text:
For a limited time only, Pentland Jaguar in Edinburgh have a special offer on this stunning 17 model year F-Type convertible which is currently in stock.
As well as its 380PS 3.0 supercharged V6 with automatic transmission, this model features over £7,000 of optional extras including:
|Initial Payment
|Monthly Rentals
|Annual Mileage
|5,000 miles
|Total Contract Mileage
|25,000 miles
|Excess Mileage
|24.12p per mile
|Duration of Agreement
|60 months
For more information contact a member of the team at Pentland Jaguar Edinburgh using the button below.
Enjoy the thrill of driving a Jaguar, hassle free. Personal Contract Hire gives you an initial rental in advance of 1-12 months (subject to underwriting), regular rental fees and no worries about disposing of your car at the end of the contract. You can also choose the reassurance of various optional service, maintenance and repair packages.
Just choose your Jaguar, agree your annual mileage and your initial rental in advance and how many monthly rental payments (between 18 and 60) you prefer.
Then choose the right optional service, maintenance and repair package for you. Your rental fee is calculated based on your choices.
At the end of the term, the vehicle must be returned and you will have nothing further to pay provided the vehicle condition is in line with BVRLA guidelines and has not exceeded the agreed mileage. If the vehicle does not meet the mileage and condition terms excess charges will apply. Choose your next Jaguar (subject to status) and, subject to status, start again.
Terms and Conditions:
Based on an JAGUAR F-TYPE CONVERTIBLE 3.0 Supercharged V6 S Auto 17MY, 60 month term, 5,000 miles per annum, non-maintained. Contract Hire subject to status. Over 18's only. You will not own this vehicle. Must be returned in good condition to avoid further charges. Excess mileage charges at 24.12p per mile. The promotion cannot be used together with other manufacturer's promotion and is subject to availability at participating Retailers only for new vehicles ordered by 30th Apil 2017. Provided by Jaguar Contract Hire a trading style of Lex Autolease Limited, Heathside Park, Heathside Park Road, Stockport, SK3 0RB.


text:
Escape/ Live 1986-1988
The highly-acclaimed band Pablo Picasso was formed in 1981 and while active in Tokyo's punk/new-wave scene began releasing such albums as 'Soft Type' with the independent label Telegraph Records, until the band's demise in 1985. After that, leader and bassist Makoto Nomura embarked on a solo project called Pablo, and from 1986 to 1988 a fluctuating change in members made up this project. While Pablo Picasso's sound evolved under the influence of Tokyo Rockers~Friction, Pablo's sound evolved through it's talented members who, not being fixed in any one genre, could absorb a variety of musical characteristics, resulting in a sound that overflowed with originality. Beginning with Miles Davis\'s electric sound from the 1970's, Pablo took various genres such as rock, jazz, and funk and mixed them together into a fusion sound, or what they called 'borderless music'. With the new wave and hip hop movement of the 80's, and the likes of Material, and The Golden Palominos (Bill Laswell, Anton Fier...etc.) out of New York, more of a variety of elements were absorbed and incisively added to further expand on Pablo's sound. This CD was edited from five live recordings and one studio recording during the end of 1987 to the beginning of 1988 in which Tsuguhito Tsukada (guitar)(Mitsuru Sawamura's Mich Live, Hajime Tachibana, Shi-Shonen, Soft Ballet...etc.) participated. In addition, one song from a live recording in 1986 was added. Other members: Takeshi Shimizu (Pablo Picasso), Masayuki Kozuka (Pablo Picasso), Kenjirou Kihara (Bachikaburi, Nubile), Nao-Ken (Concretes), and Serigano (Friction) participated in the live dub mixing.
|Escape/ Live 1986-1988
|CD Baby
|Release Date:
|Product Type:
|Item #:

subset: commoncrawl


text:
Beachy waves are a no-brainer for summer! Before you hit the hay, simply braid damp hair in two low pigtail braids and tie the ends off with loose elastics. When you wake up the next day, undo the braids and shake your hair out. If necessary, lightly run a straightener over your strands to help reduce frizz.
Perfect for a day at the beach or a casual night out, a loose side braid is by far one of our favorite hairstyles for summer. To get the look, part your hair slightly to one side and prep strands with a great texturizing spray prior to braiding. Be sure to create your braid on the side with the most hair (this should be the side opposite your part). Secure the end with a clear elastic hair tie and finish off with a light-hold hairspray. For a messier look, pull strands out at random from your braid.
A messy topknot can take you straight from the pool to the red carpet. While this style does tend to work best on dirty strands, it can easily be achieved on clean locks as well. Start by pulling your hair up into a high ponytail. (Remember: It doesn't have to be perfect.) Spray your ponytail with a volumizing spray and use a teasing brush to create even more volume. Twist large sections randomly into a big bun, securing with bobby pins as you go. Top it off with a little hairspray, and you're ready to roll.
Trust us, a braided bun is a whole lot less complicated than it looks! Pull your hair back into a high ponytail to start. Then split your ponytail into three sections and braid down to the end as normal. Without tying off the end, twist your braid into the shape of a bun on top of your head. Now, grab some bobby pins to keep everything in place and tame any flyaways with hairspray.
Seeking a quick and cute updo for a night on the town? Throw dirty or clean hair up into a ponytail that sits at the middle-back of your head and use a medium-barrel curling iron to create haphazard curls throughout. Pull your ponytail tight, add a little hairspray and voilà — you'll be out the door in 10 minutes or less, guaranteed!.
Yep, seriously! In case you haven't noticed, all the cool girls are rocking beanies this summer. Pair yours with messy waves, cutoff shorts and a cute crop top for an enviable, street-worthy look.
For a braided bun that's larger than life, just use a teasing brush to build volume before braiding.
Cute ponytail holders that double as bracelets
The lazy gal's guide to summer beauty
What you should know about moles and melanoma
And you'll see personalized content just for you whenever you click the My Feed .
SheKnows is making some changes!
b e h e a r d !
Welcome to the new SheKnows Community,
where you can share your stories, ideas
and CONNECT with millions of women.Get Started


text:
Gently polishes and brightens skin
Revive, Repair & Defend
It started with one simple question: why can't healthy, natural skincare be high performance skincare?
Meet our dedicated team of experts who share tips on skincare, wellness, nutrition, and a life well lived.
For customer service or press inquiries, we'd love to hear from you.
Showing 6 Products
Detox Gentle Brightening Fizzy Powder Wash
Key ingredient: Omega 3
A powder-to-foam treatment wash for delicate skin
Perfect Cleanse Clarifying Cleansing Oil
Key ingredient: Passion Fruit Seed Oil
A superfood-rich oil-to-milk cleanser for face and eyes. Vegan, gluten-free and GMO-free.
Detox Brightening Fizzy Powder Wash
Key ingredient: Vitamin C
A brightening effervescent powder treatment wash
Perfect Cleanse Omega Cleansing Jelly
Key ingredient: Orange Extract
A transformative daily cleansing jelly that melts away face and eye makeup.
Purify Cleansing Wash
Key ingredient: Great Burnet Root Extract
A foaming cleanser that helps balance oily and combination skin
Perfect Cleanse Nourishing Cleansing Oil
Key ingredient: Meadowfoam Oil
All-natural cleansing oil for face and eyes


text:
Now that the economy has recovered to robust health and unemployment is back below 5%, the U.S. Senate has ample time and resources to spend investigating "The Power of Google: Serving Consumers or Threatening Competition?"
Sigh. Here we go again, more antitrust regulation as corporate welfare. The problem, you see, is that Google still refuses to change its algorithm to assure that all search results appear first.
That alternative view is that whatever Google's size, the Internet remains the Internet, searchable and indexable by technologies and strategies other than the ones launched by Sergey Brin and Larry Page in their Stanford dorm.
Furthermore, Google appears vulnerable, because the characteristics of searches to be conducted on tomorrow's Internet will not entirely resemble today's. You can drive a big Google Earth van through the hole to be opened up by future search-technology opportunities.
Even if Google weren't vulnerable, the right to compete should be ironclad in America. By stopping it, we undermine the inevitable, pro-consumer competitive responses to Google.
It wasn't all that long ago that many of us were locked in to the Yahoo and AltaVista search engines. This year, Microsoft has touted Bing's market share against Google. That's only Microsoft; It and other firms could create search alliances, should it come to that.
Upheaval is unpredictable. I remember back in 1997 when Bill Gates invested $150 million in Apple as a gesture "to strengthen Apple's viability."
Back when Microsoft was the Google of the day.
Today, Apple's market capitalization is $380 billion, higher even than Exxon-Mobil. Its value is $20 billion shy of Microsoft and Google combined.
Antitrust's crystal ball is cracked more than anyone else's. And antitrust the institution is ultimately more predatory and anti-consumer than transitory dominance inevitably battered by "creative destruction."
As corporate welfare, antitrust regulation forcibly "redistributes" customers earned by some businesses to other businesses who haven't earned them. Or, it forcibly bars future access to new customers by a dominant firm.
Antitrust is regulation, much like all the other anti-jobs regulation that congressional leadership is condemning.


text:
The cast may be from Hollywood, but much of the crew working the set of "The Details," starring Tobey Maguire and Laura Linney, is from Seattle.
And so are the lamp shades.
"I don't know if you believe in fate or destiny, but it was really funny, the way this all happened," said Dawn Bassett, owner of LiT lamp shades on Capitol Hill.
At the end of July, a woman responded to an ad Bassett had posted to sublet her home while she took a trip out of town. The woman, who couldn't sleep with all the noise around the apartment she was set up in in Belltown, was the set designer for "The Details."
They met at Bassett's shop.
"She said, 'Oh my God, the lamp shades are the last things we haven't gotten!'" Bassett recalled.
Later, Bassett got a tour of the Montlake set to see where the six or seven lamp shades she sold to the film ended up, weaving in and out of the mid-century modern interiors where characters played by Maguire, Linney and Elizabeth Banks will engage in domestic disputes with each other and a few mischievous raccoons.
"I'm trying to wrap my head around what it will be like to go see this movie and catch glimpses of these shades. A normal person watches movies and just watches movies. They don't notice the lamp shades. I always notice the lamp shades," she said.
"The Details" began shooting in a couple homes in Montlake Aug. 4 and was scheduled to film there through Aug. 25.
Bassett wrote a blog post about her tour of the "Details" set. Read it here.


text:
This page shows photographs from an open house at Peach Mountain Observatory (located near Dexter, Michigan).
This photo show an open house on July 7, 2007. Dave Snyder is setting up the traffic control system (actually just some traffic cones and sawhorses). Because the McMath was not operational, we had been asking people to park down the road from the place they usually park, and the barricades were needed to prevent cars from getting too close to where the telescopes were set up.
The Lowbrows are a member of the Night Sky Network (NSN). We are provided with various "toolkits" which demonstrate astronomical principles.
The photos above were taken later in the evening (also on July 7th), and show Dave Snyder using one of these toolkits, Shadows and Silhouettes. This particular demonstration shows the scale of the Earth/Moon system, the difference between a lunar and solar eclipse and why eclipses do not occur every month (see The Night Sky Network Info page for more information).


text:
Credit for my children's love of cornbread can be rightfully given to Mrs. Laura Ingalls Wilder. Yes, the author of the "Little House on the Prairie" series of books owns the right to my boys love of cornbread as well as other favorite pioneer dishes such as Baked Beans and Fresh Churned Butter (though I admit ours usually comes churned fresh from the Farmers Market or Whole Foods). If you haven't read the series of books yet with your children, do. We actually loved listening to the books-on-cd in the car on the way to and from school. My kids were given joy and a sense of wonder from tales of pioneer adventure, and I was given the gift of quiet contentment from the back seat. A win-win!
These classic tales of a simpler way of life, though certainly not easy, are inspiring on many levels for both girls and boys. Pa's strong presence in the stories, give boys a masculine look at those times, and the tales of Ma's cooking is a treasure everyone will love. We loved them so much we went out and found "The Little House Cookbook" by Barbara M. Walker. Working our way through that book has been a great compliment to the Laura Ingalls Wilder originals.
But as the prairies and horse-drawn wagons have been replaced by skyscrapers and sports cars, yet another casualty of modern day advancement is indeed — the Cornbread. Through the magic of marketing, we as consumers have been made to believe that boxed cornbread mixes are the easy, convenient way to go. Truth-be-told, homemade cornbread from scratch is equally quick, easy and definitely more delicious than it's boxed counterpart. This Cast Iron Skillet Buttermilk Cornbread recipe is chock-full of whole, real ingredients and bakes up crisp around the edges when made in a cast iron skillet. It's time to bring back the good 'ol days of Ma and her open fire, and take our families' meals back Out of the Box.
THE COMPARISON: BETTY CROCKER AUTHENTIC CORNBREAD & MUFFIN MIX vs. OUT OF THE BOX FOOD'S CAST IRON SKILLET BUTTERMILK CORNBREAD
(All ingredients followed by an * can be referenced at www.wikipedia.org by clicking on the ingredient)
**Note – "Enriched" just means the ingredient has been processed and stripped of it's nutrients, and then had the vitamins & minerals added back in (enriched) to meet appropriate standards.
Betty Crocker Authentic Cornbread & Muffin Mix
- enriched degermed yellow corn meal (niacin, iron, thiamin mononitrate, riboflavin, folic acid)**
- enriched flour bleached (wheat flour, niacin, iron, thiamin mononitrate, riboflavin, folic acid)**
- sugar
- corn syrup*
- leavening (baking soda, sodium aluminum phosphate)
- partially hydrogenated soybean oil and/or cottonseed oil*
- dextrose*
- salt
- modified corn starch
***All listed product ingredients are taken from product's package label. Though Out of the Box Food makes every effort to provide complete ingredient information, please check the package for the most current information.
Cast Iron Skillet Buttermilk Cornbread
Special Equipment: 10 " cast iron skillet
Time: 30 minutes
- 1 1/2 cup whole wheat pastry flour
- 2 cups cornmeal
- 1 Tbsp baking powder
- 1 tsp fine sea salt
- 2 1/2 cups buttermilk, well-shaken
- 4 large eggs, room temperature
- 2 Tbsp honey
- 2 Tbsp butter
To make in oven:
- Place skillet in oven, and preheat oven to 425 degrees
- In a medium bowl, whisk together flour, corn meal, baking powder and sea salt.
- In another medium bowl, beat eggs, then whisk in buttermilk and honey until combined.
- Add wet ingredients to dry and stir with a wooden spoon until just combined. (batter will be lumpy)
- Remove hot skillet from oven and add butter into the skillet to melt.
- Pour batter into skillet and return to oven
- Bake uncovered for 20-25 minutes.
To make over campfire:
- Prepare campfire coals.
- When coals are ready, top coals with a grill grate and place skillet on grate to preheat.
- In a medium bowl, whisk together flour, corn meal, baking powder and sea salt.
- In another medium bowl, beat eggs, then whisk in buttermilk and honey until combined.
- Add wet ingredients to dry and stir with a wooden spoon until just combined. (batter will be lumpy)
- Remove skillet from fire and add butter in skillet to melt.
- Pour in batter , cover with a lid and and place away from the coals on the grill grate – corn bread must be baked over indirect heat. Do not place skillet directly on top of coals.
- Bake covered over grill for 20-25 minutes – (check periodically to be sure not to burn)
Until next week…
© 2012, kimgerber. All rights reserved.


text:
Your shopping cart is empty
GST for SMEs
Published on 05 Nov 2014 | Took place at City West Receptions, West Perth, WA
The GST affects all aspects of a SME's operations, transaction by transaction. In the vast majority of cases, the GST will have a straightforward and neutral effect for businesses. The GST collected from customers will be remitted to the ATO and the GST paid to suppliers will be claimed as input tax credits. However, in a minority of cases, the GST can be complex and a significant cost if not managed proactively.
This event provided attendees with the tools needed to first identify potential problems and then manage these towards a solution. This included straightforward practical tips which can save both SMEs and their advisors significant costs and stress in this specialist area.
Individual sessions
GST for SMEs
Tim Martino
This paper covers:
Materials from this session:
This paper covers:


text:
Magento 2.2 Developer Documentation
Everything you need to build and manage a customized Magento store.
Backend Development
Frontend Development
Release Information
Video Tutorials
Seeing is believing! Our developers sharing their knowledge of Magento. Subscribe to our YouTube channel and never miss new tutorial.
Top Recent Contributors
Our documentation is open-source on GitHub. Even the smallest of edits are appreciated, as are enhancements and clarifications to our existing content. We love when we get complete new topics from our community members! Below are our top quarterly contributors. See all quarterly contributors.
Valerij Ivashchenko
Magento Developer
Douglas Radburn
Pinpoint Designs
Chris Pook
Absolute Commerce Ltd
Ihor Sviziev
VEN Commerce Ltd


text:
21 Aug 2013
OH MY GLOB OH MY GLOB OH MY GLOB ... I was at an NFL Network event on Wednesday, and they announced that the all-22 film on NFL Game Rewind will now be high-definition. That's right: no more blurry little guys on a grainy background. Nerdquake! Nerdquake!
17 comments, Last at 11 Dec 2013, 5:05am by jono620
In case you're wondering why I love this site, the part where you open a brief about the usability of coaches' film with an Adventure Time reference is pretty high up there.
Adventure Time rocks.
The man with no sig
Now and then I'll stumble across a post like this and I'll recall that there really are still interesting pages on the web. ^_^red bottom shoes.
And charting just got a little bit easier =D
Also, totally deserving of all caps.
Will this make it possible to figure out who's on the field for each play?
What's the logistics on viewing the All-22 film? Simple as find it on NFL.com, or is there some login procedure or something? Is it all games? Just select games? All of the games? Just select plays?
It comes up as an option while watching a game on NFL Rewind. If I recall correctly, it's all games, all plays. NFL Rewind is really great, the one thing I wish it did was allow you to switch back and forth between the full broadcast and condensed versions and coaches film without losing your place in the game.
Yes, it's now all games and plays. IIRC, prior to 2012, it was only for certain plays.
You're actually supposed to be able to switch back and forth without issue, and most of the time, it works for me ... but you do get bumped back to the opening kickoff far too often, and just as bad, the bookmarks for individual plays aren't always set correctly, so it can be quite a chore to get back to the play you were watching. (The latter seems to be a game-by-game issue; some games are bookmarked just fine and others have entire quarters messed up.)
Coaches film was tough to watch w/out it
Hopefully this year they will let the Game Rewind app for iPad play on the TV. annoying that it doesn't allow it.
If you can get your feet going again as he's widening himself out, you end up creating a big hole just inside of you. Let's go to the tape again to see what I'm talking about.
Cool film online-essay-writer.org I like it a lot.
Thanks for sharing such useful information. online-essay-writer.org I'll recommend it to others!
Nice effort, very informative, http://www.masterpapers.com/ this will help me to complete my task. Thanks for share it keep it up.
I think you will forget my good, through strange the corner of the street. You use uniform skirt is placed, and I said the firm goodbye.
This is promising but I don't seem to have it yet. I also wish they would show the high end zone view from both sides of the field.
UCLA's quarterback clearly has the talent to succeed as an NFL starter. The question is whether or not he can avoid enough mistakes to become a superstar.


text:
Jose Mourinho could be without Hazard for their match against Atlético Madrid after the Chelsea midfielder missed training ahead of their Champions League semi-final
Chelsea could be without Eden Hazard for their Champions League semi-final first leg match with Atlético Madrid on Tuesday night, after the Belgian attacking midfielder missed a training session at their training ground before the trip to the Vicente Calderón. Hazard was included in a squad of 20 who travelled to Spain
The Belgium midfielder has been sidelined since suffering a calf injury in the second-leg of the quarter-final win over Paris Saint-Germain, but the Blues remain hopeful that arguably their player of the season, recovers in time for the important and tough semi final match. The London side sits five points behind leaders Liverpool in the Premier League and thus,the Champions League becomes a more plausible shot at a trophy this season and Hazard's absence against in-form Atlético will be a heavy blow to Mourinho.
For him to be in contention for the match, he would obviously need to train with his team and him missing the training only raises further doubts over his participation in the match. Assistant coach Steve Holland admitted the possibility of the Belgian not playing the match.
"To be considered, he obviously needs to train with the group very quickly," said Holland. "It's a day-by-day one at the moment."
Striker Samuel Eto'o was not included in the 20 man squad, due to a knee injury, which gives Jose Mourinho an option of starting former Atletico star Fernando Torres, against his old club. Demba Ba, who has been in good form since his winning goal in the second leg of the quarter final against PSG, of course, remains the other option for the Portuguese boss
Branislav Ivanovic can't play the match because of suspension, which means that César Azpilicueta could be switched from left-back to right-back and Ashley Cole could return. The other possibility is that David Luiz could be fielded at right-back and Azpilicueta would continue on the left. However, with Matic being ruled out (having played for Benfica earlier in the competition), the possibility of Luiz playing a little in front, as a midfielder, is higher.
Mohamed Salah is the other Chelsea player who will be ineligible for the match, as he has represented Swiss team Basel earlier in the competition.
Chelsea will be boosted with the return of Petr Cech,who missed Saturday's 'controversial' Premier League home loss to Sunderland through illness as he trained with the rest of the squad, normally.


text:
Watch The Christmas Switch Online Free 2014 Putlocker
Posted by Putlocker Under Family
Watch The Christmas Switch Online – Free Streaming 2014 Full Movie HD on Putlocker and 123movies. Through Eddie's wit and guile, he gives Sam that last night and finally finds the real meaning of Christmas the gambler's way.
Ver 2:
Ver 2:
Ver 3:
Processing your request, Please wait....


text:
Ask a Computer Question, Get an Answer ASAP!
Click on the date/time on your system tray (at the bottom-right), then make sure that the date (including year) and time are set correctly. If not, click 'Change date and time settings', then change the date and time to the correct settings accordingly.
Done that, check if this resolves the issue you are having with accessing Yahoo Mail. If you continue to face issues, just reply back to me below.Keep me posted. Thank you!
yes the moment I press open mcaffee site advisor stops me doing anything else
Click the following link:
Save and run the 'TeamViewer' file downloaded - and you will be provided with an ID and password.Keep the TeamViewer window open, and reply back to me with the ID and password, please. Thanks!
that has not worked eithere
no that aint worked
no nothing
got stuck at this point
no that's not worked
come up this page cannot be displayed


text:
This is a reader-submitted post written as part of the "I'm leaving" feature running while Kristi Gustafson, blog moderator and author, is out of the office.
The post is not written by Kristi Gustafson. Lisa Huerter is the author.
I love a good book. When I was younger, I loved to read Judy Blume. Her books were perfect for my age group, I would spend hours in my room (my father used to joke with me, calling it my dungeon), I would immerse myself in the characters world, almost as if I was becoming that person. I've always had a very active imagination and books fed that for me.
As I matured, so did my reading choices. I'm now a fan of Sandra Brown, Candace Bushnell and Debbie Macomber. Reading has become my escape. When I have gone through difficult times or if I'm having a bad day, I would pick up my latest read, cherishing the opportunity to escape everything around me, even if only for a little while. It's always been like a warm, comforting place for me to go. When I'm getting ready to take a vacation, selecting what books I'll bring is one of the highlights of my trip!
The books I've most enjoyed have usually been mysteries or coming of age stories, nothing sad or upsetting, no scary Stephen King novels for me. Whatever the story is though, I love the details. The description of whatever they are experiencing, through the characters eyes, helps to enhance what I already "see" in my mind's eye. That's my absolute favorite part. I've even been known to re-read descriptions, to make sure that I have an accurate picture in my mind of what the character is experiencing.
So no matter how crazy life gets, I love being able to dig into my bag and pull out my latest read. It really is a great escape from whatever life throws at you. Happy reading!!


text:
What was a fairy tale run for Rogers High's girls basketball team came to an abrupt end Saturday in a Class 4A regional at Juanita High as the Rams fell to Eastlake, 75-35.
"I think we always believed in ourselves," Rogers head coach Amy Looker said of the late season rally that saw the SPSL South's third-place team reach the bi-district semifinals. "I don't think a lot of outside people believed in us, but they just kept working hard every day at practice to make each other better. And we just kind of got better at the right time, at the end."
However, in the end, it wasn't enough as the harsh reality check on the Cinderella story was provided by Eastlake (15-9). Behind a barrage of 3-pointers, the Wolves dismantled the Rams.
The Rams (13-12) couldn't recover from a second quarter that saw them be outscored 22-4. The lone field goal Rogers made in the quarter came on a fastbreak layup by Mackenzie Lancaster at the buzzer.
Although Looker acknowledged Eastlake played very well, the loss wasn't the hardest part of the night.
"It was tough," Looker said. "These tears are not about that loss. This is tears that we all have are because of our team and we don't get to play with those seniors again. But as far as Eastlake, they're a very good basketball team. They're very fast and very physical. They did a great job today."
Senior guard Jordan Asher was a big part of Rogers' late-season success. Asher scored a team-high 10 points, three assists and a steal against Eastlake.
"Jordan has been our starting point guard and never has missed a game in three years," said Looker, tearing up. "She's like my right hand … on the floor. So, it will be hard to see her go."
Eastlake's Bella Zennan scored 15 and Caleigh McCabe finished with 14 points.
No. 3 Woodinville 59, Emerald Ridge 47: The KingCo champions ended the Jaguars' season in the other regional at Juanita High.
Despite playing with a broken hand, guard Taylor Buie scored 27 points for Emerald Ridge (19-6). Buie scored all but three points in the second half.
Woodinville's forward Ali Forde racked up 12 points, 18 rebounds and eight blocks.
— Chris Wells, contributing writer


text:
Benin troops ready to join anti-Boko Haram Task Force
Benin is to deploy 150 troops to a West African regional military force established to fight Boko Haram insurgents.
Officially known as the Multinational Joint Task Force (MNJTF), it comprises troops from Nigeria, Chad, Niger and Cameroon.
The Benin Minister of Defence, Yarou Robert Theophile, has already held consultations with political and military authorities of the troop contributing countries, according to MNJTF spokesman Colonel Mohammed Dole.
The Benin minister had also met with the commander of the Task Force, Major-General Lamidi Adeosun, and visited troops deployed in all the sectors where he assessed their immediate logistics and operational requirements.
The MNJTF is headquartered in the Chadian capital, N'Djamena.
Col. Dole said arrangements have been made for the provision of office living and accommodation for the Benin contingent.
The Benin troops are expected to perform garrison duties, provide escort and security for humanitarian operations, protect VIPs, and also serve as a reserve force for quick intervention when necessary.
Mr Theophile told the Task Force commander that the initial delay in Benin's deployment was due to some logistics and equipment challenges, which had since been corrected.
The first batch of the 150-man contingent will be deployed in N'Djamena before the end of April 2016, he assured.


text:
A man seriously injured in a fire near Soldotna last week in recovering.
Angeline Stewart, owner of a property at 36055 Greenridge St. outside of Soldotna that was ravaged by fire on Thursday, confirmed that Gerald Terp, 55, was the unidentified man who was airlifted to Seattle's Harborview Burn Center.
Stewart said on Monday that Terp was in "good condition," but had suffered serious burns on his left foot, right hand as well as to his lungs.
"There's a lot of unknowns," she said.
Stewart's age in the story published in Friday's Clarion was incorrectly reported by fire officials. Stewart is 47 years old.
© 2018. All Rights Reserved. | Contact Us


text:
RISE Academy Volunteers
39.53883, -119.807976)
Cause Areas
WhenIt's flexible! We'll work with your schedule.
Where494 Poplar StReno, NV 89512
Volunteers are needed in supporting adults in the Washoe County area to achieve an adult high school diploma, learn more English, and/or to obtain a high school equivalency. Tutoring and mentoring are needed for adults that are in one of the six programs available. The six program that all lead to an adult high school diploma, if one chooses, are:
- Adult High School Diploma
- Distance Education (to receive credits towards an adult high school diploma)
- HSE - High School Equivalency Test Preparation Courses and Testing
- ELL - English Language Learner Program for adults wanting to improve their English skills
- ABE -Adult Basic Education for adults to improve their literacy and numeracy skills
- High School Proficiency Exam Test Preparation Courses and Testing
- General Education
Good Match For
Teens People 55+ Group
Requirements & Commitment
- Background Check
- Must be at least 18


text:
Our SUSTAINABILITY Story
Certification to a national standard by a third-party, independent certifier enables flooring manufacturers to demonstrate their commitment to sustainability.Learn More
Meeting the stringent requirements for healthy indoor air quality through a voluntary, independent certification program.Learn More
The label that discloses the life-cycle, environmental impacts of products and services addressing the need for clear, credible, third-party certified information.Learn More
The label that discloses product ingredients and associated exposure risks.Learn More
Knowledge Center
What makes resilient flooring such a popular choice? What are the best practices for installing hard surface flooring in residential and commercial properties? What about floor maintenance? What are top designers and fresh thinkers doing with resilient flooring today?Learn More
Sustainability Center
What impacts do resilient flooring products such as vinyl, linoleum, and rubber have on the environment? How can resilient floors contribute to sustainability? How are flooring manufacturers addressing issues such as Indoor Air Quality, VOC emissions, and recycling?Learn More
News Center
What's happening at RFCI? What are industry thought leaders saying about vinyl, linoleum, and other resilient flooring products? What new trends are emerging in the residential and commercial flooring industries?
EPA Recommends Specifying Resilient Flooring with FloorScore & NSF 332
California Prop 65 Declares Ortho-Phthalate Plasticizer DINP Safe for Vinyl FlooringLearn More


text:
Our restaurant critics' picks of the latest and best eats around the country this week including Sagra, Lee Ho Fook, Statler & Waldorf, and Walk the Talk Kitchen.
In Italy, a sagra is a small festival, a bit like a country fair, often dedicated to a single ingredient. In Darlinghurst, though, Sagra is a small restaurant dedicated to celebrating simple, honest Italian food. There's talent from Sean's Panaroma in the kitchen, which makes for admirable focus on the plate, while Lucio's also figures in the restaurant's DNA, which goes some of the way to explaining the intelligence of the short, all-Italian wine list and the charm of the service. If you like your Italian food to impress through the quality of the ingredients the kitchen chooses and the care with which they're deployed rather than modernist flourishes, this is the restaurant for you. Spaghetti a la sarde comes present and correct, the sardines melting into a ragù peppered with currants and pine nuts, while the keen balance between buttery tagliatelle and violetta artichokes (pictured above) makes a virtue of restraint. It's the neighbourhood Italian that Stanley Street has been missing. Sagra, 62 Stanley St, Darlinghurst, NSW, (02) 8307 0430. PAT NOURSE
Lee Ho Fook
Victor Liong's CV includes positions at a couple of Sydney's finest - Marque and Mr Wong - and, while traces of those restaurants may be visible in his work to those who like to get forensic, Lee Ho Fook forges its own path. It's tricky to slap a label on what Liong - in partnership with Peter Bartholomew and David Mackintosh (MoVida, Pei Modern, etc) - is doing at his Smith Street diner. Modern Chinese? European with a Chinese accent? Modern Australian? Best to just tuck in, especially the snappy soy custard with hot and sour sauce, a salad that teams raw ocean trout with wonderfully textured jellyfish, or the inevitable burger/slider: a milk bun stuffed with candied pork and cucumber. The room (French wine bar Boire in an earlier incarnation) has clean, simple lines, the perfect backdrop for Liong's intriguing flavours. Lee Ho Fook, 92 Smith St, Collingwood, Vic, (03) 9077 6261. MICHAEL HARDEN
Statler and Waldorf
Drinkers, Statler and Waldorf has you covered. Fancy some school prawns with your pint of Brisbane-made Fortitude Original Golden Ale? Here they are, all crisp and correct, in an earthenware pot with chervil mayo on the side. How about a handsome ploughman's, delivering fat slices of brisket with a blue-cheese wedge and crunchy house-made pickles? It's all yours. The interiors here are suitably gastropub-simple - think low-stress bare brick walls and wooden boards. And co-owners Jay Lambert and Steve McDermott (formerly of The Bowery) know their way around a bar. No heckles from this balcony. Caxton Street is looking up. Statler and Waldorf, 25 Caxton St, Brisbane, Qld, (07) 3368 1932. FIONA DONNELLY
Walk the Talk Kitchen + Catering
Ali Seedsman has been a favourite chef of Michael Hill Smith since she was head chef at the kitchen of his Universal Wine Bar in Adelaide, and then catered events at his Shaw + Smith winery in the Adelaide Hills. Smith is now a regular at her modest café in the nearby Hills hamlet of Verdun, where she's happy doing simple, inexpensive soups, snacks and lunch plates with big flavours. Open Tuesday to Friday for breakfast and lunch, the café has a menu that changes weekly, "I'm doing whatever I feel like, really," Seedsman says. This translates to the likes of pan-fried ocean trout with coconut dhal and spiced yoghurt, or chicken and prawn laksa. There are good local wines by the glass and ample outdoor seating for when the weather is fine, but if you want takeaway meals, it's smart to phone ahead and request them early - these dishes don't wait around for anybody. Walk the Talk Kitchen + Catering, 25 Onkaparinga Valley Rd, Verdun, SA, (08) 8388 7344. DAVID SLY
Got a hot tip for our Hot Plates team? Tweet us at @gourmettweets, or tag your Instagram photos with #GThotplates.


text:
News and Rumors
Tony Watson Loses Arbitration Case to Pirates
News and Rumors
The Pittsburgh Pirates and closer Tony Watson had a hearing on Wednesday in front of a three member panel of arbitrators to decide his 2017 salary. Watson was asking for $6 M for this season, while the Pirates offered him $5.6 M. According to Jon Heyman, the Pirates won their case. The Pirates are one of numerous file-and-trial teams, which means they stop negotiating once the player has filed for arbitration. They settled with the other five arbitration-eligible players before the deadline to file on January 13th, leaving Watson as the lone player to go to a hearing for the Pirates.
In his last year before free agency, Watson was looking for a substantial raise over the $3.45 M he made last year in a down season. Taking over the closer role after Mark Melancon was dealt at the trade de...
To continue reading the rest of this article, subscribe to Pirates Prospects. Subscribers get access to every article on the site, along with all of our exclusive live coverage of the Pirates' minor league system, all for a very low monthly or yearly rate.
If you're already a member, you can log in below. If you think you're receiving this message in error, please e-mail firstname.lastname@example.com.
John was born in Kearny, NJ, hometown of the 2B for the Pirates 1909 World Championship team, Dots Miller. In fact they have some of the same relatives in common, so it was only natural for him to become a lifelong Pirates fan. Before joining Pirates Prospects in July 2010, John had written numerous articles on the history of baseball while also releasing his own book and co-authoring another on the history of the game. He writes a weekly article on Pirates history for the site, has already interviewed many of the current minor leaguers with many more on the way and follows the foreign minor league teams very closely for the site. John also provides in person game reports of the West Virginia Power and Altoona Curve.


text:
Thoughts turn today to Kenny Dalglish's last involvement in a Merseyside derby at Goodison Park. That was, of course, the famous 4-4 draw in the fifth round of the FA Cup in 1991. Less than 48 hours after the final whistle, Kenny was gone, the aftermath of the Hillsborough disaster finally taking its terrible toll. His departure signalled the end of an era for Liverpool. Everton, too, were on their way down from the heights of the 1980s, during which the pair had taken turns to be the best team in the land. That seems a long time ago now, as Louise Taylor reports.
But while the glory days have gone, the Merseyside derby has continued to deliver, the most consistently entertaining stramash in English football. Goals, red cards, thundering challenges, last-minute winners, outrageous tackles, penalties, kicks, stamps, slaps, fistfights, refereeing controversies, goalkeeping calamities, simulations of decadent nights hoovering up the jazz salt: there's usually something for everyone.
Today's brouhaha begins at: 12.45pm.
Louis Saha makes his first start of the season for Everton, who relegate captain Phil Neville to the bench: Everton: Howard, Hibbert, Jagielka, Distin, Baines, Coleman,
Fellaini, Rodwell, Osman, Cahill, Saha.
Subs: Mucha, Bilyaletdinov, Drenthe, Stracqualursi, Neville, Barkley, Vellios.
Liverpool drop Jordan Henderson for the first time in the league this season: Reina, Kelly, Carragher, Skrtel, Jose Enrique, Kuyt, Lucas, Adam, Downing, Suarez, Carroll.
Subs: Doni, Gerrard, Henderson, Coates, Spearing, Flanagan, Bellamy.
Referee: Martin Atkinson (W Yorkshire)
While we wait: Why not take a trip down memory lane with this week's Merseyside-derby-related Joy of Six?
There's a rare old atmosphere in this famous old stadium as the teams trot out:
Not everyone's anticipating a good time, though. "Hoping Liverpool thrash Everton and Moyes resigns (at last)," writes the chirpy Martin Alastair Cooke. "And I follow Everton but do not support the current regime. Moyes and Kenwright OUT OUT OUT."
And we're off! Everton get the 216th Merseyside derby underway. Suarez takes a long ball down well, then feeds the ball out wide left to Downing, who is immediately checked illegally by the oft-clumsy Hibbert. Liverpool try to work a clever free kick into the area, but don't do a very good job of it. A bright start by the Reds, though.
3 min: "Completely unrelated to anything particularly football-esque, but I was wondering who is that fine specimen of a player with the luxurious afro currently blinding my dazzled eyes on your frontpage?" asks Rhea Libert. "Clearly I am not an Everton supporter, but I may have just found the love of my life. Assistance in naming him would be greatly appreciated." That'll be Marouane Fellaini, Rhea, happy to send a little happiness and romance into this big, cruel world. And your man has just seen a shot deflected wide right of goal from the edge of the Liverpool box, after a spot of head tennis. The resulting corner by Baines is well claimed by Reina.
5 min: It's high-tempo nonsense at the moment, Suarez trying unsuccessfully to zip past Coleman down the left, Rodwell attempting much the same down the other flank for Everton. Nothing's coming off yet.
7 min: Suarez toe-pokes a ball out left to Downing, who has space to move forward towards the box. Suarez has peeled off into the centre, screaming for an instant return. Downing tries to find his team-mate, but his low cross carries too much weight and evades Suarez. That was nearly a beautifully worked goal, Everton prized open with a sudden pop.
9 min: Jagielka gets himself into all sorts of bother, slicing a clearance down the Liverpool left, level with his six-yard box. Kuyt picks up the loose ball on the byline. He dinks a cross to the far post, where Suarez heads straight at Howard. What a chance!
10 min: Everton go straight down the other end, Coleman swinging a ball into the area from the right to the far post, where Cahill tries to guide a looping header over Reina and into the top-right corner. Reina tips over the bar. After a couple of corners, Distin makes himself a bit of room in the right-hand corner of the box and attempts to curl a shot into the top left, but gets a wee bit too much on it. Lovely footwork from the defender, though. This is a really nice, bright, open start to the game, both teams seemingly in the mood to attack.
14 min: Saha, cutting inside from the right, hits a gorgeous left-footed fizzer towards the bottom-left corner. Reina would have been beaten, but the clever shot doesn't quite curl back in and sails out of play past the far post. "Sorry Martin Alastair Cooke, but Moyes AND Kenwright out out out?" bubbles Sean Boiling. You can't have your cake and eat it too. Pick one or the other. My suggestion, ditch Bill, keep Dave."
17 min: A couple of corners to Everton down the left. Another period of head tennis. Coleman has a whack from the edge of the area, but the ball's charged down. Carroll hacks clear, lumping the ball into the stand down the left, much to the amusement of the home crowd, who refer to the big man's price tag in song. "I can only imagine Martin Alastair Cooke wants a return to the pre-Moyes glory days of the Walker-Royle-Smith era," begins Michael West, "when winning games was of inferior importance to whether Duncan Ferguson was able to manage an hour's walk around a football pitch or not. And Brett Angell. And Marc Hottiger. And Preki."
20 min: After a bright start, Liverpool aren't putting many passes together. Kelly tries to get something moving down the right, but once he nears the byline, shanks his cross straight into the crowd behind.
23 min: RED CARD!!! Jack Rodwell is sent packing for a challenge on Luis Suarez. He went in studs up with his left boot, the tackle a wee bit clumsy, but though he clipped Suarez - who goes down in great pain - it really didn't look that out of control or dangerous. A yellow wouldn't have been an outrage, especially as the game's been played in a good spirit so far. Rodwell is beside himself with rage, and looks like he's going to refuse to leave the field. Luckily for him, Adam is also beside the two Rodwells, and ushers the young man off the pitch before he can get in the referee's face.
27 min: Cahill is booked for a high studs-up clip on Adam. The Goodison crowd are incandescent. Incidentally, upon departing, Rodwell hoofed a bottle down the tunnel with mighty force. He's not a happy lad. "Even Fellaini has female admirers?" splutters Morten Nutzein. "I'm going to put on my best tie and shoes, shave my face and hit Oslo once Liverpool win!" You talk about the tie and shoes as though they're a matching set. Are they matching tie and shoes?
30 min: Liverpool are pinning Everton back at the moment, though not causing the home side any great problems near the goal. Suarez is, as you'd imagine for his part in the sending off, getting pelters from the Everton faithful. "Bill Kenwright may invite criticism but I'd rather him than an oligarch, a sheikh or a American looking to expand their sports brand business," writes Gary Naylor. "Sure it means that we don't challenge for the big trophies, but at least the club feels like ours. And that'll do for me."
33 min: Kelly slides a ball towards Suarez, who races into the area down the inside-right channel and lashes a shot into the side netting from a tight angle. "In the rush to praise Suarez's many qualities, I would suggest that the less appealing side of his approach has been ignored, and that was a prime example," writes David Hopkins. "Did he really need to go down in that fashion after Rodwell's challenge?" It's fair to say he went down very easily, but a player exaggerating an injury is hardly news; the fault here is surely with the referee, who obviously thought Rodwell went in with both feet off the ground, but was sorely mistaken.
37 min: Everton can't get anything going up front. Liverpool keep coming back at them. Hunky Fellaini slides in on Lucas, flipping him into the air 25 yards from goal, just to the right of the D. Adam hits the free kick straight into the wall, then Carroll steps on the ball and falls over. Oh dear. Anyway, that red card. "One of the worst decisions you'll see all season and has spoilt what was shaping up to be a good game," sighs Robin Ashford, who is not far wrong.
40 min: "You're not fit to referee," holler the Goodison crowd. Everton, to a man, aren't in a good place. Baines lofts a long free kick to Fellaini down the right. The ball clearly bounces out of play for a goal kick, but Fellaini gives the linesman a mouthful anyway. You can understand Everton's frustration, but they need to calm down for their own good. Meanwhile here's a Prophecy Warning from Joe Pearson of Indianapolis: "A red card coming for Liverpool in the second half. As we call it over here: make-up call. Maybe you call it that over there, too?"
43 min: PENALTY FOR LIVERPOOL! Suarez, his back to goal in the left-hand corner of the Everton box, is upended by Jagielka, who comes straight through him. That was a perfectly good decision, a very clumsy challenge. The fact that it's Suarez who's gone down has, obviously, not gone down terribly well with the home fans.
44 min: PENALTY MISSED! Kuyt looks to sidefoot into the bottom-right corner. Howard goes the right way and palms round the post. Brilliant save! Although a very poor penalty kick, nowhere near the corner and very weak indeed.
45 min: Liverpool hit the crossbar! Adam picks the ball up down the inside-left channel, and unleashes a screamer towards the top-right corner. The ball batters off the woodwork, down and out! What a shot. Howard was stretching at full length, and still got nowhere near it. "No, Suarez didn't have to go down like that, but it's not like the Everton players haven't been acting theatrical after Liverpool challenges, because they have," counters Andrew Lavender. "It's not Suarez's fault Martin Atkinson is a rubbish referee."
HALF TIME: Everton 0-0 Liverpool Well, that was really cooking up towards the end of the half. Everton will be glad to hear the whistle, allowing them some time to regroup. Liverpool will go in frustrated, having missed a penalty and unluckily hit the bar. But then they've not unjustly had a man sent off, so it's swings and roundabouts. As for Morten Nutzein's matching tie and shoes set: "My favourite tie is made of red wool and obviously I always wear red socks because I am a Liverpool supporter. However my best tie is resting at my dry cleaner because I threw up on it on my birthday."
HALF-TIME ADVERTISING BREAK (starring Everton's greatest-ever supporter):
"Ah, Melissa, darling..."
More on the Rodwell incident: Having seen it again a few times now, two more points. First, Rodwell got to the ball, poking it out of the way, and by the time he made contact with Suarez his studs were no longer showing. It was never a red card in a million years, and probably not even a foul. As for Suarez: he went down under the challenge looking for the free kick, yes, but didn't do a great deal of rolling around: he had barely fallen onto his back before Martin Atkinson hoved into view waving the red card. The striker had little or no influence on it whatsoever. You might not agree with his tendency to hit the floor, but to concentrate on that would be to miss the point: this one's all down to the referee's interpretation of the challenge, which was simply incorrect. Here's a nice suggestion, though, from Simon Frank: "Wouldn't it be nice if the fouled player could rescind the red card? Last time I checked, professional sport was still sport, that is, a recreational activity for pleasure. As in, 'be a good sport'. Football must be a great game if we still watch it in spite of all the cheating and faking and lying that goes on."
And we're off again! This could be a very interesting 45 minutes. No changes. "Superb penalty save from Tim Howard but why is he dressed like one of Public Enemy's dancers?" asks Doctor Alimantado, of the camouflaged Everton goalkeeper. "Fear of a Scouse Planet?"
47 min: Kelly cuts inside from the right and hits a very weak low effort towards Howard, who collects without fuss. "As far as I'm concerned, a player has the right to make as much or as little of a foul - and it was a foul - as he wants," writes Michael Wood. "It's not up to Suarez what decision the referee makes, if Atkinson is weak enough to act upon Suarez's reaction rather than the tackle, then it's the officiating that is the problem. The whole issue of players trying to 'get a fellow professional sent off' is futile. These guys want to win and good luck to them."
49 min: Carroll has done bugger all so far. Liverpool slide a couple of pretty triangles together down the left, but as soon as Suarez slips the ball to his strike partner, the move breaks down as he miscontrols. "The thing about those Cinzano ads was that they boosted sales of Martini no end," writes Chris Barraclough. "People loved the ads but went out and bought the wrong brand."
50 min: Lucas is booked for sliding in late on Saha, who was looking to advance into space towards the Liverpool area. Ironic cheers? You want 'em, Goodison's got 'em.
52 min: Everton haven't come out just to make up the numbers (which they can't do anyway). From the right, Fellaini slips the ball to Saha by the D, who screws a low shot wide right. A decent effort under pressure from the Liverpool defence. "Maybe the camo is to lure Liverpool into thinking Tim Howard is really small (in this case just a floating head) and so they don't really have to shoot all that hard to score," suggests David Flynn. "It certainly seems to have fooled Kuyt."
53 min: Corner for Liverpool down the right. It's sent to the far post, where Carroll heads powerfully goalwards from ten yards. It's a very decent effort towards the bottom right, but Saha gets in the way to block with a flying lunge. Excellent play all round.
54 min: Carroll gets his head on another corner, not so strongly this time. It's bundled out of play. Howard claims the resulting set piece to ease the pressure on Everton. "Simon Frank is perhaps confused," suggests Justin Horton. "A 'recreational activity for pleasure' is by no means a sport, even though it may be a game (though it may not). Moreover there's a very strong case for saying that the point at which such games become 'sport', though, is the point at which 'pleasure' ceases to be the most important thing about them. People might say 'be a good sport': but they don't say 'it's only a sport'. Sport is where it gets serious."
57 min: Lucas has a swish from 30 yards. It flies about 30 yards wide right. "This match, over the years, has been brutal in terms of thuggery and cards," suggests Alistair Elder. "Clearly the Old Firm have to up their game. Alas another case of the EPL leaving the SPL behind."
59 min: A change for Everton: Coleman is replaced by Drenthe. Meanwhile here's more from our man about Oslo town, our MBM playboy, Morten Nutzein: "This game has cheered me up. I was out at Restaurant Eik last night and I fell down in the toilet because the floor was wet with piss. I am not having a good weekend."
61 min: A blistering shot from 30 yards by Saha, the ball flying only just wide left of Reina's goal. The keeper goes ballistic at his defence, who allowed the striker all the time in the world to turn.
63 min: Everton are beginning to believe they can get something from this game. Cahill brushes Jose Enrique off the ball and bombs down the right. He hits a long ball to Saha, who makes a right pest of himself, Skrtel and Carragher needing to pair up to ensure he doesn't win possession in the Liverpool area. "In fairness to Martin Atkinson, he was just evening the game up," argues Niall Mullen. "Blue ten against red ten (and Carroll). At least Everton's absentee can't get in the way."
66 min: Liverpool are beginning to get frustrated, pumping long balls up to Suarez, so they make a double change: Downing and Adam off, Bellamy and Gerrard on. Meanwhile here's Simon Frank coming straight back at Justin Horton: "Call me an epicurian then. Right, I'm off to drink some Pouilly-Fuissé and watch Brazil 1982."
69 min: Gerrard's first act is to swing a free kick into the Everton area from deep position on the right. Suarez gets his head to it at the far post, eight yards out, but can't keep his effort down.
70 min: A second change for the home side: Osman is replaced by Neville.
71 min: Hibbert crosses into the six-yard box from the right. Saha is exceptionally close to winning a header, but Carragher heads clear. Chris 'Scratch' Thomson would like to continue with the Public Enemy theme, if one email can be classified as such: "I don't know if if 911 is still a joke but in Liverpool's case 9 is a joke."
72 min: GOAL!!! Everton 0-1 Liverpool. A £35m joke? Not so much now. Bellamy tears down the left, reaches the byline, and pulls the ball back into the centre. Kuyt dives under it, aware that Carroll is standing behind him, six yards out and unmarked. He skelps a low shot straight into the bottom-right corner. He couldn't miss, but you could sense a lot of frustration put into that.
73 min: Everton come straight back at Liverpool, Saha getting a shot on target from the inside-right position, 25 yards out. But Reina is behind it all the way, and holds it to his chest.
76 min: From a central position 30 yards out, Gerrard teases a cross towards Carroll at the left-hand post. Howard comes out to claw the ball behind for a corner. The resulting set piece is a complete waste of everyone's time. Morten Nutzein, who may or may not be a fictional character whose antics are based on the nocturnal jaunts of today's goalscorer, is back: "I must stress that that was not my piss but someone else's. I fell and I sat in it but Eik is a great restaurant usually. Jesus am I tired. A girl rang to say I am cool so thanks!"
78 min: Suarez finds Bellamy in acres of space down the left, but with both Suarez and Kuyt waiting in the centre, Bellamy's resulting cross goes straight down the throat of Howard. "Saying that the players have the right to simulate and the referees should cope is akin to saying that fraud is only fraud if you get caught," argues Gary Naylor. "That's the kind of amoral spiral that leaves everyone a loser and the honest person the biggest loser of all."
79 min: Everton take their last throw of the dice: Hibbert is replaced by Vellios.
82 min: GOAL!!! Everton 0-2 Liverpool. A lot of passing from Liverpool. Eventually a ball's slid down the inside-right channel for Suarez, who makes it into the area but is dispossessed by Baines. Distin goes to clear, but hits his clearance straight into the chest of the nearby Suarez, who immediately slips the ball under Howard from a tight angle and races off in celebration. He puts defenders in a terrible panic, does Suarez; this isn't the first time his presence has encouraged defenders to self-destruct this season - see also Arsenal away - and it probably won't be the last.
85 min: Baines has a thrash from 25 yards out, the ball sailing wide left. Goodison's rage has fizzled out into a benign acceptance.
87 min: Carroll attempts an overhead kick. Best left, that. He gets up and bundles Howard into the net as the keeper punches a high ball out for a corner. No free kick, surprisingly.
88 min: Before the corner, Lucas is replaced by Henderson. Bellamy takes the set piece, finding Gerrard on the edge of the area. He guides a shot towards the top-right corner, but Jagielka deflects wide. The second corner causes a small kerfuffle, but nothing more.
90 min: There will be three added minutes of this. Applause for Doctor Alimantado, who has just sent in an email referring to Carroll as "the Matalan Ibra".
90 min +1: Drenthe has a rake from distance, but Reina is behind it all the way.
90 min +2: Suarez takes a quick corner on the left, sending Kuyt clear along the byline. He pokes an effort past Howard, only to see it clatter off the left-hand post. Everton don't deserve a three-goal belting, not after the Rodwell Incident.
FULL TIME: Everton 0-2 Liverpool. And that's that. To a chorus of boos, referee Martin Atkinson blows his whistle. A controversial match, but then few aren't these days. The final word to Rhea Libert, who nimbly pulls together all the hot issues in this MBM: "Ah, Morten Nutzein. How can you be so blind to the majestic awesome of that hairdo? Although I applaud your red tie and shoes, as it is my favourite colour, I fear dreadfully for your aesthetic tastes. As for the redcard fiasco, clearly the referee was seeing a different dimension of reality than the rest of us. Crappy decisions, unfortunately, are par for the course in very many sports."


text:
News of the Day From Across the Nation, May 24
Published 5:44 pm, Friday, May 23, 2014
1 Contamination: Officials in Portland, Ore., issued a citywide boil notice Friday after health authorities detected E. coli in the water supply. The Portland Water Bureau said residents should boil all tap water used for drinking and food preparation for at least one minute. Tri-County Health Officer Dr. Paul Lewis said the E. coli is unlikely to cause serious health problems, except for possibly diarrhea. The cause of the contamination is under investigation.
2 Fundraising: The Republican National Committee sued the Federal Election Commission in Washington on Friday an effort to raise unlimited cash. Under current rules, the RNC may only accept $32,400 each year from donors, and local-level parties are capped at $10,000. Super PACs, however, can raise unlimited money. RNC officials said they want the same ability to have independent accounts that can buy ads, send campaign mail and make phone calls.
3 Wildfire: Hundreds of firefighters worked Friday to protect communities from a wildfire chewing up a scenic Arizona canyon. The human-caused Slide Fire started Tuesday and has burned more than 11 square miles in and around Oak Creek Canyon, a recreation area between Sedona and Flagstaff that normally would be teeming with tourists as Memorial Day approaches. Firefighters made progress in keeping the fire from getting closer to communities south of Flagstaff, incident commander Tony Sciacca said Friday. Weather conditions look favorable, with increased humidity and a chance of rain.
- union_fire3 David Essling
- union_fire2 David Essling
- union_fire Christina Lalanne
- Union Street Fire San Francisco Chronicle
- Jonathan%20Lucroy%20discusses%20his%20A%E2%80%99s%20debut San Francisco Chronicle
- Hail came to Orinda on Saturday San Francisco Chronicle
- Security footage of Oakland Cat Town break-in Courtesy of Cat Town
- Jharel%20Cotton%20on%20needing%20Tommy%20John%20surgery San Francisco Chronicle
- Final version of Stephen Hawking's emulator San Francisco Chronicle
- Buggy version of Stephen Hawking's voice emulator San Francisco Chronicle
4 Torture suspect: An Ethiopian jail guard who tortured and killed dozens of people during government-sponsored violence in the 1970s was sentenced Friday by a federal judge in Denver to 22 years in prison for immigration crimes. Kefelgn Alemu Worku was convicted of assuming another man's identity and lying on U.S. immigration forms by denying he committed acts of political persecution. He lived quietly in the Denver area for eight years until 2011, when another Ethiopian recognized him outside a cafe. Worku, believed to be in his 60s, has not been charged in this country with crimes related to the violence. An Ethiopian court in 2000 convicted him in absentia of genocide and sentenced him to death. If he survives his U.S. prison term, he could be deported to his homeland.
5 Aircraft probe: Federal officials are investigating an incident in which two United Airlines planes may have flown too close to each other over Houston. The close call happened after both planes took off from Bush Intercontinental Airport on May 9. The jets came within less than a mile of each other and 400 feet apart in height, Federal Aviation Administration spokesman Lynn Lunsford said Friday. Normally planes would be separated by at least three miles in distance and 1,000 feet in altitude. An even closer call occurred last month at Newark Liberty International Airport in New Jersey, prompting the FAA to change procedures for takeoffs and landings at the airport.


text:
Get groovy, baby! This classic 70s Adult Black Shag Wig has multiple layers for the styling freedom you need to complete the look for your fancy dress costume. Sporting this little number, you can be any kind of character you want to be from this dynamic era, whether that's a disco dancer with working class roots (pun intended) in the style of John Travolta, a pop icon extraordinaire or anything else. You could even get friends going to the party with you to dress up as your fans! The seventies are always a blast when it comes to fancy dress-up, and with this little beauty you'll have one less thing to worry about. If you can dig it, prepare to boogie. Keep on truckin', far out and right on!
This hard wearing synthetic 70s black shag wig is hard wearing and easy to care for. If you already have long hair, use a wig cap, and keep your natural locks under control to create a realistic-looking hairstyle. If returning this product, the wig must be sent back in the original, unopened and sealed packaging.
The following items are pre-ordered items. Pre-ordered items are estimated to ship 1-2 business days after the in-stock date listed. View more details in our FAQ section
|Unit Price


text:
They Take All Kinds of Pills That Give 'Em All Kinds of Thrills
Anything good — hell with good; anything successful — must be copied ad nauseum, and so today's Post brings news that Rolling Stone frontman Jann Wenner will become the latest mogul to rip off Donald Trump's The Apprentice. Janny-boy is in talks with MTV Networks to create the show, in which he'll star, reports Krazy Keith Kelly.
Insiders say the basic plot will involve a team of young rock journalist wannabes who are sent out across the country to cover stories with the aim of getting an article published in the magazine — and landing a full-time editor's job.
We're sure every horn-rimmed Omaha male between 16 and 30 is hard at work on his audition tape right now, but we're worried that they might be rushing into this endeavor too quickly. Conflating Almost Famous with real life, they're probably under the mistaken impression that Wenner is a friendly, avuncular boss, a fun guy who looks out for his employees. It's falling to us, we realize, to disabuse them of that notion. As media-world folks know — and as David Carr suggested on Monday — Jann is, more often than not, an evil tyrant with a proposenity for sudden firings, a shocking cheap streak, and, perhaps most famously, a neurotic fetishization of cleanliness.
Worked for Jann and have a favorite story? Let us know: email@example.com. We'll publish a compilation later in the week, so those Omaha kids can know what they're up against.
Because that's why we do things here: For the children.


text:
Malaria, caused by mosquito-transmitted Plasmodium parasites, continues to take a major toll on global health. The development of drugs and vaccines that reduce malaria transmission from humans back to mosquitos could contribute to the control and eventual eradication of malaria, but research models for the early clinical evaluation of candidate interventions are lacking. In this issue of the JCI, Collins and colleagues report the successful transmission of Plasmodium falciparum parasites from humans to mosquitoes during controlled human malaria infection, thus providing a potential tool to accelerate the development of much needed transmission-blocking drugs and vaccines.
Kazutoyo Miura, Peter D. Crompton
As oncogenes drive carcinogenesis and promote cancer cell survival, they are highly attractive therapeutic targets, and oncogene-targeting small molecules have achieved some clinical success. While many oncogenes are presently considered to be "druggable," tumors often acquire treatment resistance, and patients are rarely cured in response to oncogene-specific treatment. In this issue of the JCI, Veatch and colleagues describe a patient with metastatic acral melanoma who experienced a complete tumor response following infusion of tumor-infiltrating T cells that targeted multiple tumor antigens, including a BRAFV600E driver mutation. T cells genetically engineered to express an anti-BRAFV600E T cell receptor (TCR) from the patient demonstrated recognition of an epitope that spanned the BRAFV600E mutation. These findings suggest that BRAFV600E might be targeted therapeutically with adoptive transfer of anti-BRAFV600E T cells. This research supports the emerging therapeutic paradigm of targeting oncogenic drivers with T cell immunotherapy.
Christian S. Hinrichs
Polypeptide vaccines effectively activate human T cells but suffer from poor biological stability, which confines both transport logistics and in vivo therapeutic activity. Synthetic biology has the potential to address these limitations through the generation of highly stable antigenic "mimics" using subunits that do not exist in the natural world. We developed a platform based on D–amino acid combinatorial chemistry and used this platform to reverse engineer a fully artificial CD8+ T cell agonist that mirrored the immunogenicity profile of a native epitope blueprint from influenza virus. This nonnatural peptide was highly stable in human serum and gastric acid, reflecting an intrinsic resistance to physical and enzymatic degradation. In vitro, the synthetic agonist stimulated and expanded an archetypal repertoire of polyfunctional human influenza virus–specific CD8+ T cells. In vivo, specific responses were elicited in naive humanized mice by subcutaneous vaccination, conferring protection from subsequent lethal influenza challenge. Moreover, the synthetic agonist was immunogenic after oral administration. This proof-of-concept study highlights the power of synthetic biology to expand the horizons of vaccine design and therapeutic delivery.
John J. Miles, Mai Ping Tan, Garry Dolton, Emily S.J. Edwards, Sarah A.E. Galloway, Bruno Laugel, Mathew Clement, Julia Makinde, Kristin Ladell, Katherine K. Matthews, Thomas S. Watkins, Katie Tungatt, Yide Wong, Han Siean Lee, Richard J. Clark, Johanne M. Pentier, Meriem Attaf, Anya Lissina, Ann Ager, Awen Gallimore, Pierre J. Rizkallah, Stephanie Gras, Jamie Rossjohn, Scott R. Burrows, David K. Cole, David A. Price, Andrew K. Sewell
Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.
Mitsugu Shimobayashi, Verena Albert, Bettina Woelnerhanssen, Irina C. Frei, Diana Weissenberger, Anne Christin Meyer-Gerspach, Nicolas Clement, Suzette Moes, Marco Colombi, Jerome A. Meier, Marta M. Swierczynska, Paul Jenö, Christoph Beglinger, Ralph Peterli, Michael N. Hall
UL18 is a human CMV (HCMV) MHC class I (MHCI) homolog that efficiently inhibits leukocyte immunoglobulin-like receptor subfamily B member 1 (LILRB1)+ NK cells. We found an association of LILRB1 polymorphisms in the regulatory regions and ligand-binding domains with control of HCMV in transplant patients. Naturally occurring LILRB1 variants expressed in model NK cells showed functional differences with UL18 and classical MHCI, but not with HLA-G. The altered functional recognition was recapitulated in binding assays with the binding domains of LILRB1. Each of 4 nonsynonymous substitutions in the first 2 LILRB1 immunoglobulin domains contributed to binding with UL18, classical MHCI, and HLA-G. One of the polymorphisms controlled addition of an N-linked glycan, and that mutation of the glycosylation site altered binding to all ligands tested, including enhancing binding to UL18. Together, these findings indicate that specific LILRB1 alleles that allow for superior immune evasion by HCMV are restricted by mutations that limit LILRB1 expression selectively on NK cells. The polymorphisms also maintained an appropriate interaction with HLA-G, fitting with a principal role of LILRB1 in fetal tolerance.
Kang Yu, Chelsea L. Davidson, Agnieszka Wójtowicz, Luiz Lisboa, Ting Wang, Adriana M. Airo, Jean Villard, Jeremie Buratto, Tatyana Sandalova, Adnane Achour, Atul Humar, Katia Boggian, Alexia Cusini, Christian van Delden, Adrian Egli, Oriol Manuel, Nicolas Mueller, Pierre-Yves Bochud, Swiss Transplant Cohort Study, Deborah N. Burshtyn
Tuberous sclerosis complex (TSC) is a dominantly inherited disease caused by hyperactivation of the mTORC1 pathway and characterized by the development of hamartomas and benign tumors, including in the brain. Among the neurological manifestations associated with TSC, the tumor progression of static subependymal nodules (SENs) into subependymal giant cell astrocytomas (SEGAs) is one of the major causes of morbidity and shortened life expectancy. To date, mouse modeling has failed in reproducing these 2 lesions. Here we report that simultaneous hyperactivation of mTORC1 and Akt pathways by codeletion of Tsc1 and Pten, selectively in postnatal neural stem cells (pNSCs), is required for the formation of bona fide SENs and SEGAs. Notably, both lesions closely recapitulate the pathognomonic morphological and molecular features of the corresponding human abnormalities. The establishment of long-term expanding pNSC lines from mouse SENs and SEGAs made possible the identification of mTORC2 as one of the mediators conferring tumorigenic potential to SEGA pNSCs. Notably, in spite of concurrent Akt hyperactivation in mouse brain lesions, single mTOR inhibition by rapamycin was sufficient to strongly impair mouse SEGA growth. This study provides evidence that, concomitant with mTORC1 hyperactivation, sustained activation of Akt and mTORC2 in pNSCs is a mandatory step for the induction of SENs and SEGAs, and, at the same time, makes available an unprecedented NSC-based in vivo/in vitro model to be exploited for identifying actionable targets in TSC.
Paola Zordan, Manuela Cominelli, Federica Cascino, Elisa Tratta, Pietro L. Poliani, Rossella Galli
A modifier variant can abrogate the risk of a monogenic disorder. DFNM1 is a locus on chromosome 1 encoding a dominant suppressor of human DFNB26 recessive, profound deafness. Here, we report that DFNB26 is associated with a substitution (p.Gly116Glu) in the pleckstrin homology domain of GRB2-associated binding protein 1 (GAB1), an essential scaffold in the MET proto-oncogene, receptor tyrosine kinase/HGF (MET/HGF) pathway. A dominant substitution (p.Arg544Gln) of METTL13, encoding a predicted methyltransferase, is the DFNM1 suppressor of GAB1-associated deafness. In zebrafish, human METTL13 mRNA harboring the modifier allele rescued the GAB1-associated morphant phenotype. In mice, GAB1 and METTL13 colocalized in auditory sensory neurons, and METTL13 coimmunoprecipitated with GAB1 and SPRY2, indicating at least a tripartite complex. Expression of MET-signaling genes in human lymphoblastoid cells of individuals homozygous for p.Gly116Glu GAB1 revealed dysregulation of HGF, MET, SHP2, and SPRY2, all of which have reported variants associated with deafness. However, SPRY2 was not dysregulated in normal-hearing humans homozygous for both the GAB1 DFNB26 deafness variant and the dominant METTL13 deafness suppressor, indicating a plausible mechanism of suppression. Identification of METTL13-based modification of MET signaling offers a potential therapeutic strategy for a wide range of associated hearing disorders. Furthermore, MET signaling is essential for diverse functions in many tissues including the inner ear. Therefore, identification of the modifier of MET signaling is likely to have broad clinical implications.
Rizwan Yousaf, Zubair M. Ahmed, Arnaud P.J. Giese, Robert J. Morell, Ayala Lagziel, Alain Dabdoub, Edward R. Wilcox, Sheikh Riazuddin, Thomas B. Friedman, Saima Riazuddin
BACKGROUND. Drugs and vaccines that can interrupt the transmission of Plasmodium falciparum will be important for malaria control and elimination. However, models for early clinical evaluation of candidate transmission-blocking interventions are currently unavailable. Here, we describe a new model for evaluating malaria transmission from humans to Anopheles mosquitoes using controlled human malaria infection (CHMI). METHODS. Seventeen healthy malaria-naive volunteers underwent CHMI by intravenous inoculation of P. falciparum–infected erythrocytes to initiate blood-stage infection. Seven to eight days after inoculation, participants received piperaquine (480 mg) to attenuate asexual parasite replication while allowing gametocytes to develop and mature. Primary end points were development of gametocytemia, the transmissibility of gametocytes from humans to mosquitoes, and the safety and tolerability of the CHMI transmission model. To investigate in vivo gametocytocidal drug activity in this model, participants were either given an experimental antimalarial, artefenomel (500 mg), or a known gametocytocidal drug, primaquine (15 mg), or remained untreated during the period of gametocyte carriage. RESULTS. Male and female gametocytes were detected in all participants, and transmission to mosquitoes was achieved from 8 of 11 (73%) participants evaluated. Compared with results in untreated controls (n = 7), primaquine (15 mg, n = 5) significantly reduced gametocyte burden (P = 0.01), while artefenomel (500 mg, n = 4) had no effect. Adverse events (AEs) were mostly mild or moderate. Three AEs were assessed as severe — fatigue, elevated alanine aminotransferase, and elevated aspartate aminotransferase — and were attributed to malaria infection. Transaminase elevations were transient, asymptomatic, and resolved without intervention. CONCLUSION. We report the safe and reproducible induction of P. falciparum gametocytes in healthy malaria-naive volunteers at densities infectious to mosquitoes, thereby demonstrating the potential for evaluating transmission-blocking interventions in this model. TRIAL REGISTRATION. ClinicalTrials.gov NCT02431637 and NCT02431650. FUNDING. Bill & Melinda Gates Foundation.
Katharine A. Collins, Claire Y.T. Wang, Matthew Adams, Hayley Mitchell, Melanie Rampton, Suzanne Elliott, Isaie J. Reuling, Teun Bousema, Robert Sauerwein, Stephan Chalon, Jörg J. Möhrle, James S. McCarthy
BACKGROUND. Sporadic vascular malformations (VMs) are complex congenital anomalies of blood vessels that lead to stroke, life-threatening bleeds, disfigurement, overgrowth, and/or pain. Therapeutic options are severely limited, and multidisciplinary management remains challenging, particularly for high-flow arteriovenous malformations (AVM). METHODS. To investigate the pathogenesis of sporadic intracranial and extracranial VMs in 160 children in which known genetic causes had been excluded, we sequenced DNA from affected tissue and optimized analysis for detection of low mutant allele frequency. RESULTS. We discovered multiple mosaic-activating variants in 4 genes of the RAS/MAPK pathway, KRAS, NRAS, BRAF, and MAP2K1, a pathway commonly activated in cancer and responsible for the germline RAS-opathies. These variants were more frequent in high-flow than low-flow VMs. In vitro characterization and 2 transgenic zebrafish AVM models that recapitulated the human phenotype validated the pathogenesis of the mutant alleles. Importantly, treatment of AVM-BRAF mutant zebrafish with the BRAF inhibitor vemurafinib restored blood flow in AVM. CONCLUSION. Our findings uncover a major cause of sporadic VMs of different clinical types and thereby offer the potential of personalized medical treatment by repurposing existing licensed cancer therapies. FUNDING. This work was funded or supported by grants from the AVM Butterfly Charity, the Wellcome Trust (UK), the Medical Research Council (UK), the UK National Institute for Health Research, the L'Oreal-Melanoma Research Alliance, the European Research Council, and the National Human Genome Research Institute (US).
Lara Al-Olabi, Satyamaanasa Polubothu, Katherine Dowsett, Katrina A. Andrews, Paulina Stadnik, Agnel P. Joseph, Rachel Knox, Alan Pittman, Graeme Clark, William Baird, Neil Bulstrode, Mary Glover, Kristiana Gordon, Darren Hargrave, Susan M. Huson, Thomas S. Jacques, Gregory James, Hannah Kondolf, Loshan Kangesu, Kim M. Keppler-Noreuil, Amjad Khan, Marjorie J. Lindhurst, Mark Lipson, Sahar Mansour, Justine O'Hara, Caroline Mahon, Anda Mosica, Celia Moss, Aditi Murthy, Juling Ong, Victoria E. Parker, Jean-Baptiste Rivière, Julie C. Sapp, Neil J. Sebire, Rahul Shah, Branavan Sivakumar, Anna Thomas, Alex Virasami, Regula Waelchli, Zhiqiang Zeng, Leslie G. Biesecker, Alex Barnacle, Maya Topf, Robert K. Semple, E. Elizabeth Patton, Veronica A. Kinsler
T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune checkpoint inhibitor therapy or adoptive cell transfer. Unfortunately, most neoantigens result from random mutations and are patient specific, and some cancers contain few mutations to serve as potential antigens. We describe a patient with stage IV acral melanoma who achieved a complete response following adoptive transfer of tumor-infiltrating lymphocytes (TILs). Tumor exome sequencing surprisingly revealed fewer than 30 nonsynonymous somatic mutations, including oncogenic BRAFV600E. Analysis of the specificity of TILs identified rare CD4+ T cells specific for BRAFV600E and diverse CD8+ T cells reactive to nonmutated self-antigens. These specificities increased in blood after TIL transfer and persisted long-term, suggesting they contributed to the effective antitumor immune response. Gene transfer of the BRAFV600E-specific T cell receptor (TCR) conferred recognition of class II MHC–positive cells expressing the BRAF mutation. Therapy with TCR-engineered BRAFV600E-specific CD4+ T cells may have direct antitumor effects and augment CD8+ T cell responses to self- and/or mutated tumor antigens in patients with BRAF-mutated cancers.
Joshua R. Veatch, Sylvia M. Lee, Matthew Fitzgibbon, I-Ting Chow, Brenda Jesernig, Tom Schmitt, Ying Ying Kong, Julia Kargl, A. McGarry Houghton, John A. Thompson, Martin McIntosh, William W. Kwok, Stanley R. Riddell
Single cancer cell sequencing studies currently use randomly-selected cells, limiting correlations between genomic aberrations, morphology and spatial localization. We laser-captured microdissected single cells from morphologically-distinct areas of primary breast cancer and corresponding lymph node metastasis and performed whole-exome or deep-target sequencing of greater than 100 such cells. Two major subclones co-existed in different areas of the primary tumor, and the lymph node metastasis originated from a minor subclone in the invasive front of the primary tumor with additional copy number changes including 8q gain, but no additional point mutations in driver genes. Lack of metastasis-specific driver events lead us to assess whether other clonal and subclonal genomic aberrations pre-existing in primary tumors contribute to lymph node metastasis. Gene mutations and copy number variations analyzed in five breast cancer tissue sample sets revealed that copy number variations in several genomic regions, including areas within chromosome 1p, 8q, 9p, 12q and 20q, harboring several metastasis-associated genes, were consistently associated with lymph node metastasis. Moreover, clonal expansion was observed in an area of morphologically-normal breast epithelia, likely driven by a driver mutation and a subsequent amplification in chromosome 1q. Our study illuminates the molecular evolution of breast cancer and genomic aberrations contributing to metastases.
Li Bao, Zhaoyang Qian, Maria B. Lyng, Ling Wang, Yuan Yu, Ting Wang, Xiuqing Zhang, Huanming Yang, Nils Brünner, Jun Wang, Henrik J. Ditzel
Painful diabetic neuropathy (PDN) is an intractable complication of diabetes that affects 25% of patients. PDN is characterized by neuropathic pain and small-fiber degeneration, accompanied by dorsal root ganglion (DRG) nociceptor hyperexcitability and loss of their axons within the skin. The molecular mechanisms underlying DRG nociceptor hyperexcitability and small-fiber degeneration in PDN are unknown. We hypothesize that chemokine CXCL12/CXCR4 signaling is central to this mechanism, as we have shown that CXCL12/CXCR4 signaling is necessary for the development of mechanical allodynia, a pain hypersensitivity behavior common in PDN. Focusing on DRG neurons expressing the sodium channel Nav1.8, we applied transgenic, electrophysiological, imaging, and chemogenetic techniques to test this hypothesis. In the high-fat diet mouse model of PDN, we were able to prevent and reverse mechanical allodynia and small-fiber degeneration by limiting CXCR4 signaling or neuronal excitability. This study reveals that excitatory CXCR4/CXCL12 signaling in Nav1.8-positive DRG neurons plays a critical role in the pathogenesis of mechanical allodynia and small-fiber degeneration in a mouse model of PDN. Hence, we propose that targeting CXCR4-mediated DRG nociceptor hyperexcitability is a promising therapeutic approach for disease-modifying treatments for this currently intractable and widespread affliction.
Nirupa D. Jayaraj, Bula J. Bhattacharyya, Abdelhak A. Belmadani, Dongjun Ren, Craig A. Rathwell, Sandra Hackelberg, Brittany E. Hopkins, Herschel R. Gupta, Richard J. Miller, Daniela M. Menichella
Recent studies reveal that airway epithelial cells are critical pulmonary circadian pacemaker cells, mediating rhythmic inflammatory responses. Using mouse models, we now identify the rhythmic circadian repressor REV-ERB as essential to the mechanism coupling the pulmonary clock to innate immunity, involving both myeloid, and bronchial epithelial cells in temporal gating and determining amplitude of response to inhaled endotoxin. Dual mutation of REV-ERBα and its paralog REV-ERBβ in bronchial epithelia further augmented inflammatory responses and chemokine activation, but also initiated a basal inflammatory state, revealing a critical homeostatic role for REV-ERB proteins in the suppression of the endogenous pro-inflammatory mechanism in un-challenged cells. However, REV-ERBα plays the dominant role as deletion of REV-ERBβ alone had no impact on inflammatory responses. In turn, inflammatory challenges cause striking changes in stability and degradation of REV-ERBα protein, driven by SUMOylation and ubiquitination. We developed a novel selective oxazole-based inverse agonist of REV-ERB, which protects REV-ERBα protein from degradation and used this to reveal how pro-inflammatory cytokines trigger rapid degradation of REV-ERα in the elaboration of an inflammatory response. Thus, dynamic changes in stability of REV-ERα protein couple the core clock to innate immunity.
Marie Pariollaud, Julie Gibbs, Thomas Hopwood, Sheila Brown, Nicola Begley, Ryan Vonslow, Toryn Poolman, Baoqiang Guo, Ben Saer, D. Heulyn Jones, James P. Tellam, Stefano Bresciani, Nicholas C.O. Tomkinson, Justyna Wojno-Picon, Anthony W.J. Cooper, Dion A. Daniels, Ryan P. Trump, Daniel Grant, William Zuercher, Timothy M. Willson, Andrew S. MacDonald, Brian Bolognese, Patricia L. Podolin, Yolanda Sanchez, Andrew S.I. Loudon, David W. Ray
Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of a particular aldolase, aldolase B, results in the accumulation of intracellular phosphorylated fructose thus leading to phosphate sequestration and depletion, increased ATP turnover and a plethora of conditions leading to clinical manifestations including fatty liver, hyperuricemia, Fanconi syndrome and severe hypoglycemia. Unfortunately, to date, there is no treatment for HFI and avoiding sugar and fructose in our society has become quite challenging. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI using aldolase B knockout mice. We thus provide evidence for the first time of a potential therapeutic approach for this condition. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.
Miguel A. Lanaspa, Ana Andres-Hernando, David J. Orlicky, Christina Cicerchi, Cholsoon Jang, Nanxing Li, Tamara Milagres, Masanari Kuwabara, Michael F. Wempe, Joshua D. Rabinowitz, Richard J. Johnson, Dean R. Tolan
The remarkable regeneration capability of skeletal muscle depends on coordinated proliferation and differentiation of satellite cells. The self-renewal of satellite cells is critical for long-term maintenance of muscle regeneration potential. Hypoxia profoundly affects the proliferation, differentiation, and self-renewal of cultured myoblasts. However, the physiological relevance of hypoxia and hypoxia signaling in satellite cells in vivo remains largely unknown. Here, we report that satellite cells are in an intrinsic hypoxic state in vivo and express hypoxia-inducible factor 2A (HIF2A). HIF2A promotes the stemness and long-term homeostatic maintenance of satellite cells by maintaining the quiescence, increasing the self-renewal and blocking the myogenic differentiation of satellite cells. HIF2A stabilization in satellite cells cultured under normoxia augmented their engraftment potential in regenerative muscle. Reversely, HIF2A ablation led to the depletion of satellite cells and the consequent regenerative failure in the long-term. In contrast, transient pharmacological inhibition of HIF2A accelerated muscle regeneration by increasing satellite cell proliferation and differentiation. Mechanistically, HIF2A induces the quiescence/self-renewal of satellite cells by binding the promoter of Spry1 gene and activating Spry1 expression. These findings suggest that HIF2A is a pivotal mediator of hypoxia signaling in satellite cells and may be therapeutically targeted to improve muscle regeneration.
Liwei Xie, Amelia Yin, Anna S. Nichenko, Aaron M. Beedle, Jarrod A. Call, Hang Yin
In this issue, Stavrou et al. pursue coagulation factor FXII's functions in neutrophil-mediated inflammation during wound healing. The cover image depicts translocation of FXII (green) to the plasma membrane of activated neutrophils, where it acts as an autocrine signal to enhance neutrophil adhesion, migration, chemotaxis, and NET formation (purple lines). Image credit: Erika Woodrum.
JCI This Month is a digest of the research, reviews, and other features published each month.
Fibrosis describes a maladaptive response to injury that results in pathogenic production of extracellular matrix, the formation of stiff scar tissue, and compromised organ function. Although it is most often associated with chronic liver conditions and progressive lung disease, fibrosis can affect any organ of the body. There are few treatment options for this progressive, often fatal condition, but as ongoing research identifies the molecular pathways that initiate and propagate fibrotic remodeling, therapeutic possibilities may become available. The reviews in this series discuss recent insights into genetic predisposition to fibrotic disorders, the origins of fibroblasts and myofibroblasts, scar tissue formation, organ regeneration, and more, revealing opportunities to interrupt or even reverse disease progression.