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Articles tagged grey gardens
7 Jan 2010 // 10:00 PM
Mazur checks out the year's best female acting and offers up a mostly alternative opinion to the boring Oscar-begging consensus picks including some you might not have heard about, yet.READ more
20 Apr 2009 // 2:50 AM
The new Grey Gardens is safe, providing a dash of self-reflexivity, but wasting more opportunities than it takes.READ more
18 Apr 2009 // 6:32 AM
In celebration of the premiere of HBO's stellar TV movie on the Beales, SE&L brings you this review of the original documentaries that started it all.READ more
15 Apr 2009 // 4:36 AM
What is, is never the whole story. What made it that way - that's where deeper fascination lies. Especially when it's as stranger-than-fictionREAD more
13 Apr 2009 // 5:21 AM
For years, you've been crushing on Drew Barrymore. The sugar-and-spice personality, the infectious giggle, the crinkly eyes, the way you want to buy herREAD more
19 Jun 2007 // 11:00 PM
When it comes to post-modern moviemaking, everyone stereotypes the Me Decade as the genre's defining moment. In this case -- as illustrated by the 10 films that represent it -- the categorization is more than accurate.READ more
10 Jun 2007 // 4:04 AM
- //News
The most coveted prize on Broadway? For a producer, it's you in a paid seat, and for just about everyone else, it's aREAD more
11 Apr 2002 // 1:00 AM
What makes the Maysles' work special lies in how they manage, by focusing so intently on their subjects, to elicit a body of information that the audience is compelled to examine for its possible meaning.READ more
The Brevet "Hold On" (video) (premiere) // Music
Estrangers "Croc Rock" (audio) (premiere) // Music
Sean McVerry 'Hourglass Switchboard 2' (EP stream) (premiere) // Music
Call For Papers: Celebrating Star Trek's 50th Anniversary
// Announcements
"To celebrate the 50th anniversary of the hit franchise, PopMatters seeks submissions about Star Trek, including: the TV series, from The Original Series (TOS) to the highly anticipated 2017 new installment; the films, both the originals and the J.J. Abrams reboot; and ancillary materials such as novelizations, comic books, videogames, etc.READ the article


text: Here Are the Craziest Things Lil Mama Has Said on America's Best Dance CrewEric Jackman6/05/11 7:33pmFiled to: VideoLil MamaAmerica's Best Dance CrewTelevisionDanceReality TVcompilationTweetd82EditInvite manuallyPromoteDismissUndismissHideShare to KinjaToggle Conversation toolsGo to permalink America's Best Dance Crew judge Lil Mama, of VMA stage crashing fame, has become known for delivering heartfelt critiques to the contestants. At times, they're a source of inspiration. Other times—or really, most of the time—she butchers the English language, leaving one dumfounded at the degree to which words can be mispronounced and expressions can be misspoken on television. Here's a "Best of the Worst" compilation of Lil Mama's six seasons on the show. Reply82 repliesLeave a reply

subset: commoncrawl


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- Swimmer Ryan Lochte reveals one of his worst dates - US Weekly
- Get the latest on Dr. Dre's arrest - TMZ
- Despite rumors, Eddie Murphy's daughter is not pregnant - Gossip Cop
- The Vampire Diaries star Michael Trevino steps out for a good cause - Just Jared Jr
- Are Blac Chyna and Kylie Jenner on good terms? - Radar
- Blue Ivy is just as stylish as her mom Beyonce! - Lainey Gossip
- This Narcos star confirms he's not coming back for another season of the show - The Hollywood Reporter
12 November 2013 at 7:48 PM
Shailene Woodley & Theo James: New 'Divergent' Poster!
About this photo set: Check out this brand new poster for the highly anticipated movie Divergent featuring Shailene Woodley and Theo James. New character posters were also released… Read More Here
Photo #: 2991163
Posted to Divergent, Jai Courtney, Maggie Q, Mekhi Phifer, Miles Teller, Shailene Woodley, Theo James, Zoe Kravitz
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Really good. I don't know why, but it looks like Italian buildings really age and wither in style.
Salut Pom', voilà donc à quoi tu bossais ! ;) Une nouvelle série italienne en perspective j'imagine. Je constate que tu as décidé de voyager plus léger en troquant ton Canon contre un Lumix.
dear emr Santa severina is a wonderful old village of southern Italy, and it's really stylish. I'll certainly post more pics of it.
salut Michel :) oui ce fut un plus dur labeur que tu sembles l'imaginer, ce jour là le mercure dépassait 30 allègrement, et ça grimpe dur dans ces nids d'aigle calabrais. Et en effet mon bon vieux TZ3 déforme moins les poches que mon reflex à gros zoom ;)
It's more than an architecture picture dear Pom'. Like emr2 I can't easily say why. It's the old and the new, it's the existence of life or the absence of it, or maby it's the combination of these two under the god's dome which is as allways in a better condition (compared with the mortal's buildings)...I don't really know. After all it must be an interesting place to be there and taking pictures dear Pom'!
Many shk, Niki
Bellissimo edificio con quei due balconi che mi sembra antico, bellissima composizione ciao Giovanni
soon to come a larger view of this old village dear Mi@Ni. it has an outstanding site and an harmonious medieval style. people from the place say it has been classified among the "20 most beautiful villages of Italy". and yes it has been great to be there in Santa Severina :)
Giovanni grazie del commento caloroso !
I like the old house.
Cheers, Jeff
thanks for your kind words Jeff !
Great shot Pom'!
c'est beau et bien vu
thank you Marcel !
merci elisette, l'Italie n'est pas avare de ces scènes agréables.
What different roofs (Dächer).
I like these too.
let me see your roofs, leon !
no problem dear leon !
Really beautiful! Like! Greetings!
Photo taken in 88832 Santa Severina KR, Italy


text: Situated in a beautiful old village of Lama perched on the hill. Nice ambiance, beautiful view. Food was good, but not exceptional . Staff was nice. They were only two tables occupied for dinner in mid June.I have the feeling that food will get better with the start of high season. They offer fixed menu.


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I have a simple problem: I want to write the date in an asp:label in the following format: MMM dd, yyyy I tried this:
lblDate.Text = System.DateTime.Today.ToString("MMM dd, yyyy");
the result is: "okt. 12, 2012"
- I want to remove the dot from it.
- The month's name should begin with a capital letter.
the right format: "Okt 12, 2012"
how can I do this?


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6 posts tagged with midwest and moving.
Displaying 1 through 6 of 6. Subscribe:
Should we stay or should we go now?
My boyfriend and I currently live in NYC. We hate it - we're tired of the noise, the garbage, the tiny apartments and the high prices for nearly everything. But we're considering having a baby in the next few years, and both our families are nearby - should we stay for family support or move to a location where we would likely be happier? [more inside]
Yes, I have heard it's a lovely town
I'm moving to Madison, WI and everyone loves it. But why? And is it really perfect? [more inside]
Yet another where should we move? question: the liberal gay Northern edition [more inside]
Ambiguity is scary
I'm moving from Small Town, Midwest to Big Metro Area, East Coast within the next month. What do I need to know to prepare myself mentally for the transition? [more inside]
Roadtrip filter: world's largest ball of twine?
Roadtrip Filter: what can I stop and see for fun when I drive from Boston to St. Louis this weekend? [more inside]
How to adjust to the Midwest?
Moving to Kansas City, single and mid twenties. How do people here socialize? Where do they socialize? [more inside]
Page: 1


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Edit -> Media, WordPress SEO -> Advanced -> 301 Redirect: [myurlredirect]
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My entry [myurlredirect] did not "stick" on update. Same thing seemed to happen for the other Advanced field, Canonical URL.
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Loyalty and the Promotional Bottleneck
Text Illustration shared by Sermon Central Staff, Outreach Inc.
August 2011
Scripture: Mark 3:13-3:19 (add scripture)
Tags: Leadership General (add tag)
Category: Quotes
About Text Illustration Contributor
Peter Drucker gave this warning to those who would push back this principle, "Contrary to popular legend, subordinates do not, as a rule, rise to position and prominence over the prostrate bodies of incompetent bosses. If their boss is not promoted, they will tend to be bottled up behind him. And if their boss is relieved for incompetence or failure, the successor is rarely the bright, young man next in line. He usually is brought in from the outside and brings with him his own bright, young men. Conversely, there is nothing quite as conducive to success, as a successful and rapidly promoted superior" (The Effective Executive. New York: Harper & Row, 1985, page 93).
Loyalty is necessary because it is Biblical (Hebrews 13:17) and because it promotes the unity and effectiveness of the ministry where it is practiced.
(From a sermon by Tim White, Six Marks of Leadership, Mark 3, 5/9/2011)
Other text illustrations you might like
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Baltimore journalist Adam Marton was looking at homicide data when he saw the name of the man he says stole his car, and remembered the scene: a subwoofer, a baby seat, a pile of job applications.
For a while, the president's plan for increasing vehicles' fuel efficiency worked — he said it would save money and reduce carbon pollution. Then came cheap gas, and the improvements have stalled.
Protesters angry about the shooting death of Laquan McDonald at the hands of Chicago police say the mayor should resign. But Emanuel is weathering the crisis, and a recall effort faces obstacles.
Five years ago Friday, a gunman opened fire in a parking lot in Tucson, Ariz., killing six and wounding others — including Mary Reed, who had been protecting her daughter. This is their story.
Monique Pressley is called "masterful" in her public message. She hits the spotlight of the Bill Cosby case after a career as a defense attorney, prosecutor and religion-based broadcaster.
Everything you absolutely must know about personal finance fits on an index card — according to a blog post that went viral in 2013. Now its author has expanded the basics into a book, The Index Card.
The Republican front-runner stopped in one of the most liberal states in the country for a raucous rally.
The U.S. had 10 weather events in 2015 that cost $1 billion or more in damage, with December the warmest and wettest month on record. Climate scientists blame a warming climate and strong El Nino.
From concussions to domestic violence, a current pro football player tells all about what's it really like on the gridiron and beyond in NFL Confidential: True Confessions from the Gutter of Football.
South Korea made the announcement after Pyongyang claimed it tested a hydrogen bomb.


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We set up our handsome 3 day festival camp once again in the beautiful lands of Bakewell in The Peak District National Park. The weekend of the 17-19th 2016 June marked the third chapter of Eroica Britannia. We spent a glorious, carefree weekend of music, food, drink, acres of shopping and as much fun as you can have in 3 days!
On Sunday 19th June 2016 our adventurers gathered, bikes polished and magnificent for a 3 route tour of the Peak District. Bells rang and the thrill of 4,500 riders on pre-1987 bikes resonated around hill and through vale for Eroica Britannia.
Join the challenge of The Great British Adventure as we adventure through the beauty of the Peak District for the ride of 2016! Pre 1987 bikes only!More Information
Fun for all the family! Three days of live music, entertainment, acres of shopping, the World's biggest Bike Jumble and our GRAZE Food Festival.More Information
Camp with friends and family in the heart of the festival. Home Fields is the perfect place to be in on all the action.More Information
We pay homage to the humble Wellington boot and BHI WorkwearRead More
A Land and Weather UpdateRead More
A huge thank you to everyone who entered this year!Read More
To keep up to date with Eroica Britannia News please fill out the form below to subscribe to our newsletter.


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How can I redirect from https://mysite.com to https://www.mysite.com? The SSL certificate is bought for www.mysite.com and shows a warning if accessed without www.
It will be too late. Users will have already seen the error message and had to accept it by the time the redirect happens unless you get another certificate. The previous answer has that problem.
Ignoring that, you can create a named based virtual host on port 443, set up ssl on that, and then have it rewrite. Note that instead of using your existing certificate (which will generate an error) you can have a cheap, valid certificate under mysite.com on that virtual host so that you don't get an error prior to the redirect.


text:
- Swimmer Ryan Lochte reveals one of his worst dates - US Weekly
- Get the latest on Dr. Dre's arrest - TMZ
- Despite rumors, Eddie Murphy's daughter is not pregnant - Gossip Cop
- The Vampire Diaries star Michael Trevino steps out for a good cause - Just Jared Jr
- Are Blac Chyna and Kylie Jenner on good terms? - Radar
- Blue Ivy is just as stylish as her mom Beyonce! - Lainey Gossip
- This Narcos star confirms he's not coming back for another season of the show - The Hollywood Reporter
13 June 2014 at 11:59 PM
Iggy Azalea & Boyfriend Nick Young Are a Cute Couple at Lunch!
About this photo set: Iggy Azalea and Nick Young make their way out of Toast restaurant after having lunch outside on the patio on Friday afternoon (June 13) in West Hollywood, Calif.… Read More Here
Photo #: 3135082
Posted to Iggy Azalea, Nick Young
powered by ZergNet


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COSHH (Control of Substances Hazardous to Health)
What is COSHH?
COSHH stands for the Control of Substances Hazardous to Health, and is concerned primarily with the safe handling, usage and storage of chemicals and substances that pose a danger to the health of either those handling the substances or to other people.
COSHH regulations and legislation forces businesses and organisations to be responsible for preventing or sufficiently limiting exposure to hazardous substances. This is done either through total avoidance (e.g. keeping workers away from waste dumps), or, if the substances form an unavoidable part of a person's job, through providing the correct personal protective equipment such as gloves, breathing apparatus etc. Employers can be fined, or even imprisoned in extreme cases, for failing to provide sufficient protection or control measures.
COSHH Risk Assessments and COSHH Substances
One of the first stages in putting into place effective COSHH procedures is to perform a COSHH risk assessment, in order to identify hazards and aim to foresee potential problems. By performing a risk assessment and identifying potential problems, it allows the organisation to put into place control measures that should hopefully prevent such a problem from becoming a reality. Whilst it is impossible to foresee and predict every conceivable accident and risk, performing a COSHH risk assessment and identifying the potential problems will greatly reduce the chances of such problems occurring.
There are many substances which are hazardous to human health, ranging from minor irritants to potential killers, depending on both the type of substance and the exposure levels. The substances can be waste products produced at the end of a process, cleaning products, dust, chemical ingredients etc. The sheer number of hazardous substances in the world means that organisations in different industries will face different hazards according to the products they produce or the services they provide. For instance, a restaurant worker will handle cleaning products, but is unlikely to come into contact with construction-related substances like a builder would, which will again differ from a car mechanic dealing with hydraulic fluid, oil etc.
Related COSHH Pages:
- COSHH - Hazardous Substances Routes of Entry
- COSHH Risks on a Construction Site
- COSHH Exposure Over Time
- COSHH Contamination and Accidental Ingestion
- COSHH Risks From Mists
- COSHH - Different Chemicals Used in Virtually All Industries
- Construction Site COSHH Risks - Cement
- COSHH Risks - Fungi
- COSHH Risks - Limit of Knowledge
- Why Should Hazardous Substances Be Stored Properly?
- Reducing COSHH Exposure
COSHH Courses
This variation in COSHH products makes it difficult and often impractical to run a COSHH training open course, as large parts of it will be irrelevant for the people on the course if they come from greatly differing industries. For this reason, we primarily run our COSHH courses as bespoke in-house courses, which are specifically tailored to an organisation's working environment, and the specific COSHH risks its workers face.
Many of our health and safety training courses such as the NEBOSH Environmental Certificate touch on COSHH to some extent, but for those who are serious about COSHH training for their employees, a bespoke course is really the only effective way to go. We have two COSHH courses that are occasionally offered as open courses, the details of which can be found below, however, these more often form the basis for a bespoke COSHH course which is tailored to the client's requirements.


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Hot 97 »
Hot 97's Who's Next Live: Ladies Edition w/ Nitty Scott, Snow Tha Product, Leaf & Young Ma
Hot 97's leading music event is back and this time the spotlight is on the ladies! This edition of "Who's Next" Live will feature performances from Nitty Scott MC, Snow Tha Product, Leaf andRead More »
Hot 97's #OneVoice Live Stream Discussion Recap
A couple days ago, the city that never sleeps came to a halt as radio programming on Hot 97, WLIB and WBLS, joined forces for #OneVoice. Moderated by Ebro Darden and Lisa Evers, #OneVoiceRead More »
Live Stream Hot 97's #OneVoice Today At 4 pm (EST)
The other day we shared information about Hot 97's #OneVoice, an open discussion on the relationship between the African American community and police. Joining in on the conversation will be Hot 97's Ebro Darden,Read More »
DJ Drama Talks Drake Meek Mill Beef And Defends the New Generation Of Hip-Hop (Video)
It looks like DJ Drama is making his radio rounds to boost his forthcoming project, Quality Street Music 2. This serves as the follow-up to his 2012 release, which hosted one of his biggest record, "My Moment,"Read More »
Hot 97: Rudy Giuliani & Pokemon Go Enthusiasts, You Played Yourself!
In a recent airing of Hot 97's Ebro in the Morning, Ebro, Rosenberg & Laura Stylez share their thoughts on how Rudy Giuliani and Pokemon Go players played themselves. If you've listened to theRead More »
Hot 97 To Simulcast "One Voice: An Open Discussion On The Relationship Between The African American Community & Police"
It's always a beautiful thing when the Hip Hop community can come together as "One Voice." On Thursday, July 14th at 4 pm EST, Hot 97 – along with 107.5 FM & WLIB-AM 1190Read More »
Joey Bada$$ Freestyles On Hot 97
Joey Bada$$ follows up his new single, "Devastated," with a new freestyle on Hot 97 with Funkmaster Flex. "I make these rap airwaves so hard to breathe through. Took a student of the gameRead More »
Hot 97's Best of BK w/ Jack Daniels Event Recap
Last week, Hot 97 repped for the borough of Brooklyn as they hosted the Neighborhood Flavor: Best of Brooklyn party with Jack Daniel's Honey. Held in Brooklyn's, The Villain, the event was one bigRead More »


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- Runtime:
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- Views:
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- Date:
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- Rating:
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Jennifer's Archive
Jessica Alba in Current/Elliott Star Print Jeans
Out in London, Jessica Alba and a friend were seen getting some lunch together. Later in the day, Jessica attended the 2012 Glamour Women of the Year awards. She tweeted from the event, "Dinner #glamourawards w @sofiavergara n @piersmorgan accosted our table."
While out with her friend, Jessica wore a pair of Current/Elliott's star print jeans with a neon tee shirt and a leather vest. I love these jeans, but I really like how the gray is a bit more subtle than the blue pair. You can buy these jeans online from Stylebop for $265.
Charlize Theron in Current/Elliott
Charlize Theron catches a flight out of LAX wearing a pair of Current/Elliott skinny jeans with a gray blazer and white tee. Charlize was headed to NYC to appear on the Today show to promote her latest film, Snow White and The Huntsman.
It's been a while since we've seen Charlize out in Current/Elliott. She's been wearing a lot of different trends lately, but I love how effortless this outfit is! Buy Current/Elliott online at SSENSE.
Sofia Vergara in Habitual
Out in New York, Sofia Vergara was seen doing some shopping in the SoHo Scoop store. Sofia has been spending some time in New York recently, earlier in the month, she attended the MET ball and appeared on Saturday Night Live.
Sofia is one celeb who we usually see out in flares over skinny jeans. Typically she wears Hudson, but this time she switched it up for a pair of Habitual Plush Denim Hayworth jeans in Ablaze with a dark red leather jacket. One thing I love about Sofia's style is that she's not afraid of wearing color and the red of her jacket really pops against the dark wash of the jeans.
Images from Pacificcoastnews.com
Jennifer Garner in J Brand
Jennifer Garner has been spotted out in J Brand quite a few different times over the past few weeks. First, she wore a pair of J Brand's 814 mid-rise cigarette jeans with a silk blue shirt while picking up her daughters from school.
She wore the same pair out again while running errands, only she paired them with a bold pink blouse. She wore a more casual pair, the Aoko cropped cuff jeans in Tulum while picking up her children from school too. You can buy J Brand jeans online at Jbrandjeans.com.
Images from Wenn.com


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|Home | About | Journals | Submit | Contact Us | Français
The let-7 tumor suppressor microRNAs are known for their regulation of oncogenes, while the RNA-binding proteins Lin28a/b promote malignancy by blocking let-7 biogenesis. In studies of the Lin28/let-7 pathway, we discovered unexpected roles in regulating metabolism. When overexpressed in mice, both Lin28a and LIN28B promoted an insulin-sensitized state that resisted high fat diet-induced diabetes, whereas muscle-specific loss of Lin28a and overexpression of let-7 resulted in insulin resistance and impaired glucose tolerance. These phenomena occurred in part through let-7-mediated repression of multiple components of the insulin-PI3K-mTOR pathway, including IGF1R, INSR, and IRS2. The mTOR inhibitor rapamycin abrogated the enhanced glucose uptake and insulin-sensitivity conferred by Lin28a in vitro and in vivo. In addition, we found that let-7 targets were enriched for genes that contain SNPs associated with type 2 diabetes and fasting glucose in human genome-wide association studies. These data establish the Lin28/let-7 pathway as a central regulator of mammalian glucose metabolism.
There is an emerging consensus that metabolic disease and malignancy share common biological mechanisms. Reprogramming towards glycolytic metabolism can increase a cancer cell's ability to generate biomass, a phenomenon termed the "Warburg Effect" (Denko, 2008; Engelman et al., 2006; Gao et al., 2009; Guertin and Sabatini, 2007; Laplante and Sabatini, 2009; Vander Heiden et al., 2009; Yun et al., 2009). Likewise, many genes identified in type 2 diabetes (T2D) genome wide association studies (GWAS) are proto-oncogenes or cell cycle regulators (Voight et al., 2010). MicroRNAs (miRNAs) are also emerging as agents of metabolic and malignant regulation in development and disease (Hyun et al., 2009; Peter, 2009). The let-7 miRNA family members act as tumor suppressors by negatively regulating the translation of oncogenes and cell cycle regulators (Johnson et al., 2005; Lee et al., 2007; Mayr et al., 2007; Kumar et al., 2008). Widespread expression and redundancy among the well-conserved let-7 miRNAs raise the question of how cancer and embryonic cells are able to suppress this miRNA family to accommodate rapid cell proliferation. In human cancers, loss of heterozygosity, DNA methylation, and transcriptional suppression have been documented as mechanisms to reduce let-7 (Johnson et al., 2005; Lu et al., 2007). Another mechanism for let-7 downregulation involves the RNA-binding proteins Lin28a and Lin28b (collectively referred to as Lin28a/b), which are highly expressed during normal embryogenesis and upregulated in some cancers to potently and selectively block the maturation of let-7 (Heo et al., 2008; Newman et al., 2008; Piskounova et al., 2008; Rybak et al., 2008; Viswanathan et al., 2008). By repressing the biogenesis of let-7 miRNAs and in some cases through direct mRNA binding and enhanced translation (Polesskaya et al., 2007; Xu and Huang, 2009; Xu et al., 2009; Peng et al., 2011), Lin28a/b regulate an array of targets involved in cell proliferation and differentiation in the context of embryonic cells, stem cells, and cancer.
Little is known about the in vivo function of the Lin28/let-7 axis. The pathway was first revealed in a screen for heterochronic mutants in C. elegans, where loss of lin-28 resulted in precocious vulval differentiation and premature developmental progression (Ambros and Horvitz, 1984; Moss et al., 1997; Nimmo and Slack, 2009), whereas loss of let-7 led to reiteration of larval stages and delayed differentiation (Abbott et al., 2005; Reinhart et al., 2000). We previously showed that Lin28a gain of function promotes mouse growth and delays sexual maturation, recapitulating the heterochronic effects of lin-28 and let-7 in C. elegans, as well as the height and puberty phenotypes linked to human genetic variation at the Lin28b locus identified in GWAS (Zhu et al., 2010). The conservation of Lin28 and let-7's biochemical and physiological functions throughout evolution suggests an ancient mechanism for Lin28 and let-7's effects on growth and developmental timing.
In this report we found that both Lin28a and LIN28B transgenic mice were resistant to obesity and exhibited enhanced glucose tolerance. In contrast, muscle-specific Lin28a knockout and inducible let-7 transgenic mice displayed glucose intolerance, suggesting that the Lin28/let-7 pathway plays a specific and tightly regulated role in modulating glucose metabolism in mammals. In vitro experiments revealed that Lin28a enhances glucose uptake via an increase in insulin-PI3K-mTOR signaling due in part to the derepression of multiple direct let-7 targets in the pathway, including IGF1R, INSR, IRS2, PIK3IP1, AKT2, TSC1 and RICTOR. Experiments with the mTOR-specific inhibitor rapamycin demonstrate that Lin28a regulates growth, glucose tolerance, and insulin sensitivity in an mTOR-dependent manner in vivo. In addition, analysis of T2D and fasting glucose whole genome associations suggests a genetic connection between multiple genes regulated by let-7 and glucose metabolism in humans. These metabolic functions for Lin28a/b and let-7 in vivo provide a mechanistic explanation for how this pathway might influence embryonic growth, metabolic disease and cancer.
We previously described a tetracycline-inducible Lin28a transgenic mouse that showed leaky constitutive Lin28a expression in the absence of induction (See Experimental Procedures, "Lin28a Tg" mice: Zhu et al., 2010). In that study, we showed that these mice cleared glucose more efficiently during glucose and insulin tolerance testing (GTT and ITT), classic metabolic tests used for the characterization of whole animal glucose handling. Given that young Lin28a Tg mice exhibited enhanced glucose metabolism, we tested if old Lin28a Tg mice were also resistant to age-induced obesity. Compared to Lin28a Tg mice, wild-type mice fed a normal diet gained significantly more fat mass with age (Figure 1A). Dual Energy X-ray Absorptiometry scans showed increased percentage lean mass and reduced percentage body fat in the Lin28a Tg mice (Figure 1B,C). To rule out behavioral alterations, we measured activity over three days in isolation cages and found no differences in horizontal activity, O2/CO2 exchange, and food/water intake between wild-type and Tg mice (Figure S1A,B). To determine if these mice were resistant to HFD-induced obesity, we fed mice a diet containing 45% kcals from fat, and observed resistance to obesity in the Lin28a Tg mice (Figure 1D). Lin28a Tg mice consumed as much high-fat food as their wild-type littermates, ruling out anorexia (data not shown). Furthermore, we inquired if Lin28a Tg mice were resistant to HFD-induced diabetes and found that they had markedly improved glucose tolerance and insulin sensitivity under HFD conditions (Figure 1E,F). Lin28a Tg mice also showed resistance to HFD-induced hepatosteatosis (Figure 1G). Taken together, leaky Lin28a expression in the muscle, skin and connective tissues (Zhu et al., 2010) protected against obesity and diabetes in the context of aging and HFD.
Although Lin28a and Lin28b both block let-7 miRNAs, they are differentially regulated, resulting in distinct expression patterns during normal development and malignant transformation (Guo et al., 2006; Viswanathan et al., 2009). Given that LIN28B is overexpressed more frequently than LIN28A in human cancer, we sought to determine if LIN28B exerts a similar effect on glucose metabolism. Thus, we generated a mouse strain with human LIN28B driven by a tetracycline transactivator rtTA placed under the control of the Rosa26 locus (iLIN28B mouse) (See Experimental Procedures). After 14 days of treatment with the tetracycline analogue doxycycline (dox), high levels of LIN28B were induced and mature let-7's were repressed in metabolically important organs (Figure 1H,I), resulting in hypoglycemia with an average fasting glucose of <50 mg/dL in induced mice compared to >150 mg/dL in control mice (p < 0.01). To determine the kinetics of this effect, we measured fed state glucose daily and noted falling glucose levels after 5 days (Figure 1J). Glucose and insulin tolerance tests on dox-induced animals on normal diets showed considerable improvements in glucose tolerance and insulin sensitivity (Figure 1K,L). In checking for islet β cell hyperactivity, we found that iLIN28B mice produced no more insulin than control littermates during glucose challenge (data not shown). Under HFD, we found that induced iLIN28B mice were surprisingly resistant to weight gain (Figure 1M) despite a trend towards increased food intake (9.9 vs. 4.8 g/mouse/day; p = 0.075). These mice continued to exhibit superior glucose tolerance after 14 days of dox induction under HFD (Figure 1N), when average weights were 34.5 ± 1.05 grams for controls and 27.1 ± 0.99 grams for iLIN28B mice, demonstrating that HFD had a strong obesogenic and diabetogenic effect on control but not on LIN28B induced animals. Unlike the Lin28a Tg mice, expression was not leaky in the iLIN28B mice (Figure 1H and and3F)3F) and uninduced mice exhibited no growth or glucose phenotypes (Figure S1C,D), making this a better model for inducible Lin28 hyperactivation. These data show that both Lin28 homologues have similar effects on glucose metabolism and obesity, suggesting that these effects are mediated through common mRNA or miRNA targets of the Lin28 family.
We then asked if Lin28a is physiologically required for normal glucose metabolism in one specific adult tissue compartment, skeletal muscle, since previous studies have found low but significant levels of Lin28a expression in the muscle tissues of mice (Yang and Moss, 2003; Zhu et al, 2010). We generated a skeletal muscle-specific knockout of Lin28a by crossing the mouse myogenic factor 5 Cre recombinase strain (Myf5-Cre) to the Lin28afl/fl conditional loss of function mouse (See Experimental Procedures). These muscle-specific knockout mice showed impaired glucose tolerance (Figure 1O) and insulin resistance (Figure 1P) relative to wild-type littermates, demonstrating that Lin28a activity in skeletal muscles is required for normal glucose homeostasis. We analyzed miRNA expression in muscle tissue by qRT-PCR and found no significant difference in let-7 levels during adult (data not shown) or embryonic stages (Figure S1E), suggesting that Lin28a loss of function affects glucose homeostasis either through let-7-independent mRNA binding or through changes in the spatiotemporal distribution of let-7 miRNA. Together, these data show that Lin28 isoforms are important and essential regulators of glucose homeostasis.
In addition to their ability to suppress let-7 biogenesis, Lin28a and Lin28b also regulate mRNA targets such as Igf2, HMGA1, OCT4, histones and cyclins through non-let-7 dependent mechanisms of mRNA binding and enhanced translation (Polesskaya et al., 2007; Xu and Huang, 2009; Xu et al., 2009; Peng et al., 2011). To test if altered let-7 expression might produce the opposite phenotypes of Lin28a/b gain of function, we generated a mouse strain in which let-7g can be induced with dox under the control of the Rosa26 locus (iLet-7 mouse, See Experimental Procedures). To ensure that endogenous Lin28 would not block pri- or pre-let-7g biogenesis, we used a chimeric let-7g species called let-7S21L (let-7g Stem, mir-21 Loop), in which the loop region of the precursor miRNA derives from mir-21 and cannot be bound by Lin28, thus allowing for let-7 processing despite Lin28 expression (Piskounova et al., 2008). Global transgene induction from three weeks of age onwards increases mature let-7g levels in liver (>50-fold), skin (>20-fold), fat (~4-fold) and muscle (~4-fold) (Figure 2A). This level of let-7 overexpression led to reduced body size and growth rates in induced animals (Figure 2B,C). Growth retardation was proportional and not manifested as preferential size reduction in any particular organs (Figure S2A). Similar to the iLIN28B mice, leaky expression was not detected and uninduced male mice exhibited no growth or glucose phenotypes (Figure S2B–D).
After 5 days of let-7 induction, these iLet-7 mice produced an increase in fed state glucose (Figure 2D). GTT revealed glucose intolerance in mice fed normal (Figure 2E) or HFD (Figure 2F). Surprisingly, ITT failed to detect a difference in insulin sensitivity (Figure 2G). The decreased glucose tolerance in the setting of comparable insulin sensitivity suggested either decreased insulin production from islet β cells in response to glucose, or higher insulin secretion to compensate for peripheral insulin resistance. Thus, we measured insulin production following glucose challenge, and found that iLet-7 mice produced more insulin than controls (Figure 2H). These results demonstrated that broad overexpression of let-7 results in peripheral glucose intolerance and compensatory overproduction of insulin from islet β cells.
To test if let-7 induction could abrogate the glucose uptake phenotype of LIN28B overexpression, we crossed the iLIN28B to the iLet-7 inducible mice. After 10 days of induction, simultaneous induction of LIN28B and let-7g did not result in any differences in glucose tolerance (Figure 2I,J), in contrast to LIN28B or let-7g induction alone. Taken together, the opposing effects of Lin28 and let-7 expression on glucose regulation show that Lin28 overexpression influences metabolism in part by suppressing let-7, and that let-7 alone is sufficient to regulate glucose metabolism in vivo.
To dissect the molecular mechanism of the effects of Lin28 and let-7 on glucose regulation, we turned to the C2C12 cell culture system. Overexpression of Lin28a in C2C12 myoblasts resulted in protein levels of Lin28a similar to that observed in mouse embryonic stem cells (ESCs) (Figure 3A), and led to robust let-7 suppression (Figure 3B). In C2C12 myotubes differentiated for 3 days, Lin28a promoted Ser473 phosphorylation of Akt and Ser235/236 phosphorylation of S6 ribosomal protein, suggesting activation of the PI3K-mTOR pathway (Figure S3A). In this setting, Lin28a increased myotube glucose uptake by 50% (Figure 3C). Lin28a-dependent glucose uptake was abrogated by 24hr treatment with the PI3K/mTOR inhibitor LY294002 or the mTOR inhibitor rapamycin (Figure 3C), but not the MAPK/ERK inhibitor PD98059 (Figure S3B), demonstrating that Lin28a-dependent glucose uptake requires the PI3K-mTOR pathway.
To exclude myotube differentiation-dependent phenomena, we tested the effects of Lin28a on PI3K-mTOR signaling in undifferentiated myoblasts under serum-fed, serum-starved, and insulin-stimulated conditions (Figure 3D). In the serum-fed state, we found that Lin28a promoted the activation of PI3K/Akt signaling by increasing Akt phosphorylation at both Ser473 and Thr308, compared to the pBabe control. Furthermore, we found that Lin28a robustly increased the phosphorylation of mTORC1 signaling targets S6 and 4EBP1 in the serum-fed state. Serum-starvation for 18 hours abrogated the phosphorylation of Akt, S6 and 4EBP1, indicating that Lin28a-induction of PI3K-mTOR signaling requires exogenous growth factor stimulation. Upon insulin stimulation, Akt phosphorylation increased dramatically and, both phospho-S6 and phospho-4EBP1 levels were increased even further by Lin28a overexpression, suggesting that Lin28a increases the insulin-sensitivity of C2C12 myoblasts. Importantly, we found that rapamycin abrogated the Lin28a-induction of phospho-S6 and phospho-4EBP1 upon insulin stimulation, but did not affect let-7 levels (Figure S3C) or Lin28a itself (Figure 3D), indicating that the mTOR dependence is occurring downstream of Lin28a.
To test if the effects of Lin28a on insulin-PI3K-mTOR signaling are let-7-dependent, we transfected either mature let-7f duplex or a negative control miRNA into both Lin28a-overexpressing and pBabe control myoblasts (Figure S3D and Figure 3E). Because mature let-7 duplexes cannot be bound and inhibited by Lin28a protein, this experiment tests if PI3K-mTOR activation is occurring downstream of let-7. Transfection with control miRNA did not affect Lin28a-induction of the phosphorylation of Akt, S6, or 4EBP1 in serum-starved myoblasts upon insulin stimulation. Transfection with let-7f, however, attenuated the Lin28a-induction of phospho-Akt (Ser473), and abrogated the increase in S6 and 4EBP1 phosphorylation upon insulin stimulation in Lin28a-overexpressing myoblasts (Figure 3E). In pBabe control myoblasts, let-7 duplex still suppressed S6 and 4EBP1 phosphorylation in the serum-fed state, serum-starved, and insulin-stimulated conditions, relative to total S6 and 4EBP1 protein. The suppression of mTOR signaling by let-7 even in the absence of Lin28a implies that let-7 can act independently downstream of Lin28a. Together with data indicating that let-7 abrogates Lin28a-specific induction of p-Akt, p-S6 and p-4EBP1 upon insulin stimulation, this demonstrates that the effects of Lin28a on PI3K-mTOR signaling are at least in part due to let-7 and that Lin28 and let-7 exert opposing effects on PI3K-mTOR signaling.
To test if these effects of Lin28 on insulin-PI3K-mTOR signaling are also relevant in vivo, we examined the quadriceps muscles of iLIN28B mice and found that dox-induction led to increases in the phosphorylation of Akt (S473), S6 and 4EBP1, the targets of PI3K-mTOR signaling (Figure 3F). Furthermore, the Insulin-like growth factor 1 receptor (Igf1r) and the Insulin receptor (Insr) proteins were also upregulated in the muscles upon LIN28B induction, reinforcing the fact that Lin28a/b drives insulin-PI3K-mTOR signaling in C2C12 myoblasts and within mouse tissues. On the other hand, similar analysis of the Lin28a muscle-specific knockout mice revealed reduced Insr and p-4EBP1 expression (Figure 3G), demonstrating that Lin28a is both necessary and sufficient to influence glucose metabolism through the regulation of insulin-PI3K-mTOR signaling in vivo.
On the RNA level, Lin28a overexpression in C2C12 myoblasts leads to an increase in mRNA levels of multiple genes in the insulin-PI3K-mTOR signaling pathway (Figure S4A). Although both Lin28a suppression of let-7 and direct Lin28a binding to mRNAs could increase mRNA stability and thus increase mRNA levels, it is possible that these increases do not reflect direct interactions. To find direct targets, we performed a bioinformatic screen using the TargetScan 5.1 algorithm (Grimson et al., 2007), and found that 16 genes in the insulin-PI3K-mTOR pathway contained evolutionarily conserved let-7 binding sites in their respective 3′UTRs (Figure 4A,B). Next, we performed 3′ UTR luciferase reporter assays to determine if these genes were bona fide and direct targets of let-7. To do this, we generated luciferase reporters with twelve human 3′UTR fragments containing conserved let-7 sites. Luciferase reporter expression in human HEK293T cells after transfection of either mature let-7f duplex or a negative control miRNA demonstrated that the 3′ UTRs of INSR, IGF1R, IRS2, PIK3IP1, AKT2, TSC1 and RICTOR were targeted by let-7 for suppression (Figure 4C). Three-base mismatch mutations in the seed region of the let-7 binding sites abrogated let-7's suppression of INSR, IGF1R and IRS2. To confirm that the luciferase reporters predicted actual changes in protein expression mediated by let-7, we assayed the endogenous expression of some of these proteins upon Lin28a/b overexpression. We found that an increase in Lin28a upregulated Irs2 (Figure 4D) in vitro, and that an increase in LIN28B upregulated Igf1r and Insr protein in skeletal muscles in vivo (Figure 3F). Conversely, INSR and IRS2 are reduced upon both let-7f transfection and LIN28B shRNA knockdown in HEK293T, demonstrating that these regulatory mechanisms hold in both mouse and human cells, and in the setting of both LIN28B gain and loss of function (Figure 4E). This establishes a direct mechanism for let-7's repression and Lin28's derepression of multiple components in the insulin-PI3K-mTOR signaling cascade.
Previously, Lin28a has been shown to enhance Igf2 translation independently of let-7 (Polesskaya et al., 2007), offering an alternative mechanism by which Lin28a might activate the insulin-PI3K-mTOR pathway. To determine the relative contribution of this mechanism, we performed in vitro and in vivo loss of function experiments. Following siRNA knockdown of Igf2 in C2C12 (the efficacy of knockdown is shown in Figure S4B), we found only minimal changes in S6 and 4EBP1 phosphorylation (Figure S4C). In these C2C12 myotubes, glucose uptake was unaffected by Igf2 knockdown, but significantly decreased by let-7a (Figure S4D). In addition, we crossed the Lin28a Tg mice with Igf2 knockout mice and found that the absence of Igf2 did not abrogate enhanced glucose uptake, insulin sensitivity, or the anti-obesity effect mediated by Lin28a (Figure S4E–H). Taken together, these data indicate that the metabolic phenotypes we have observed are not solely due to the ability of Lin28a/b to promote translation of Igf02 mRNA, but do not rule out the possibility that Lin28a/b might modulate other mRNAs in the insulin-PI3K-mTOR signaling pathway.
Given that Lin28a activates the insulin-PI3K-mTOR pathway both in vitro and in vivo, we asked whether the metabolic effects of Lin28a in vivo could be abrogated by pharmacological inhibition of the mTOR pathway. To do this, we injected Lin28a Tg and wild-type littermates with rapamycin 3 times per week beginning when mice were 18 days old. Rapamycin abrogated the growth enhancement in Lin28a Tg mice at doses that had minimal growth suppressive effects on wild-type mice (Figure 5A,B), suggesting that Lin28a promotes growth in an mTOR-dependent manner. Selective suppression of Lin28a-driven growth was observed using several parameters: weight (Figure 5B,C), crown-rump length (Figure 5D), and tail width (Figure 5E). We also tested if the enhanced glucose uptake phenotype in vivo was likewise dependent on mTOR. Indeed, glucose tolerance testing showed that short-term rapamycin reversed the enhanced glucose uptake effect of Lin28a (Figure 5F,G) and reduced the insulin-sensitivity of Lin28a Tg mice to wild-type levels (Figure 5H,I). These data indicate that the glucose uptake, insulin sensitivity and animal growth phenotypes of Lin28a overexpression in vivo are dependent on mTOR signaling.
Finally, we sought to assess the relevance of the Lin28/let-7 pathway to human disease and metabolism, using human genetic studies of T2D and fasting glucose levels. Because the Lin28/let-7 pathway has not been previously implicated in T2D, we first asked whether any of the genes that lie in T2D association regions identified in T2D GWAS and meta-analyses (Voight et al., 2010) are known or predicted let-7 targets. We used TargetScan 5.1 to computationally predict let-7 targets (Grimson et al., 2007), and found that 14 predicted let-7 target genes lie in linkage disequilibrium to 39 validated common variant associations with T2D, including IGF2BP2, HMGA2, KCNJ11 and DUSP9 (strength of T2D association signals p < 4x10−9) (Table 1). Of the computationally predicted let-7 targets associated with T2D, IGF2BP1/2/3 and Hmga2 have been verified as let-7 targets in several studies (Boyerinas et al., 2008; Mayr et al., 2007). To validate the connection between Lin28 and GWAS candidate genes, we analyzed the expression of Igf2bp and Hmga family members in C2C12 cells with and without Lin28a overexpression, and observed increases in Igf2bp1, Igf2bp2, and Hmga2 mRNA following Lin28a overexpression (Figure 6A). To ensure that this was not a C2C12- or muscle-specific phenomenon, we confirmed the upregulation of these genes in 3T3 cells following human LIN28A or LIN28B overexpression on the mRNA (Figure 6B) and the protein level for the Igf2bp family (Figure 6C). We also observed increased expression of Igf2bp2 and Igf2bp3 (Figure 6D) in Lin28a Tg muscle, confirming this link in vivo.
We next asked whether there is a more widespread connection between T2D susceptibility and let-7 targets, in addition to the targets in validated T2D association regions (p < 5x10−8). To address this, we applied a computational method called MAGENTA (Meta-Analysis Gene-set Enrichment of variaNT Associations) (Segre et al., 2010) to GWAS meta-analyses of T2D and fasting glucose blood levels, and tested whether the distributions of disease or trait associations in predefined let-7 target gene sets are skewed towards highly ranked associations (including ones not yet reaching a level of genome-wide significance) compared to matched gene sets randomly sampled from the genome (Table 1). We tested three types of let-7 target definitions with increasing levels of target validation, from in silico predicted let-7 targets using TargetScan 5.1 (Grimson et al., 2007) to experimentally defined targets. For the latter, we used (i) a set of genes with at least one let-7 site in their 3′ UTR and whose mRNA was downregulated by let-7b overexpression in primary human fibroblasts (Legesse-Miller et al., 2009), and (ii) a set of genes whose protein levels were most strongly downregulated by let-7b overexpression in HeLa cells (Selbach et al., 2008). We first tested the let-7 target sets against the latest T2D meta-analysis of eight GWAS (called DIAGRAM+) (Voight et al., 2010), and found significant enrichment (Table 1). The enrichment rose from 1.05-fold for the broadest definition of let-7 targets predicted using TargetScan (~1800 genes; p = 0.036) to 1.92-fold for the experimentally validated target set based on protein level changes in response to let-7 overexpression (~100 genes; p = 1x10−6). In the latter case, an excess of about 20 genes regulated by let-7 at the protein level are predicted to contain novel SNP associations with T2D. Notably IGF2BP2, which is a canonical let-7 target that lies in a validated T2D association locus, was found in all types of let-7 target definitions in Table 1. Furthermore, the genes driving the T2D enrichment signals for the different let-7 target sets include both functionally redundant homologues of T2D-associated genes, such as IGF2BP1 (IGF2BP2), HMGA1 (HMGA2), DUSP12 and DUSP16 (DUSP9), and genes in the insulin-PI3K-mTOR pathway, including IRS2, INSR, AKT2 and TSC1 (best local SNP association p = 10−4 to 4*10−3).
We next tested for enrichment of let-7 target gene associations with fasting glucose levels, using data from the MAGIC (Meta-Analysis of Glucose and Insulin-related traits Consortium) study of fasting glucose levels (Dupuis et al., 2010). We observed an over-representation of multiple genes modestly associated with fasting glucose at different levels of significance for the different let-7 target gene sets (Table 1). The strongest enrichment was found in the genes downregulated at the mRNA level by let-7, an enrichment of 1.20 fold over expectation (p = 1*10−4). Taken together, our human genetic results support the hypothesis that genes regulated by let-7 influence human metabolic disease and glucose metabolism.
Recently it has also become clear that Lin28a/b has important let-7-independent roles in RNA metabolism, as evidenced by numerous direct mRNA targets whose translation is enhanced by LIN28A (Peng et al., 2011). Using GSEA, we found that this list of direct mRNA targets is also significantly enriched for glucose, insulin and diabetes-related genes (Table S1). Thus, Lin28a/b may regulate metabolism through direct mRNA-binding as well as let-7 targets.
Our work defines a new mechanism of RNA-mediated metabolic regulation. In mice, Lin28a and LIN28B overexpression results in insulin sensitivity, enhanced glucose tolerance, and resistance to diabetes. Our analysis of iLet-7 Tg mice shows that let-7 upregulation is also sufficient to inhibit normal glucose metabolism, supporting the idea that gain of Lin28a/b exerts effects on whole animal glucose metabolism at least in part through let-7 suppression. Previously, we showed that transgenic overexpression of Lin28a causes enhanced growth and delayed puberty, phenotypes that mimicked human traits linked to genetic variation in the Lin28/let-7 pathway in GWAS (Zhu et al., 2010). Given that Lin28a/b is downregulated in most tissues after embryogenesis, while let-7 increases in adult tissues, lingering questions from our earlier report were first, whether let-7 was sufficient to influence organismal growth, and second, what function does let-7 have in adult physiology? Our observation that the iLin28a, iLIN28B, and iLet-7 Tg gain of function mice, as well as muscle-specific Lin28a loss of function mice manifest complementary phenotypes supports the notion that Lin28a/b and let-7 are both regulators of growth and developmental maturation. We propose that different developmental time-points demand distinct metabolic needs, and that global regulators such as Lin28 temporally coordinate growth with metabolism. The dynamic relationship between Lin28, let-7 and metabolic states during major growth milestones in mammals is reminiscent of the heterochronic mutant phenotypes originally defined in C. elegans (Ambros and Horvitz, 1984; Moss et al., 1997; Boehm and Slack, 2005), and suggests that metabolism, like differentiation, is temporally controlled.
We have shown that Lin28a/b and let-7 regulates insulin-PI3K-mTOR signaling, a highly conserved pathway that regulates growth and glucose metabolism throughout evolution. PI3K/Akt signaling is known to promote Glut4 translocation to upregulate glucose uptake, while mTOR signaling can promote glucose uptake and glycolysis by changing gene expression independently of Glut4 translocation (Brugarolas et al., 2003; Buller et al., 2008; Duvel et al., 2010). Previous studies have shown that Lin28a directly promotes Igf2 (Polesskaya et al., 2007) and HMGA1 translation (Peng et al., 2011), and that let-7 suppresses IGF1R translation in hepatocellular carcinoma cells (Wang et al., 2010). Consistent with these findings, our results define a model whereby Lin28a/b and let-7 coordinately regulate the insulin-PI3K-mTOR pathway at multiple points (Figure 6E), a concept that is consistent with the hypotheses that miRNAs and RNA binding proteins regulate signaling pathways by tuning the production of a broad array of proteins rather than switching single components on or off (Kennell et al., 2008; Hatley et al., 2010; Small and Olson, 2011). Coordinated regulation is important because negative feedback loops exist within the insulin-PI3K-mTOR pathway. Loss-of-function and pharmacological inhibition studies have shown that the mTOR target S6K1, for instance, inhibits and desensitizes insulin-PI3K signaling by phosphorylating IRS1 protein and suppressing IRS1 gene transcription (Harrington et al., 2004; Shah et al., 2004; Tremblay et al., 2007; Um et al., 2004). Conversely, TSC1–2 promotes insulin-PI3K signaling by suppressing mTOR signaling (Harrington et al., 2004; Shah et al., 2004). Although the effects of let-7 and Lin28a/b on the expression of individual genes are modest, simultaneous regulation of multiple components such as IGF2, IGF1R, INSR, IRS2, PIK3IP1, AKT2, TSC1, RICTOR in the insulin-PI3K-mTOR signaling pathway could explain how this RNA processing pathway coordinately regulates insulin sensitivity and glucose metabolism by effectively bypassing these negative feedback loops.
Whereas our work has implicated let-7 as a regulator of insulin-PI3K-mTOR signaling, we do not exclude a parallel role for direct mRNA targets of Lin28a/b in glucose metabolism, a hypothesis supported by the recent findings that HMGA1 is translationally regulated by LIN28A and mutated in 5–10% of T2D patients (Peng et al., 2011; Chiefari et al., 2011). Such non-let-7 functions are also suggested by the fact that muscle-specific loss of Lin28a results in glucose derangement without significant let-7 changes. Nevertheless, it remains likely that during other developmental stages or in other tissues, let-7 suppression by Lin28a or Lin28b is required for normal glucose homeostasis. The effects of the Lin28/let-7 pathway on glucose metabolism in our murine models, together with our observation that genes regulated by let-7 are associated with T2D risk in humans, indicates important functional roles for both Lin28a/b and let-7 in human metabolism.
Metabolic reprogramming in malignancy is thought to promote a tumor's ability to produce biomass and tolerate stress in the face of uncertain nutrient supplies (Vander Heiden et al., 2009). During their rapid growth phase early in development, embryos may utilize similar programs to maintain a growth-permissive metabolism. Dissecting the genetic underpinnings of embryonic metabolism would likely provide important insights into the nutrient uptake programs that are co-opted in cancer. While loss of function studies in the early embryo would help define the metabolic roles of oncofetal genes in their physiologic context, classical in vivo metabolic assays are difficult to perform in embryos. Lin28a and Lin28b are oncofetal genes, and thus highly expressed in early embryogenesis and then silenced in most adult tissues, but reactivated in cancer (Yang and Moss, 2003; Viswanathan et al., 2009). Cancer cells may utilize the embryonic function of Lin28a/b to drive a metabolic shift towards increased glucose uptake and glycolysis – a phenomenon termed the "Warburg effect." Previously, we showed that Lin28a expression promotes glycolytic metabolism in muscle in vivo and in C2C12 myoblasts in vitro (Zhu et al., 2010). Though we cannot yet readily determine the metabolic effects of shutting off Lin28a/b within the embryo, we have dissected the potent effects of reactivating and inactivating this oncofetal program in adults. Conversely, in normal adult tissues that do not express high levels of Lin28a or Lin28b, one might ask if a role for the highly abundant let-7 is to lock cells into the metabolism of terminally differentiated cells to prevent aberrant reactivation of embryonic metabolic programs. Further studies are required to understand how this pathway may link mechanisms of tumorigenesis and diabetogenesis.
Our report implicates Lin28a/b and let-7 as important modulators of glucose metabolism through interactions with the insulin-PI3K-mTOR pathway and T2D-associated genes identified in GWAS. Although it is likely that additional mechanisms and feedback loops exist, our data suggests a model whereby Lin28a/b and let-7 coordinate the GWAS identified genes and the insulin-PI3K-mTOR pathway to regulate glucose metabolism (Figure 6E). It also suggests that enhancing Lin28 function or abrogating let-7 may be therapeutically promising for diseases like obesity and diabetes. Likewise, results from this work might shed light on the physiology of aging and, specifically, how the accumulation of let-7 in aging tissues may contribute to the systemic insulin resistance that accompanies aging.
All animal procedures were based on animal care guidelines approved by the Institutional Animal Care and Use Committee. Mouse lines used in this study are described in the Extended Experimental Procedures and Figure S5.
The apparatus used was a set of 16 OxyMax® Metabolic Activity Monitoring chambers (Columbus Instruments; Columbus, OH, USA). Each chamber consisted of a self-contained unit capable of providing continuous measurements of an individual mouse's total activity and feeding behavior. Monitoring occurred over a 3-day period. Each subject was placed into an individual chamber on day 1, with free access to food and water during the course of the experiment. Subjects were maintained under a normal 12:12 h light:dark cycle. All measurements were sampled periodically (at approximately 12-min intervals) and automatically recorded via the OXYMAX Windows V3.22 software. Activity measures over the final 24-h period were parceled into 2-h bins and these were used to express diurnal activity levels.
Performed with standard methods, which are described in detail in the Extended Experimental Procedures.
Tissue samples were fixed in 10% buffered formalin or Bouin's solution and embedded in paraffin.
Overnight-fasted mice were given i.p. glucose (2 mg/g body weight). For insulin tolerance test, 5 hour fasted mice were given 0.75 U insulin/kg body weight by i.p. injection (Humulin). Blood glucose was determined with a Lifescan One Touch glucometer. Insulin, GH, and Igf1 levels were measured by ELISA (Crystal Chem).
Murine Lin28a and human LIN28B cDNA was subcloned into pBabe.Puro and pMSCV.Neo retroviral vectors. LIN28B and Control shRNA in lentiviral plasmids were purchased from Sigma-Aldrich and previously reported in Viswanathan et al., 2009. UTR cloning for luciferase reporters is described in Supplemental Table S2.
Performed using standard methods as described in the Extended Experimental Procedures.
In vitro glucose uptake assays were performed as described in Berti and Gammeltoft, 1999.
Rapamycin was injected i.p. 3 times a week for mouse experiments. For cell culture, C2C12 myotubes differentiated for 3 days were incubated with inhibitors for 1 day prior to glucose uptake assays. See Extended Experimental Procedures for further details.
Performed using standard methods. Detailed methods and reagents used are described in the Extended Experimental Procedures.
10 ng of each construct was co-transfected with 10 nM miRNA duplexes or into HEK-293T cells in a 96-well plate using lipofectamin-2000 (Invitrogen). After 48 hours, the cell extract was obtained; firefly and Renilla luciferase activities were measured with the Promega Dual-Luciferase® reporter system.
See Results, Table 1 Legend, and Extended Experimental Procedures for detailed methods.
Data is presented as mean ± SEM, and Student's t-test (two-tailed distribution, two-sample unequal variance) was used to calculate p values. Statistical significance is displayed as p < 0.05 (one asterisk) or p < 0.01 (two asterisks). The tests were performed using Microsoft Excel where the test type is always set to two-sample equal variance.
We thank John Powers, Harith Rajagopalan, Jason Locasale, Abdel Saci, Akash Patnaik, Charles Kaufman, Christian Mosimann and Lewis Cantley for invaluable discussions and advice, Roderick Bronson and the Harvard Medical School Rodent Histopathology Core for mouse tissue pathology, and the Harvard Neurobehavior Laboratory for CLAMS experiments. This work was supported by grants from the US NIH to G.Q.D., a Graduate Training in Cancer Research Grant and a American Cancer Society Postdoctoral Fellowship to H.Z., the NSS Scholarship from the Agency for Science, Technology and Research, Singapore for N.S.C, an NIH NIDDK Diseases Career Development Award to M.G.K, and an American Diabetes Association Postdoctoral Fellowship for A.V.S. J.M.E. was supported by the National Human Genome Research Institute (NHGRI). R.I.G. was supported by US National Institute of General Medical Sciences (NIGMS) and is a Pew Research Scholar. D.A. is a Distinguished Clinical Scholar of the Doris Duke Charitable Foundation. G.Q.D. is a recipient of Clinical Scientist Awards in Translational Research from the Burroughs Wellcome Fund and the Leukemia and Lymphoma Society, and an investigator of the Howard Hughes Medical Institute and the Manton Center for Orphan Disease Research.
AUTHOR CONTRIBUTIONSH.Z. and N.S.C designed and performed the experiments, and wrote the manuscript. A.V.S. and D.A. performed bioinformatic analysis on let-7 targets in GWAS. G.S. and S.P.S. performed expression analysis, metabolic assays and mouse husbandry. G.S., W.S.E. and A.T. generated the mouse strains. J.E.T, R.T. and R.I.G. assisted with the luciferase assays. J.P.H., R.I.G., G.S., and A.T generated the conditional knockout mice. M.G.K. helped to design the experiments. G.Q.D. designed and supervised experiments, and wrote the manuscript.
The authors declare no competing financial interests.
Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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The Mississippi Epsilon Chapter of the Kappa Mu Epsilon National Mathematics Honor Society recently held its annual initiation. Students hnored this year include: (left to right) Syndey Claire Sullivant, Hope Rainey, Katie
Home » News and Events » Archive by category "Academics" (Page 8)
Category Archives: Academics
The Delta State University Choirs will present "Carmina Burana" April 12 at 7:30 p.m. in the Bologna Performing Arts Center. "Carmina Burana" is a cantata composed by Carl Orff, and uses the text of 24 medieval poems.
Delta State University recently announced Don Allan Mitchell, associate professor of English, as the chair of the Department of Languages & Literature. Mitchell had served as chair on an interim basis since July of
Delta State University recently announced Dr. Karen Fosheim, professor of music, as the new chair of the Department of Music. Fosheim had served as the interim chair since July of 2015. "The music faculty at DSU is
A group of Delta State faculty known as the Advising Champions are continuing their advising efforts dedicated to the development of a streamlined campus-wide advising process. Each Advising Champion is a faculty member


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Cub Contingent Leads Solar Sox to Victory
Andrew Cashner threw four innings of no run, no hit ball, and Starlin Castro had two hits, drove in a run and scored two more, and made the defensive play of the day, as the Mesa Solar Sox exterminated the Scottsdale Scorpions 12-5 in Arizona Fall League action this afternoon at HoHoKam Park in Mesa.
Pitching on a cool & breezy day with the wind blowing out at 15-20 MPH gusting to 30, the 23-year old Cashner (Cubs #1 draft pick out of TCU in 2008) had no trouble with the Scorpions. He threw just 44 pitches (25 strikes) in his four innings of work, getting ahead of most of the hitters as he mixed a 94-96 MPH fastball with a sharp breaking ball and an occasional change-up. The only glitches were a four-pitch walk to Steve Susdorf (Phillies) leading off the 3rd and a walk to Brandon Allen (Diamondbacks) on a 3-1 pitch with two outs in the 4th. He struck out four (including Phillies top position-player prospect Domonic Brown, swinging), got four outs on ground balls, and another four on fly balls or pop-ups.
Starlin Castro played SS for the Solar Sox and hit 2nd today, and got five plate appearances. He grounded a single sharply through the box into CF off RHP Chaz Roe (Rockies) with one out and nobody on base in the bottom of the 1st inning and later scored on a Josh Vitters RBI single, lined out to right on a hit & run play with a runner on 1st base and no outs in the 2nd off junkballin' RHP Tooru Murata (Tokyo Yomiuri Giants), punched an RBI single to left through a drawn-in infield off RHP Edgar Garcia (Phillies) in the bottom of the 3rd and later scored, struck out swinging on a hard-breakin' slider in the dirt against RHP Andrew Johnston (Rockies) in the 5th, and reached base on an E-4 (short-hopper ricocheted off Scottsdale 2nd baseman Chase D'arnaud's chest).in the 7th.
Castro also turned-in the defensive play of the day, showing off his range and his arm as he made a diving stop behind second base, and then, from his knees, threw out speedy lead-off man Jose Tabata (Pirates). Castro also made a nice turn on a 6-4-3 DP in the 8th. And although Castro was charged with an error on a D'arnaud RBI double in the top of the 5th when his relay throw got past Solar Sox catcher Hank Conger (Angels) allowing D'arnaud to advance from 2nd to 3rd on the play at the plate, the throw really wasn't that bad. Conger just couldn't catch the short-hop.
Josh Vitters (Cubs #1 draft pick in 2007) was the Solar Sox DH and hit 5th. He grounded an RBI single through the box to CF (scoring Castro) off Roe in his first AB in the bottom of the 1st and scored later in the inning, and then he ripped another hit through the box off Murata in the bottom of the second. He flied out to the warning track in CF in the 3rd, bounced into an inning-ending 5-4-3 DP against Johnston in the 5th, and struck out swinging on a 1-2 breaking ball at his shoe top (and looked bad doing it, too) in the 7th against LHP Matt Reynolds (Rockies).
LHP James Russell entered the game in the top of the 8th and pitched a shutout inning (11 pitches - eight strikes). He gave up a lead-off line-drive single to LF to Brandon Crawford (Giants), but then got Buster Posey (Giants) to ground into a 4-6-3 DP (that was the nice turn by Castro) and Susdorf (Phillies) to ground out weakly 3-U to end the inning. Russell had a really good change-up today, and he threw strikes, which is the key for him.
After allowing three runs in his first AFL outing a couple of weeks ago, Russell has thrown five consecutive shutout innings over his last four appearances. The son of one-time MLB closer Jeff Russell, James was the Cubs 14th round selection in the 2007 Rule 4 Draft out of the University of Texas, although he did get "3rd round money" to give up his senior year in college (he was considered to be likely unsignable going into the draft, which is why he fell to the 14th round). He should be a strong candidate for a back-of-the-rotation starter gig at Iowa in 2010.
Re: Cub Contingent Leads Solar Sox to Victory
thanks for the report...
have you seen any of the defensive yips that seemed to plague Castro during the season?
And is James Russell just a younger Sean Marshall?
Re: Cub Contingent Leads Solar Sox to Victory
how fast does the infield surface play? how good/bad predictable are the bounces through the infield?
Re: Cub Contingent Leads Solar Sox to Victory
thanks. been told a long time they play fast, but that was years ago and groundskeeping techniques tend to make strides every few years.
Re: Cub Contingent Leads Solar Sox to Victory
What do you make of the poor performance in the AFL of Gaub and Parker?
Re: Cub Contingent Leads Solar Sox to Victory
i thought parker was doing well....
Re: Cub Contingent Leads Solar Sox to Victory
only 3-6 more games until the official offseason
Re: Cub Contingent Leads Solar Sox to Victory
i hate the offseason...but it does give me time to catch up on movies.
by dec/jan i'm ready for spring training games.
Re: Cub Contingent Leads Solar Sox to Victory
Overture? Make-Good? That Jaramillo connection?
Mark DeRosa underwent wrist surgery Monday to repair a torn tendon sheath in his left wrist, an official with DeRosa's agent's office confirmed this afternoon. The surgery was performed Monday in Atlanta by hand surgery Dr. Gary Lourie.
The Cardinals plan to go into 2010 with rookie David Freese having a chance to win the starting third base job. That doesn't eliminate their interest in having DeRosa return, but it does limit the role DeRosa could see for himself. At the end of the season, he said he wanted to look for the best opportunity for playing time and for contending.
The Chicago Cubs figured to make an overture toward DeRosa as a make-good for trading him to Cleveland before the 2009 season — a move general manager Jim Hendry conceded was a mistake.
Re: Cub Contingent Leads Solar Sox to Victory
Hopefully Hendry isn't stupid enough to give DeRosa 3/30 NTC type of deal.
However I would be all for bringing DeRosa back on a 1 year and maybe a vesting option for year 2 type of deal. Especially if they money isn't more than 5-7 million per season.
Re: Cub Contingent Leads Solar Sox to Victory
How about getting Greg Maddux and Ryne Sandberg back?
You can bitch about who we got for DeRosa, but trading him when he was at his peak value was probably the best move Hendry made last year. 2008 is gone, let it go.
Re: Cub Contingent Leads Solar Sox to Victory
Unless DeRosa was the one missing link that would've put them over the top? It's possible...
Re: Cub Contingent Leads Solar Sox to Victory
On Mike and Mike this morning, Yankee anouncer Michael Kay speculated that with loss yesterday and bring back CC on 3 days rest that Chad Gaudin would be the game five starter.
Re: Cub Contingent Leads Solar Sox to Victory
the one missing link...
Neanderthal DeRosa?
Re: Cub Contingent Leads Solar Sox to Victory
AustraloDeRosacus? DeRosalopithecus?
Re: Cub Contingent Leads Solar Sox to Victory
baseball prospectus' prospect guru, Kevin Goldstein, had this to say about Cashner after his 4 inning shutout stint:
Andrew Cashner, RHP, Cubs (AFL: Mesa)
Yesterday's stats: 4 IP, 0 H, 0 R, 2 BB, 4 K
Whatever order you want to put them, Cashner, along with infielders Josh Vitters and Starlin Castro, are the top three prospects in the Cubs system, and all of them are having outstanding seasons so far for Mesa. Four no-hit innings are even more impressive considering the offensive context of the league, and his stuff matched the stats, as he sat at 92-96 mph with his fastball, and his slider is a wipeout offering at times.
Re: Cub Contingent Leads Solar Sox to Victory
Earlier on Castro:
Generating a ton of buzz right now in the desert is Castro, the 19-year-old shortstop who, after Tuesday's outburst, is now 12-for-23 in six games for the Solar Sox without a strikeout. His ability to put the bat on the ball is remarkably advanced for his age. While he's not the next Ozzie Smith, he is a true shortstop who also has surprisingly solid defensive fundamentals for such a young talent, as he's also yet to make an error in Arizona. Is he the top prospect in the system? You could at least make the argument.
At some point this season I could swear he called him a 2nd basemen... I'll have to stalk around a bit more and see if I can find it.
Re: Cub Contingent Leads Solar Sox to Victory
Here we go:
"markDC (Washington, DC): Starlin Castro - starting Cubs shortstop in 2011?
Kevin Goldstein: No. Second base, maybe, but not shortstop."
Which maybe I read into too much, but it seems like he's come around since then.
Re: Cub Contingent Leads Solar Sox to Victory
if you just look at numbers you'd jump to the conclusion he wasn't destined for SS.
they're horrid. i asked about them not too long ago (here) because i didnt know much about the guy. i was told his numbers were lieing. it seems that may be true.
Re: Cub Contingent Leads Solar Sox to Victory
That's not something he typically does.
I often wonder how much a scouts' appraisal of a player's defense goes up as the player's bat improves.
Re: Cub Contingent Leads Solar Sox to Victory
yeah, he used to work for BA and did a lot of west coast work and he's got his cred, etc...i just wonder how stretched out he is.
it's ultimately his call on whether he thinks a player is destined to move, but he seemed pretty adamant about it in the quote.
Re: Cub Contingent Leads Solar Sox to Victory
CarrieMuskat: Jeff Samardzija threw six shutout innings, struckout seven in Mexicali win Friday. He's expected to make at least one more start
Recent comments
First team to 60 wins! Onward to 70, 80, 90 and 100!
I. Hate. The. Mets.
OK Marlins -- take 'em down. Fernandez, at home, tomorrow for the Fish.
Gotta say, though -- as much as I can't stand them, the Cardinals have had some very impressive late-inning wins against premier closers.
Very impressive that he hit a 3-2 curve ball. Such a dynamic ballplayer. If he ever learns the strike zone....
If Jason Hammel doesn't get a potato chip sponsorship deal, somebody messed up. Attaboy, Jason!
I am looking forward to AChap facing the Cardinals.
Sure is fun to watch them score finally. To think they were no-hit until the 7th...
Got to admit it - it was comforting seeing Rondon come out for the eighth after just taking a two run lead ... And put the hammer down with a 7 pitch inning. Good stuff
blown the hell open...7 run lead
11 hits off Wainwright tonight. Everything going right for the Cards right now. Motherfucking motherfuckers.
it was more no-doubt than bryant's HR. it wont make any end-of-season highlight reels, but that one was booked to leave on contact.
Javy! Javy! Javy!
How sweet was that - Cranked it!
393 happy feet
cubs take a 2 run lead in the 7th. sweet.
...and the Cards tie and take the lead in the 9th. off Familia.
Familia blows his first save of the season -- gives up 2 in 9th to the Cards.
Not much going our way these days.
bryant's back!
no-doubt HR towering to CF...tie game.


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Tomatoes and Leeks With Fresh Sage
Total Time
Prep 0 mins
Cook 7 mins
From 1,000 Lowfat Recipes. Original recipe called for dried sage but I chose to use fresh sage.
Ingredients Nutrition
- 2 small leeks, thinly sliced (remove green tops)
- 1 -2 garlic clove, minced
- 1 tablespoon olive oil
- 2 beefsteak tomatoes, firm but fresh (about 1 pound)
- 1 tablespoon fresh sage, minced
- 1⁄4 teaspoon salt
- 1⁄8 teaspoon fresh ground black pepper
- Heat up the olive oil in a large saute pan over medium heat.
- Saute the leeks in the oil until golden. Add the garlic the last minute and saute.
- Cut up the tomatoes into wedges. Add them to the pan along with the sage, salt and black pepper. Cook the tomatoes about 3-4 minutes until the tomatoes start to soften, but do not turn to mush.
- Serve warm.
Most Helpful
The most difficult part of this recipe is the tedious cleaning of the leeks. Absolutely delicious! Not to dirty extra dishes, we served it on top of our fettucine w/garlic butter. ;) It worked very well. I doubled the recipe & had no leftovers! Made for Veggie Swap 11/12.


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Be Fabulous (Or Else)
Roxanne Lowit discusses her new exhibition of photos from behind-the-fashion-scene.
The legendary fashion and celebrity photographer Roxanne Lowit found her calling in the late '70s when her friend, the late fashion illustrator Antonio Lopez, gave her an Instamatic 110 camera. Soon after, Lowit, who had been working as a textile designer, established the art of backstage photography when she became one of the first to document the hectic scene behind the scene at a Halston show. "I didn't look like a photographer," recalled Lowit. "Photographers had these big safari jackets on with huge cameras and lenses hanging off them, and I was much thinner, and wore dresses then and color, and was quite stylish."
Lowit would go on to capture the fashion world at close range, from the Bacchanalian nights when Yves Saint Laurent and Karl Lagerfeld ruled the Paris fashion scene — "People would dance all night and think they'd live forever," she remembered — to the height of supermodel stardom in the '90s to John Galliano's Dior couture shows in the aughts to the drag queen scene of the twenty-tens. Now, her photos from the last four decades are the subject of the exhibition "Roxanne Lowit: Be Fabulous," on view through January 18, 2014, at Steven Kasher Gallery in New York.
In one iconic image from 1990, supermodels Christy Turlington, Linda Evangelista, and Naomi Campbell fool around in a bathtub at the Ritz in Paris. "I don't know how they got in there, if they got in themselves, or if I encouraged it, or what," said Lowit. "They were drinking their champagne in the bathtub, cause that makes a good picture. Their feet were going up, and they were laughing." Another photo from 1979 captures a New Year's Eve dinner in New York at Laurent with Salvador Dalí. Lowit didn't believe that Dalí would actually be there. "Lo and behold, there was Dalí, and he saw me with my camera, so he just took [a guest's] hand and kissed it for me," said Lowit. "He performed for the camera."
Lowit says that secret to her success is having patience to wait for the perfect moment and being in the right place at the right time. "There were just so many things that were amazing, that I was lucky enough to walk through those different worlds," said Lowit. "It was incredible that I photographed them."
"Roxanne Lowit: Be Fabulous" is on view at Steven Kasher Gallery, 521 West 23rd Street, New York, through January 18.Follow Us:
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