children with Lupus across Different Continents.
Preliminary Composite Response Index for Raynaud's Phenomenon.
Preliminary Criteria for Global Disease Flares in Juvenile Systemic Lupus Erythematosus (jSLE).
Preliminary Definition of Remission and Minimal Disease Activity Cut-Points for the Juvenile Arthritis Disease Activity Score (JADAS).
Preliminary Findings of Functional Magnetic Resonance Imaging (fMRI) Assessments of Specific Cognitive Domains in Childhood-Onset Systemic Lupus Erythematosus (cSLE) Patients and Best-Friend Controls.
Preliminary Results: Baseline Nutritional Vitamin D Level Does Not Predict Progression of Subclinical Atherosclerosis in Women with SLE.
Preliminary Rheumatoid Arthritis (RA) Flare Assessment for Randomized Clinical Trials (RCTs): An Outcome Measures in Rheumatology (OMERACT) Data-Driven, Patient-Centered, and Consensus-Based Initiative.
Preliminary Scores for the Evaluation of Disease Activity in Familial Mediterranean Fever, Mevalonate Kinase Deficiency, TNF-Receptor Associated Periodic Syndrome and Cryopyrin-Associated Diseases: Results from the AIDAI Consensus Conference.
Preliminary Validation for the Short Version of the Valued Life Activities Questionnaire (S-VLA).
Pre-Pubertal Onset Systemic Lupus Erythematosus in Girls: Clinical and Serologic Manifestations Differ from Post-Pubertal Onset SLE.
Prescription Patterns in Pregnant Women with Rheumatoid Arthritis.
Presence and Predictors of Poor Functional Outcomes in US Hispanics with Rheumatoid Arthritis (RA).
Presence of HMGB1 (High Mobility Group Box 1) and Antibodies to HMGB1 in Systemic Lupus Erythematosus (SLE).
Prevalence and Characteristics of Uveitis in US Veterans with Seronegative Spondyloarthropathy.
Prevalence and Clinical Significance of Cryofibrinogenemia in Patients with Renal Disorders.
Prevalence and Correlates of Sleep Disturbance in Systemic Sclerosis Results from the UCLA Scleroderma Quality of Life Study.
Prevalence and Persistence of Low Infliximab Serum Trough Levels in RA Patients with Low Disease Activity in Daily Clinical Practice.
Prevalence and Persistence of Metabolic Syndrome in a Multicentre International Inception Cohort of Patients with SLE.
Prevalence and Predictors of Pain in Rheumatoid Arthritis Patients in DAS28 Remission.
Prevalence and Prognostic Significance of Thrombotic Microangiopathy in Rheumatologic Patients: Clinical and Immunological Associations.
Prevalence and Risk Factors of Glucocorticoid-Induced Diabetes Mellitus in Patients with Systemic Lupus Erythematosus.
Prevalence of Antibodies to Prothrombin (PT) and Prothrombin/Phosphatidylserine (PS) in a Cohort of Lupus Anticoagulant (LAC) Positive Samples.
Prevalence of Associated Autoimmune Diseases in a Spanish Population with Systemic Sclerosis.
Prevalence of Atherosclerotic Risk Factors and the Metabolic Syndrome in Patients with Chronic Inflammatory Arthritis.
Prevalence of Behet's Disease in Southern Sweden.
Prevalence of Coronary Heart Disease in a Cohort of Australian Scleroderma Patients.
Prevalence of Enthesitis in Pediatric Patients with Enthesitis-Related Arthritis.
Prevalence of Flow Mediated Dilatation and Its Association with Framingham Risk Score in a Population of Women with Systemic Lupus Erythematosus.
Prevalence of Hyperuricemia in the US General Population: The National Health and Nutrition Examination Survey (NHANES) 19992008.
Prevalence of Metabolic Syndrome in Patients with Seronegative Spondyloarthritis.
Prevalence of MRI-Detected Joint Pathology of the Knee in a Population-Based Sample: Framingham Osteoarthritis Study.
Prevalence of Osteoporosis and Osteoporotic Fractures: A Population Based Survey Including Vertebral Fracture Assessment by Morphometry (VFA).
Prevalence of Psoriatic Arthritis in Thai Psoriasis at Ramathibodi Hospital.
Prevalence of Reactivation of Hepatitis B Virus Replication in Rheumatoid Arthritis Patients.
Prevalence of Symptomatic Knee and Hip OA: A Population-Based Survey in France.
Prevalence, Impact and Risk Factors for Musculoskeletal Pain among HIV Infected Adults: An Epidemiologic Study.
Prevention of Flare Recurrences in Childhood Refractory Chronic Uveitis: An Open-Label Comparative Study of Adalimumab Versus Infliximab.
Primary Anti-TNF Failures Experience Better Clinical Responses but Similar Health Care Utilization to a Second Anti-TNF Agent Than Secondary Failures: Analysis of the Alberta Rheumatoid Arthritis Biologics Registry.
Primary Central Nervous System Vasculitis Presenting with Intracranial Hemorrhage.
Primary Central Nervous System Vasculitis: Analysis of 131 Patients.
Primary Sjgren's Syndrome-Associated Non Ataxic Sensory Neuropathies and Sensorimotor Neuropathies Are Characterized by Distinctive Immunological Profiles.
Proactively Contacting Men with Prostate Cancer Treated with Anti-Androgen Medications Improves the Evaluation and Treatment of Osteoporosis.
Productivity at Home and Work Place in SclerodermaAnalysis from the UCLA Scleroderma Quality of Life Study.
Progesterone Receptors Regulate Humoral Immunity.
Prognosis of Non-Hodgkin Lymphomas in Primary Sjogren's Syndrome.
Prognostic Factors in Hepatitis C Virus Patients with Systemic Vasculitis.
Progression of Carotid Atherosclerosis and Its Determinants in Lupus Patients.
Progression Patterns of Radiographic Damage: Results from SONORA Study.
Progressive Multifocal Leukoencephalopathy Associated with Biologic and Synthetic DMARD Therapy in Rheumatic Diseases: An Analysis of the FDA Adverse Event Reporting System Database.
Progressive Reduction in Tophus Burden with Pegloticase Therapy in Patients with Chronic Gout Refractory to Conventional Therapy.
Progressive Resistance Exercise in Women with Knee Osteoarthritis.
Pro-Inflammatory Activity of SIRT1 in Monocytes.
Pro-Inflammatory Properties of IL-35 and Its Association with Disease Activity in Patients with Rheumatoid Arthritis.
Projecting Lifetime Risk of Symptomatic Knee OA and Total Knee Replacement (TKR) in Persons Sustaining a Complete Anterior Cruciate Ligament (ACL) Tear in Early Adulthood.
Projecting the Effects of a 5-Point Reduction in Body Mass Index on Knee or Hip Osteoarthritis and Health-Related Quality of Life in a Closed Population to 2031: A Microsimulation Study.
Prolonged Serologically Active Clinically Quiescent (SACQ) Systemic Lupus Erythematosus (SLE): Novel Predictors of Flare?
Proof of Concept Study for a Potent p38 MAPK Dual Action Inhibitor BMS-582949 in Subjects with RA Receiving Concomitant Methotrexate.
Propensity-Adjusted Medication Effects on Survival in Rheumatoid Arthritis: 22-Year Follow-Up of 5629 Patients.
Prospective Serum Levels Assessment of DKK-1 and SOST in Patients with Ankylosing Spondylitis and Treated with Anti-TNFa Treatments.
Prospective Study of Infliximab for Treatment of Pediatric Uveitis.
Protection from Cardiovascular Events and Nephritis in SLE Correlates with Levels of IgM Natural Autoantibodies to Different Apoptosis-Associated Antigens.
Protection from Collagen-Induced Arthritis in a CX3CR1-Deficient Mouse Strain.
Protective Human CD4CD25FOXP3 Regulatory T Cells Generated Ex-Vivo with IL-2, Retinoic Acid and TGF-bets Are Resistant to Pro-Inflammitory Cytokines.
Proteomic Analysis of Systemic Sclerosis Serum Identifies the Toll-Like Receptor Agonists S100A8/A9 as a Novel Possible Pathogenic Marker.
Proteomic Mass Spectra Classification in Fibromyalgic Patients.
Protocolised Versus Non-Protocolised Rituximab Treatment for Refractory ANCA-Associated Vasculitis.
Pseudo-Hypertrophic Osteoarthropathy in Lung Transplant Recipients on Long Term Voriconazole Therapy.
Psoriatic Arthritis and OnycholysisResults from a Study of 1116 Patients with Psoriasis, and Follow-Up of Those with Psoriatic Arthritis over 16 Years.
Psoriatic Arthritis: Oligoarticular or Polyarticular Presentation?
Psychological Factors but Not Clinical Markers of Disease Activity Predict Adherence among Rheumatoid Arthritis (RA) Patients Receiving DMARDs and Adalimumab (ADA): Results from the British Society for Rheumatology Biologics Register (BSRBR).
Psychometric Properties of a Self-Administered Early Inflammatory Arthritis Detection Tool.
Psychometric Properties of Synovitis Assessed in Rheumatoid Arthritis: Improved Intraobserver Reliability of Ultrasound vs. Clinical Evaluation in an Ancillary Study of the Etanercept Versus DMARDs Randomized, Prospective, Multicentre Study.
Pulmonary Artery Diameter Is Associated with Pulmonary Hypertension in Patients with Systemic Sclerosis (SSc).
Pulmonary Function in Patients with Rheumatoid Arthritis Treated with Anti-TNF Biologic Agents.
Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma (PHAROS): Comparison of Outcomes in Subtypes of Pulmonary Hypertension.
Pulmonary Hypertension by Age of Scleroderma Onset and Subtype.
Pulmonary Manifestations of Polymyositis and Long-Term Outcomes A Retrospective Study.


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Gill, Al & team offer a warm welcome at their beautifully restored 17th Century Coaching Inn here in Dolton North Devon betwixt the two beautiful National Parks Exmoor and Dartmoor and only a short 20 minutes' drive from the sandy beaches of North Devon. All 9 bedrooms have recently been refurbished to high, modern standards and finished with unique and antique furniture thus still in keeping with the old and ensuring a perfect, relaxing night's sleep.
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Check out - by 11:00am
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Opening Hours
Winter opening Hours
Mon: 3pm-8pm - No food served all day
Tue & Wed: 3pm-10pm - Food served 5-8.00pm
Thurs: 12pm-10pm - Food served 12-3pm and 5-8.00pm
Fri & Sat: 11am-11pm - Food served 12-3pm and 6-9pm
Sun: 11am-6pm - Food served 12-5pm
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Key dates to get booking:
Food through the decades; 26th March Mothering Sunday lunch, Tuesday 4 April Food through the decades; 50's night.


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These authors contributed equally to this work.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).
Maurocalcine is a highly potent cell-penetrating peptide isolated from the Tunisian scorpion
Maurocalcine (MCa) is a 33 amino acid residue peptide that was isolated in 2000 from the venom of the Tunisian chactid scorpion
Besides its Ca2+ channel activity, MCa is also used as a cell-penetrating peptide (CPP). Its properties have been investigated in detail. It was soon discovered that MCa could act as vector for the cell penetration of a variety of cargoes, including proteins [
The hydrophobic domain of MCa is an efficient CPP. (
Even if the mechanism(s) of penetration of CPP are subject to debate [
A schematic representation of MCa illustrates that the amino acid sequence 1 to 9 tops the rest of the peptide (yellow residues) and defines an independent more hydrophobic face (
We compared the efficacy of MCaUF1-9 for cell penetration within the glioma rat cell line F98 to other very popular peptides, comprising TAT, penetratin (Pen) and poly-Arg (poly-R). All peptides included an additional C-terminal Cys residue that was labeled with the Cy5 fluorochrome which served the purpose of cargo in this study. Of note, the extra Cys residue in MCaUF1-9-C-Cy5 is at its natural position as in the folded/oxidized MCa (Cys10) where it is linked to Cys21 by a disulfide bridge. In contrast, Cys3 of MCaUF1-9 was replaced by an isosteric 2-aminobutyric acid (Abu) residue to avoid mislabeling by Cy5 in the middle of the sequence. A series of confocal microscopy images were taken immediately after a 2 h incubation of F98 cells with various concentrations of the four peptides tested (MCaUF1-9-C-Cy5, TAT-C-Cy5, Pen-C-Cy5 and poly-R-C-Cy5). As shown, cell penetration of MCaUF1-9-C-Cy5 is perceptible at concentrations as low as 100 nM, whereas none of the other peptides showed penetration at this concentration (
Our data also illustrate that the control linker-cargo, a single Cys residue linked to Cy5 (C-Cy5), does not penetrate at all into F98 cells (at concentrations up to 33 µM), demonstrating the peptide specificity of cell entry (
Punctiform distribution of MCaUF1-9-C-Cy5 may be interpreted as a cell entry that is mainly based on a form of endocytosis. This point was assessed by FACS analyses using various drugs at the 2 h cell entry timepoint of 1 µM MCaUF1-9-C-Cy5 in F98 cells. We tested amiloride, a macropinocytosis inhibitor, methyl-β-cyclodextrin to deplete membrane cholesterol and inhibit lipid raft-dependent pathways, nocodazole to prevent microtubule formation, and cytochalasin D to stop F-actin elongation, required for macropinocytosis and clathrin-dependent endocytosis [
The 18.5% inhibition observed by cytochalasin D, while being non-significant, was in agreement with the contribution of macropinocytosis to the cell entry of the peptide. Quite surprisingly, both methyl-β-cyclodextrin and nocodazole produced 24.7 and 48.9% increases in the cell entry of MCaUF1-9-C-Cy5. The lack of inhibition by methyl-β-cyclodextrin indicates that caveolae-mediated endocytosis is not involved in the entry of this peptide. The observed increase in cell penetration may indicate on the contrary that one preferential route of cell entry by translocation may be in lipid rafts. Preventing the loss of lipid rafts by blocking endocytosis at this level would increase the surface area devoted to lipid rafts and hence peptide entry.
Effect of endocytosis inhibitors on MCaUF1-9 peptide penetration in F98 cells. (
Similarly, it is possible that microtubules hinder cell penetration explaining why blocking their formation may help peptide entry to this large extent. These observations demonstrate that while the intracellular distribution of MCaUF1-9-C-Cy5 in F98 cells looks punctiform, this is not necessarily the consequence of a cell entry by endocytosis.
Next, we attempted to design a number of MCaUF1-9 peptide analogues in order to get some hints on what structural determinants may be important for the efficacy of this peptide in cell penetration. At the N-terminal side of Cys3 (replaced by Abu) of MCaUF1-9, there are two residues that appear of minor importance (Gly1 and Asp2). Removing these two residues yields MCaUF3-9. As shown, MCaUF3-9-C-Cy5 still accumulates very well in F98 cells (
Structural determinants of MCaUF1-9 peptide penetration. (
At the quantitative level, there was a 1.25-decrease in cell penetration efficacy at 3 µM, indicating that these two residues were most likely not essential for cell penetration. This deletion brings the size of this efficient CPP down to seven amino acid residues which is remarkably short. At position 3 of the wild-type MCa there is normally a Cys residue that engages itself into a disulfide bridge. The lateral chain of this residue is therefore not exposed towards the outside face of the molecule and is unlikely to play a role in cell penetration. MCaUF1-9 contains an Abu residue instead of a Cys residue and the peptide is quite efficient for cell penetration. We nevertheless probed this position by replacing the Abu residue by Trp, Gln or Ala. As shown, none of these replacements at position 3 within MCaUF1-9-C-Cy5 hindered the cell penetration of these analogues (
The inability to produce MCaUF1-9 peptides with greater cell penetration efficacies tends to indicate that sequence variation of this hydrophobic domain needs to be considered more cautiously to design optimized peptides. Interestingly, MCa belongs to a larger family of peptides that have, most of them, never been assessed for cell penetration. Results have been presented indicating that imperatoxin A also behaves as a CPP [
The most differing peptide sequence is the one derived from hadrucalcin with two extra N-terminal residues. Interestingly, the sequence SerGluLys replaces the Gly1 residue of MCa, but Asp2 of MCa is conserved. Also, four internal substitutions are noticeable. Leu4, Pro5, Lys8 and Leu9 of MCa are substituted by Iso, Lys, Gln and Arg, respectively. Finally, HadUF1-11 has an additional basic amino acid compared to MCaUF1-9. We next evaluated the ability of these peptides to accumulate into F98 cells. At 1 µM, it was obvious, according to confocal imaging, that ImpUF1-9-C-Cy5 (equivalent to Opi1UF1-9-C-Cy5 or Opi2UF1-9-C-Cy5) is less efficient for cell penetration than MCaUF1-9-C-Cy5 and HadUF1-11-C-Cy5 (
Cell penetration properties of the hydrophobic domains of toxins from the calcin family. (
This indicates that a series of very selective set of amino acid substitutions are required to improve MCaUF1-9 cell penetration properties. They also demonstrate that the calcin family can accommodate some variation in cell penetration efficacy for the activation of the ryanodine receptor. Nevertheless, it remains to be investigated whether the additional basic face and pharmacophore region are necessary to improve the characteristics of cell penetration of imperatoxin A, opicalcin 1 or opicalcin 2. In any case, it is obvious that HadUF1-11 is a remarkable cell penetration peptide by the extent of its efficacy compared to the popular peptides challenged in
Close examination of the amino acid sequence of MCa reveals that it contains a histidine residue at position 6. This residue is therefore also present in MCaUF1-9. According to
A fit of the data with a decreasing exponential suggests that the peptide enters into F98 cells with a 2.8-fold lower efficacy than at acidic pH values. Half of this decrease in efficacy occurs for a variation in pH from 5.0 to 5.7 indicating that the pKa value of this histidine residue within MCaUF1-9-C-Cy5 may be close to 5.7. The involvement of His6 in this pH-dependence of the cell penetration of the peptide is demonstrated by the lack of pH-dependence in cell penetration of the mutant peptide MCaUF1-9(W6)-C-Cy5 in which His6 is replaced by Trp6 (
One property of CPP is that they enter quite rapidly into cells. However, the persistence of their intracellular accumulation is seldom looked after. We investigated this question with three peptides. We used MCaUF1-9-C-Cy5, a non or poorly charged peptide depending on the protonation level of His6, MCaUF11-33-C-Cy5, a highly charged peptide mainly encompassing the two C-terminal thirds of MCa, and HadUF3-11-C-Cy5 which is less hydrophobic than MCaUF1-9-C-Cy5. One could expect that hydrophobic peptides may more readily escape from the cell interior than charged peptides. To test this idea, F98 cells were loaded 2 h with 1 µM of each of these peptides, extensively washed, maintained in culture for a variable duration (between 0 and 34 h, washout time), treated with trypsin and the fluorescence level remaining in the cells estimated by FACS (
As shown and quite remarkably, the fluorescence levels of the accumulated peptides fade away only slowly with time indicating that the cell entry of the peptides are faster than their cell exit (
pH-dependence and persistence of the cell penetration of MCaUF1-9-C-Cy5. (
While all MCa truncations and/or disruptions of disulfide bridges produce a loss of the 3D structure, MCaUF1-9 is more susceptible than other truncated peptides to preserve some of the structural characteristics that it may possess within the full-length MCa as it encloses by itself the entire hydrophobic face of MCa. At this stage, one may only speculate as to why MCa presents one hydrophobic face diametrically opposite to a highly charged basic face. It may present a strong advantage for the peptide if it has to deal with both a hydrophilic environment (extracellular space and cytoplasm) and a hydrophobic one (membrane lipids). Besides it may be essential to the mechanism of cell translocation if the peptide needs to cope with the amphiphilic nature of membrane lipids. The strong dipole moment of the peptide, resulting from the existence of these two different faces, probably orients the peptide in its interaction with the plasma membrane. The highly basic nature of MCa should also speed up the peptide entry through electrochemical attraction if one considers that it diffuses freely through the plasma membrane, in a similar way that Na+ or Ca2+ ions would do when permeating through adequate ion channels while attracted by the inside negative membrane potential. Such a mechanism, if proven, would result in peptide accumulation against the concentration gradient. What the effect of a physical separation between these two peptide entities (hydrophobic face and basic face) might be on the cell penetration mechanism remains however unclear. One may notice at this point that MCaUF1-9-C-Cy5 and MCaUF11-33-C-Cy5 produce quite similar intracellular punctiform distributions in F98 cells arguing that they share nonetheless similar mechanisms of cell penetration. This was also the case for the other CPP investigated in this study (poly-R-C-Cy5, Tat-C-Cy5 and Pen-C-Cy5). It is of interest to note however that the cell distribution of fluorescent D-MCa, a full-length and well-structured analogue of MCa, is mostly diffuse [
The most interesting information that we could gather from our mutagenesis program of MCaUF1-9-C-Cy5 was that the two first amino acid residues were the most dispensable for its penetration properties. This truncation approach led to the design of a 7-mer CPP that has greater potency than most popular CPPs on the market. Investigating the cell penetrating properties of peptides derived from the hydrophobic face of other peptides members of the calcin family turned out as a more interesting approach than mutagenesis. Most of these peptides differ by only a few amino acid residues, with the notable exception of hadrucalcin. Coherent with the mono-substitution we performed at amino acid 9 of MCaUF1-9-C-Cy5, the cell penetration properties of ImpUF1-9-C-Cy5, Opi1UF1-9-C-Cy5 and Opi2UF1-9-C-Cy5, all presenting Arg9 instead of Leu9, were reduced to some extent compared to MCaUF1-9-C-Cy5. Remarkably, multiple amino acid substitution as demonstrated within HadUF1-11-C-Cy5 resulted in an important and unexpected improvement of cell penetration. Similarly to MCaUF1-9-C-Cy5, removing the two first N-terminal amino acid residues of HadUF1-11-C-Cy5 produced a peptide with quite significant levels of cell penetration. The core of the sequence, the one we assume to be important for cell penetration (after Abu3 in MCaUF1-9), contains no less than 4 substitutions (Leu4 by Ile, Pro5 by Lys, Lys8 by Gln, and Leu9 by Arg). This indicates that quite elaborate alterations need to be done to MCaUF1-9 sequence to further improve it cell penetrating properties. In any case, these findings (i) define a novel CPP with unprecedented efficacy, and (ii) open the door for the design of hadrucalcin/MCa chimeras 1 µM MCaUF1-9-C-Cy5 fluorescence at any given concentration and never in terms of starting concentration at which cell entry was observed. These observations suggest that the affinity of these peptides for plasma membrane components remains unaltered.
Since we are interested in developing a number of applications in oncology for MCa analogues, we also investigated the role of His6 in cell entry into the glioma F98 cells. Of great interest for future applications, we found that protonation of His6, occurring at more acidic pH, but in a range compatible with pH values observed in glioma, produced a three-fold more potent peptide for cell penetration. We assume that protonated His6 may form a salt bridge with Asp2 in the non-structured MCaUF1-9. It is likely that, without this salt bridge, the negative charge carried by Asp2 may disfavor cell penetration of MCaUF1-9. This observation on the importance of protonation in peptide cell penetration will be useful for the future design of new MCa analogues in which important basic amino acid residues may be substituted by His residues in order to further improve the tumor-selectivity of these potent CPP. Interesting positions will include Lys19, Lys20, Lys22 and Arg24 all shown to contribute to the cell penetration efficacy of the full length MCa [
Chemical syntheses of truncated toxin peptides were performed as previously described [
Each peptide was labeled with Cy5 according to the manufacturer's protocol (GE Healthcare). Peptides were dissolved at 200 µg/mL in 1 M NaHCO3 buffer, pH 9.3. 500 µL of solubilized peptides were added to Cy5-maleimide containing tubes. The mixtures were incubated during 2 h at room temperature and then purified by HPLC using an analytical Vydac C18 column. Elution of the Cy5-labeled peptides was performed with a 5–90% acetonitrile linear gradient containing 0.1% trifluoroacetic acid. The pure peak fractions were lyophilized and peptides quantified by UV spectrophotometer at 650 nm.
Undifferentiated malignant glioma rat (F98) cell line (from ATCC) was maintained at 37 °C in 5% CO2 in DMEM/F-12 nutrient medium (Invitrogen, Cergy Pontoise, France) supplemented with 2% (v/v) heat-inactivated fetal bovine serum (Invitrogen) and 100 µg/mL streptomycine and 100 units/mL penicillin (Invitrogen).
For analysis of the cell entry of Cy5-labeled-truncated toxin peptides in living cells, cell cultures were incubated with the fluorescent peptides (in DMEM/F-12 nutrient medium only) for 2 h, and then washed twice with phosphate-buffered saline (PBS) alone. The plasma membrane was stained with 50 μg/mL rhodamine-conjugated concanavalin A (Invitrogen, Cergy Pontoise, France) for 5 min. Cells were washed once more. Live cells were then immediately analyzed by confocal laser scanning microscopy using a Zeiss LSM operating system. Rhodamine (561 nm) and Cy5 (633 nm) were sequentially excited and emission fluorescence were collected.
F98 cells were incubated with various concentrations of Cy5-labeled peptides in DMEM/F-12 culture medium without serum at 37 °C for 2 h. The cells were then washed with PBS to remove excess extracellular peptide and treated with 0.48 mM versene (Invitrogen) for 5 min at 37 °C to detach cells from the surface, and centrifuged at 200
Using Sybyl X 1.3 (Tripos Inc., St. Louis, MO, USA) and PDB structure of MCa (code 1C6W) and imperatoxin A (code 1IE6), we generated 3D models of opicalcin 1 and 2, hemicalcin and hadrucalcin. There is a sequence homology (76% up to 91%) between these proteins. Based on previous reports [
In this manuscript, we have demonstrated that MCaUF1-9-C-Cy5 starts to show detectable penetration in glioma F98 cells at concentrations as low as 33 nM (5-fold increase over control) as detected by FACS. The process is visible at 100 nM by confocal microscopy and a comparative analysis reveals that it is highly competitive compared to TAT, penetratin or Poly-R CPP. One analogue turns out to be extremely competitive, MCaUF3-9, owing to its performance, length and ease of synthesis. Nevertheless, we also demonstrate that engineered optimization of its cell penetrating properties is hard to achieve but that Mother Nature has provided an elegant solution to this problem by selecting itself the best amino acid substitutions under the form of new calcin analogues. In that respect, the hydrophobic domain of hadrucalcin outperforms that of MCa. We evidence for the first time the possibility to modulate peptide cell penetration by external pH provided that His residues are strategically incorporated within the amino acid sequence. This finding enlarges the potential application of these peptides to the treatment of glioma. Additionally, the observation that the residency time of these peptides in glioma F98 cells is quite long suggest that these peptides may be best used when injected once inside a solid tumor rather than by intravenous route.
We acknowledge financial support to MDW by Inserm and by the Nanofret grant and LabEx ICST of the Agence Nationale de la Recherche (ANR). MDW is a recipient of a contrat d'interface from Inserm and Grenoble Hospital. EB has a fellowship from ANR. We also thank the Région Rhône Alpes for the financial support of CT by an Emergence grant.


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Up Close With Marga Gomez (MLF)
The Commonwealth Club
Wednesday, August 27, 2014 from 12:00 PM to 1:15 PM (PDT)
Marga Gomez, Comedian; Playwright; Humorist; Twitter @margagomez
Join The Commonwealth Club for a lunchtime discussion with GLAAD award-winning comedian, writer, performer Marga Gomez as she prepares to bring her latest solo play "Lovebirds" to The Marsh Berkeley. Gomez is the author and performer of 10 solo plays that have been produced nationally and internationally. She teaches solo performance as a 2014 artist in residence at San Francisco's Brava Theater. Gomez is also a triple winner of the SF Bay Guardian's "Best Comedian" award and received Theatre LA's Ovation Award. She got her comedy start in San Francisco at the historic gay comedy clubs Valencia Rose and Josie's. Her television credits include HBO's "Comic Relief," Showtime's "Latino Laugh Festival" and LOGO's "One Night Stand Up." Gomez's acting credits include Off-Broadway and national productions of "The Vagina Monologues" and roles in Warner Bros films Sphere and Batman Forever.
Location: SF Club Office
Time: 11:30 a.m. check-in, noon program
Cost: $20 non-members, $8 members, $7 students (with valid ID)
Program organizer: Wes McGaughey
Also know: Photo by Steven Underhill
All ticket sales are final and nonrefundable.
The Commonwealth Club is the leading national forum open to all for the impartial discussion of public issues.
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