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This book will draw you in fast and not let go..... very fast paced mystery/ thriller with twists & turns & a "WOW" ending!
Very little action, uninteresting characters, a bad execution of premise, and an equally dumb ending were the highlights I took away from this novel.
The problem is, aside from this idea, the book keeps the reader hanging thinking someone better is going to happen and nothing does.
This book has Amazon reviewers wildly divided. Like me, they have all read this author's earlier work and I think that is a big part of the problem. Read morePublished 2 months ago by carol irvin
I've always enjoyed this author's books but red 123 an outstanding literary achievementPublished 3 months ago by Amazon Customer
Good grief. This was ridiculous. I have read a couple of Katzenbach's other books and was impressed with the writing and the suspense although he seems to consistently run out of... Read morePublished 3 months ago by Dinesen
His book state of mind made me a fan but this book was a little of a let down.
predictable at times.... Read more
He was one of my favorite authors until his last two books. Wow what a disappointment. If you are a fan of his earlier books you will shocked at how slow and predictable this... Read morePublished 4 months ago by JMiller8200
I have been a fan of Katzenbach's since Just Cause, and he certainly did not disappoint in 1-2-3 Red. Read morePublished 4 months ago by mamamamalisa
This book was great...had me turning pages like crazy..great night reading....I would recommend this book to anyone who enjoys suspense thrillers..Published 4 months ago by quigley
Entertaining, and kept my attention. I would have liked to have seen the Wolf developed and explained a bit more, but perhaps the author wanted to keep the character's past and... Read morePublished 5 months ago by Ryan Kelly

subset: commoncrawl


text: NanoName: NanoRank/Function: HackerMental Age: 20Allegiance: DecepticonAlt mode: Transforms into a black iphoneRelationship status: SingleAppearance: A small black and silver mech with red optics. His torso, lower armor/legs/arms and his helm helm are black, his midsection, faceplate, upper arms/legs/ neck and hands are silver.Personality: An intelligent Decepticon who is picky on who he hangs out with, anyone who is lower than him, is considered a loser to him. He gets easily picked on due to his small size. He's an excellent hacker and because of his small size, it's easier for him to sneak by the Autobots without getting detected. He uses his tentacles to upload or download information and to also make hacking easier for him. He hates it when someone compares him to someone who isn't intelligent at all. Whenever he does get mad, he kicks things around or throws something at someone to calm himself down. However, when he's forced to be around the humans to get spy on the Autobots,


text:
View Models
Demo Built-In Refrigeration In A Nearby Showroom
Where to Buy Built-In Refrigeration
Ultimate guardian of food's goodness
Refined design, endless possibilities
What's your look? Compare built-in and integrated styles
The two most popular Sub-Zero product lines, built-in refrigeration and integrated refrigeration, share many performance and design features. And both are built for exceptionally long life. Determining which is the better choice for your home largely hinges on whether you prefer a refrigerator that makes a strong visual statement on its own (as with the iconic stainless steel grille of built-in models) or one that blends, or even disappears, into the décor.
36" Built-In Refrigerator/Freezer(BI-36UFD)
* - sold as sales accessory
At our showroom, there's inspiration everywhere you look. Try out Sub-Zero and Wolf appliances in spectacular, full-scale kitchens. Talk with experts. And get a taste for all that your new kitchen can be.
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Visit a dealer featuring a Sub-Zero and Wolf Living Kitchen, where our products are installed in kitchen vignettes, and specialists are on-hand to walk you through the details of your new appliance purchase.
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Which of the following best describes why you are looking to purchase a new appliance?*
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I would like to receive a free Sub-Zero and Wolf brochure.*


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Cody Simpson - Not Just You [Official Video]
Cody Simpson - Not Just You [Official Video]...
this music video makes me cry i love it so much im sooo jelous of that girl!!! its not fair i looooooove cody simpson nd omg its such a good song!!! CODY COME TO CANADA!!!!!!!!!!!
Cody i love ya wish i could be that lucky girl if i could see you again i would kiss you im youre biggest fan i love ya my boyfriend is mad at me becuase i love you my room is full of posters of you
this is a cute video sometimes it makes me feel that way but someday we all going to find the perfect person
im crying for him and im his biggest fan!!!!!!!!!!!!!!!!!!!!! if i was to meet him i would cry bullets!!!!!!!!!!!!!!!!!!!!!! if cody simpson sees this coment and writes back i would freak out!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
Haven't we talked about this before? I'm almost crying! I can't concentrate at my homeworks just because of you! Your'e amazing but i think you already heard that!? 143
Cody is looking toooooooooo
Cody is looking toooooooooo good!!!!
When I first heard this song it made me cry.My fave part is when Cody notices it wasn't just the girls fault.What is your fave part???


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StyleCaster Media Group
has been acquired by .
Find out more about this story.
Brad Pitt burst onto the scene as the sexy, scruffy bad boy in Thelma and Louise. In recent years, the father of six has tried out everything from surfer bleach blond to an A-list honey-blond crop and a natural short do with matching beard.


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Latest News
PDRF introduces innovative Butterfly Housing Project to Tacloban City
As part of its continuing programs for the recovery and rehabilitation of Yolanda-stricken communities, PDRF is introducing the Butterfly House Project to 50 pilot beneficiaries...
Update on Typhoon Haiyan/Yolanda efforts
as of June 15, 2014
As part of continuing recovery efforts for Leyte, PDRF hosted a Summer Sports Clinic for over 300 school children...
NEWS CLIPPING: PDRF to build 100 houses in Zamboanga City
As seen in The Philippine Star, The Good News Section, June 9, 2014
PDRF and Smart partner with DSWD to kick off mangrove and beach forest project in Yolanda-hit areas, over 1,000 new jobs to be created
Over a thousand new jobs are projected for typhoon survivors in the Yolanda-hit communities of Leyte and Samar...
PDRF supports the upcoming Disaster Preparedness Forum 2014
In cooperation with CSR Asia and PRUDENCE Foundation, PDRF encourages its members, partners and benefactors to join the upcoming Disaster Preparedness Forum 2014.
NEWS CLIPPING: Sports therapy for 'Yolanda's' young survivors
As classes ended and summer began, young survivors of Supertyphoon "Yolanda" in Leyte received a special treat—a sports clinic organized by Smart Communications and Digitel Mobile Philippines (Sun Cellular), with PDRF.
PDRF, PBSP to help revive the sari-sari store economy in Yolanda-hit Leyte
The Philippine Disaster Recovery Foundation and the Philippine Business for Social Progress, in cooperation with the Hapinoy Sari-Sari Store Program of Microventures Foundation Inc.
Update on Typhoon Haiyan/Yolanda efforts as of March 15, 2014
We are happy to continue working with PDRF on reviving the sari-sari store economy in Tacloban.
Update on Typhoon Haiyan/Yolanda efforts as of February 15, 2014
PDRF continues to help people get back on their feet by giving them a means for livelihood and stimulating the local economy.
NEWS CLIPPING: For Yolanda–and future calamities–the private sector stands ready
As is often the case when major natural calamities strike, the country's largest private firms rush to the aid of affected communities.
Stanford University Students From Otero Dorm Give Dollars to Help Yolanda Victims Through PDRF
Led by Mika Limcaoco, students from the Otero Dorm at Stanford University in California mounted a fundraising drive to help victims of Typhoon Yolanda/Haiyan and gave the proceeds to PDRF.
After the Yolanda devastation last year, 20 sari-sari store owners from various barangays in Tacloban City are now back in business...


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Definition of drill sergeant in English:
drill sergeantSyllabification: drill ser·geant
A noncommissioned officer who trains soldiers in basic military skills.
More example sentences
- Tapes of military marches, a drill sergeant's orders and nostalgic 1950s songs add to the atmosphere.
- He previously served as a mechanized rifle company master gunner, drill sergeant, and Bradley fighting vehicle instructor.
- Something is wrong in our society when a high school football coach is allowed to be harder on his players than a drill sergeant is allowed to be on his soldiers in basic training.
Definition of drill sergeant in:
- The British & World English dictionary
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Word of the day retroflex
Pronunciation: ˈrɛtrə(ʊ)flɛks
turned backwards


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more BBC America Shows on Tumblr »
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Stay tuned to your dash! We're posting NEW images from Doctor Who, Series 8, Ep 2, 'Into the Dalek' over the next few minutes.
A Dalek fleet surrounds a lone rebel ship, and only the Doctor can help them now … With the Doctor facing his greatest enemy, he needs Clara by his side. Confronted with a decision that could change the Daleks forever he is forced to examine his conscience. Will he find the answer to the question, "Am I a good man?"
Click through to watch the teaser for 'Into the Dalek', premiering this Saturday August 30th at 9/8c on BBC America. (x)
Find more 'Into the Dalek' images here: (x)
Oh, we'll just leave these awesome new still images from Doctor Who: The Time of the Doctor here.
See you December 25th at 9/8c for the Doctor Who Christmas special.
More new images from the Doctor Who Christmas Special, Doctor Who: The Time of the Doctor.
Premiering December 25th 2013 at 9/8c.
See a full gallery on BBCAmerica.com.
@BBCAMERICA #tca13 party about to kick-off! We arrived by #Tardis, naturally.
Just met the littlest Dalek at the BBC America booth at San Diego Comic-Con
Announcement: it's the return of Livetumblring the BBC America broadcast premieres of Doctor Who!
We're livetumblring the east coast and west coast US premieres of Asylum of the Daleks on BBC America as we do with all new episodes!
For those who haven't seen this sort of thing before, we reblog your reactions, your quotes, along with screenshots and gifs as they happen on the broadcast — it happens on your tv and you see it in your dashboard.
We do this from 9p-10:15p EDT, take a break to adjust the Helmic regulator, put up some non-spoilery posts during the break and then livetumbl again from 9:00p-10:15p Pacific Time.
Because we're doing it in real time — there is no way for us to avoid posting spoilers during these hours!
**SO** if you need to avoid spoilers, install Tumblr Savior. <— That's a link to instructions for all browsers. We will tag all of our posts 'Asylum of the Daleks'. This will be the tag to avoid. We're pinning this post to make sure that everyone sees *this specific piece of information*.
Alternate solutions include unfollowing and refollowing us or just stepping away from your dashboard for a bit b/c the UK premiere is just two hours away and we're not the only ones who will be excited and posting reactions.
So yeah, for those of you who were with us for last season, we are so happy to have you back! For those who are #newtoWHO we are so happy you are here! We have it on good authority that this season is going to be amazeballs!
See you tonight!
This is a dalek made out of nothing but Legos.
Oh. My. Doctor. I NEED this!!!!!!!!!!!!!
(via doctorwho)


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The Leading eBooks Store Online
for Kindle Fire, Apple, Android, Nook, Kobo, PC, Mac, BlackBerry ...
The Book of Burger
Preview (read now) Add to my own site Give this ebook to a friend Add to my wishlist Author's page Publisher's page
moreRachael Ray, #1 New York Times bestselling author and media mogul, offers up the ultimate burger book. The Book of Burger is filled with over 300 recipes for burgers, sliders, sides, sloppies, hot dogs, sandwiches, sauces, toppings and more.
The Queen of Burgers has drawn together her tastiest recipes for the ultimate between-the-buns experience. Whether you're cooking for one or for one hundred in your own backyard burger bash, The Book of Burger has you covered for bringing family and friends together for the love of burgers! Please 'em all—big and small—with everything from burgers to sandwiches, hot dogs, fries, sliders, and sloppies, and so much more.
Start with Rach's "Big Spicy Mac," tempting you from the cover, or go with the heavenly French Onion Burgers. And if beef isn't your thing, there are plenty of chicken, pork, salmon, veggie, and lamb patties. Want a mind-blowing sandwich? Whip up the BEST one Rachael has ever made: the 7-Hour Smoked Brisket Sandwich with Smoky BBQ Sauce. Rachael even shares her legendary pickle recipe and her own homemade burger blend. Want a fun, cute, tasty bite-size treat to pass around? Rachael is slider obsessed and you will be, too: try the Mexican Pulled Pork Sliders.
Rachael's friends from the New York and South Beach Wine & Food Festivals' Burger Bashes also contribute their award-winning recipes, including Bobby Flay's Louisiana Burger and Masaharu Morimoto's Kakuni Burger.
Twelve original videos (directly accessible by links throughout the text) make The Book of Burger a truly multimedia experience and a smart book that celebrates the infinite possibilities of everybody's favorite food. less
Atria Books; February 2013
338 pages; ISBN 9781476744735
Download in secure PDF format
338 pages; ISBN 9781476744735
Download in secure PDF format
More Food
Eat to Live 2011 US$ 7.99
The Pound a Day Diet 2014 US$ 12.99
French Women Don't Get Fat 2004 US$ 9.99 1 pages
Wheat Belly 2011 US$ 20.99 306 pages
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"A good GI bill would increase the recruit pool.
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The backlash to LeBron James' departure from the Cleveland Cavaliers rivaled, or perhaps superseded, that of Art Modell's betrayal. His return is reminiscent of the biblical account of the prodigal son.
A record amount of $2,875 was raised at this year's Gnadenhutten Fireworks Festival auction.
Sugarcreek Village Council
Strasburg Board of Education
Corey Kluber allowed four runs in six innings, and Nick Swisher hit a two-run homer in the fifth, leading the Cleveland Indians to a 7-4 win over the Chicago White Sox on Friday night.
How do you solve a problem like Saul Goodman? According to Better Call Saul showrunner
David Blatt was running a summer league practice with the Cleveland Cavaliers on Friday morning, and the sound of someone shrieking suddenly filled the gym.
AMC has given a straight-to-series order to martial arts drama Badlands, the network announced Friday.Loosely based on the classic Chinese tale "Journey to the West," Badlands is a genre-bending series that tells the...
VH1 is taking first date jitters to a new level!The cable network's new dating series Dating...
The state of Ohio's overpayment of food-stamp benefits last year exceeded the national average.


text:
PLOS Biology: New Articles PLOS http://www.plosbiology.org/ firstname.lastname@example.com Publishing science info:doi/10.1371/feed.pbio This work is licensed under a Creative Commons Attribution-Share Alike 3.0 License http://www.plosbiology.org/${webserver-url}images/favicon.ico http://www.plosbiology.org/${webserver-url}images/favicon.ico 2014-10-26T01:51:16Z Subscribe with My Yahoo!Subscribe with NewsGatorSubscribe with My AOLSubscribe with BloglinesSubscribe with NetvibesSubscribe with GoogleSubscribe with Pageflakes A Homeostatic Sleep-Stabilizing Pathway in Drosophila Composed of the Sex Peptide Receptor and Its Ligand, the Myoinhibitory Peptide Yangkyun Oh et al. info:doi/10.1371/journal.pbio.1001974 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Yangkyun Oh, Sung-Eun Yoon, Qi Zhang, Hyo-Seok Chae, Ivana Daubnerová, Orie T. Shafer, Joonho Choe, Young-Joon Kim
 Sleep, a reversible quiescent state found in both invertebrate and vertebrate animals, disconnects animals from their environment and is highly regulated for coordination with wakeful activities, such as reproduction. The fruit fly, Drosophila melanogaster, has proven to be a valuable model for studying the regulation of sleep by circadian clock and homeostatic mechanisms. Here, we demonstrate that the sex peptide receptor (SPR) of Drosophila, known for its role in female reproduction, is also important in stabilizing sleep in both males and females. Mutants lacking either the SPR or its central ligand, myoinhibitory peptide (MIP), fall asleep normally, but have difficulty in maintaining a sleep-like state. Our analyses have mapped the SPR sleep function to pigment dispersing factor (pdf) neurons, an arousal center in the insect brain. MIP downregulates intracellular cAMP levels in pdf neurons through the SPR. MIP is released centrally before and during night-time sleep, when the sleep drive is elevated. Sleep deprivation during the night facilitates MIP secretion from specific brain neurons innervating pdf neurons. Moreover, flies lacking either SPR or MIP cannot recover sleep after the night-time sleep deprivation. These results delineate a central neuropeptide circuit that stabilizes the sleep state by feeding a slow-acting inhibitory input into the arousal system and plays an important role in sleep homeostasis. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001974 From "Silent Teachers" to Models Roos Eisma et al. info:doi/10.1371/journal.pbio.1001971 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Roos Eisma, Tracey Wilkinson
 For decades, embalmed cadavers have played an important role in teaching anatomy to the scientists and doctors of the future. Most anatomy departments use a traditional formaldehyde-based embalming method, but formalin embalming makes the bodies very rigid, which limits their usefulness for procedures other than dissection. A more recent embalming method developed by W. Thiel has allowed these "silent teachers" to take on a further role in applied anatomy research and teaching: to act as models for surgical training and medical research. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001971 Adaptive Management and the Value of Information: Learning Via Intervention in Epidemiology Katriona Shea et al. info:doi/10.1371/journal.pbio.1001970 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Katriona Shea, Michael J. Tildesley, Michael C. Runge, Christopher J. Fonnesbeck, Matthew J. Ferrari
 Optimal intervention for disease outbreaks is often impeded by severe scientific uncertainty. Adaptive management (AM), long-used in natural resource management, is a structured decision-making approach to solving dynamic problems that accounts for the value of resolving uncertainty via real-time evaluation of alternative models. We propose an AM approach to design and evaluate intervention strategies in epidemiology, using real-time surveillance to resolve model uncertainty as management proceeds, with foot-and-mouth disease (FMD) culling and measles vaccination as case studies. We use simulations of alternative intervention strategies under competing models to quantify the effect of model uncertainty on decision making, in terms of the value of information, and quantify the benefit of adaptive versus static intervention strategies. Culling decisions during the 2001 UK FMD outbreak were contentious due to uncertainty about the spatial scale of transmission. The expected benefit of resolving this uncertainty prior to a new outbreak on a UK-like landscape would be £45–£60 million relative to the strategy that minimizes livestock losses averaged over alternate transmission models. AM during the outbreak would be expected to recover up to £20.1 million of this expected benefit. AM would also recommend a more conservative initial approach (culling of infected premises and dangerous contact farms) than would a fixed strategy (which would additionally require culling of contiguous premises). For optimal targeting of measles vaccination, based on an outbreak in Malawi in 2010, AM allows better distribution of resources across the affected region; its utility depends on uncertainty about both the at-risk population and logistical capacity. When daily vaccination rates are highly constrained, the optimal initial strategy is to conduct a small, quick campaign; a reduction in expected burden of approximately 10,000 cases could result if campaign targets can be updated on the basis of the true susceptible population. Formal incorporation of a policy to update future management actions in response to information gained in the course of an outbreak can change the optimal initial response and result in significant cost savings. AM provides a framework for using multiple models to facilitate public-health decision making and an objective basis for updating management actions in response to improved scientific understanding. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001970 Building Blocks of Temporal Filters in Retinal Synapses Bongsoo Suh et al. info:doi/10.1371/journal.pbio.1001973 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Bongsoo Suh, Stephen A. Baccus
 Sensory systems must be able to extract features of a stimulus to detect and represent properties of the world. Because sensory signals are constantly changing, a critical aspect of this transformation relates to the timing of signals and the ability to filter those signals to select dynamic properties, such as visual motion. At first assessment, one might think that the primary biophysical properties that construct a temporal filter would be dynamic mechanisms such as molecular concentration or membrane electrical properties. However, in the current issue of PLOS Biology, Baden et al. identify a mechanism of temporal filtering in the zebrafish and goldfish retina that is not dynamic but is in fact a structural building block—the physical size of a synapse itself. The authors observe that small, bipolar cell synaptic terminals are fast and highly adaptive, whereas large ones are slower and adapt less. Using a computational model, they conclude that the volume of the synaptic terminal influences the calcium concentration and the number of available vesicles. These results indicate that the size of the presynaptic terminal is an independent control for the dynamics of a synapse and may reveal aspects of synaptic function that can be inferred from anatomical structure. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001973 A Synaptic Mechanism for Temporal Filtering of Visual Signals Tom Baden et al. info:doi/10.1371/journal.pbio.1001972 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Tom Baden, Anton Nikolaev, Federico Esposti, Elena Dreosti, Benjamin Odermatt, Leon Lagnado
 The visual system transmits information about fast and slow changes in light intensity through separate neural pathways. We used in vivo imaging to investigate how bipolar cells transmit these signals to the inner retina. We found that the volume of the synaptic terminal is an intrinsic property that contributes to different temporal filters. Individual cells transmit through multiple terminals varying in size, but smaller terminals generate faster and larger calcium transients to trigger vesicle release with higher initial gain, followed by more profound adaptation. Smaller terminals transmitted higher stimulus frequencies more effectively. Modeling global calcium dynamics triggering vesicle release indicated that variations in the volume of presynaptic compartments contribute directly to all these differences in response dynamics. These results indicate how one neuron can transmit different temporal components in the visual signal through synaptic terminals of varying geometries with different adaptational properties. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001972 Occipital Alpha Activity during Stimulus Processing Gates the Information Flow to Object-Selective Cortex Johanna M. Zumer et al. info:doi/10.1371/journal.pbio.1001965 2014-10-21T21:00:00Z 2014-10-21T21:00:00Z
by Johanna M. Zumer, René Scheeringa, Jan-Mathijs Schoffelen, David G. Norris, Ole Jensen
 Given the limited processing capabilities of the sensory system, it is essential that attended information is gated to downstream areas, whereas unattended information is blocked. While it has been proposed that alpha band (8–13 Hz) activity serves to route information to downstream regions by inhibiting neuronal processing in task-irrelevant regions, this hypothesis remains untested. Here we investigate how neuronal oscillations detected by electroencephalography in visual areas during working memory encoding serve to gate information reflected in the simultaneously recorded blood-oxygenation-level-dependent (BOLD) signals recorded by functional magnetic resonance imaging in downstream ventral regions. We used a paradigm in which 16 participants were presented with faces and landscapes in the right and left hemifields; one hemifield was attended and the other unattended. We observed that decreased alpha power contralateral to the attended object predicted the BOLD signal representing the attended object in ventral object-selective regions. Furthermore, increased alpha power ipsilateral to the attended object predicted a decrease in the BOLD signal representing the unattended object. We also found that the BOLD signal in the dorsal attention network inversely correlated with visual alpha power. This is the first demonstration, to our knowledge, that oscillations in the alpha band are implicated in the gating of information from the visual cortex to the ventral stream, as reflected in the representationally specific BOLD signal. This link of sensory alpha to downstream activity provides a neurophysiological substrate for the mechanism of selective attention during stimulus processing, which not only boosts the attended information but also suppresses distraction. Although previous studies have shown a relation between the BOLD signal from the dorsal attention network and the alpha band at rest, we demonstrate such a relation during a visuospatial task, indicating that the dorsal attention network exercises top-down control of visual alpha activity. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001965 Correction: A SCARECROW-RETINOBLASTOMA Protein Network Controls Protective Quiescence in the Arabidopsis Root Stem Cell Organizer The PLOS Biology Staff info:doi/10.1371/journal.pbio.1001997 2014-10-20T21:00:00Z 2014-10-20T21:00:00Z
by The PLOS Biology Staff
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001997 A Conserved Endoplasmic Reticulum Membrane Protein Complex (EMC) Facilitates Phospholipid Transfer from the ER to Mitochondria Sujoy Lahiri et al. info:doi/10.1371/journal.pbio.1001969 2014-10-14T21:00:00Z 2014-10-14T21:00:00Z
by Sujoy Lahiri, Jesse T. Chao, Shabnam Tavassoli, Andrew K. O. Wong, Vineet Choudhary, Barry P. Young, Christopher J. R. Loewen, William A. Prinz
 Mitochondrial membrane biogenesis and lipid metabolism require phospholipid transfer from the endoplasmic reticulum (ER) to mitochondria. Transfer is thought to occur at regions of close contact of these organelles and to be nonvesicular, but the mechanism is not known. Here we used a novel genetic screen in S. cerevisiae to identify mutants with defects in lipid exchange between the ER and mitochondria. We show that a strain missing multiple components of the conserved ER membrane protein complex (EMC) has decreased phosphatidylserine (PS) transfer from the ER to mitochondria. Mitochondria from this strain have significantly reduced levels of PS and its derivative phosphatidylethanolamine (PE). Cells lacking EMC proteins and the ER–mitochondria tethering complex called ERMES (the ER–mitochondria encounter structure) are inviable, suggesting that the EMC also functions as a tether. These defects are corrected by expression of an engineered ER–mitochondrial tethering protein that artificially tethers the ER to mitochondria. EMC mutants have a significant reduction in the amount of ER tethered to mitochondria even though ERMES remained intact in these mutants, suggesting that the EMC performs an additional tethering function to ERMES. We find that all Emc proteins interact with the mitochondrial translocase of the outer membrane (TOM) complex protein Tom5 and this interaction is important for PS transfer and cell growth, suggesting that the EMC forms a tether by associating with the TOM complex. Together, our findings support that the EMC tethers ER to mitochondria, which is required for phospholipid synthesis and cell growth. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001969 Melanoma Cells Break Down LPA to Establish Local Gradients That Drive Chemotactic Dispersal Andrew J. Muinonen-Martin et al. info:doi/10.1371/journal.pbio.1001966 2014-10-14T21:00:00Z 2014-10-14T21:00:00Z
by Andrew J. Muinonen-Martin, Olivia Susanto, Qifeng Zhang, Elizabeth Smethurst, William J. Faller, Douwe M. Veltman, Gabriela Kalna, Colin Lindsay, Dorothy C. Bennett, Owen J. Sansom, Robert Herd, Robert Jones, Laura M. Machesky, Michael J. O. Wakelam, David A. Knecht, Robert H. Insall
 The high mortality of melanoma is caused by rapid spread of cancer cells, which occurs unusually early in tumour evolution. Unlike most solid tumours, thickness rather than cytological markers or differentiation is the best guide to metastatic potential. Multiple stimuli that drive melanoma cell migration have been described, but it is not clear which are responsible for invasion, nor if chemotactic gradients exist in real tumours. In a chamber-based assay for melanoma dispersal, we find that cells migrate efficiently away from one another, even in initially homogeneous medium. This dispersal is driven by positive chemotaxis rather than chemorepulsion or contact inhibition. The principal chemoattractant, unexpectedly active across all tumour stages, is the lipid agonist lysophosphatidic acid (LPA) acting through the LPA receptor LPAR1. LPA induces chemotaxis of remarkable accuracy, and is both necessary and sufficient for chemotaxis and invasion in 2-D and 3-D assays. Growth factors, often described as tumour attractants, cause negligible chemotaxis themselves, but potentiate chemotaxis to LPA. Cells rapidly break down LPA present at substantial levels in culture medium and normal skin to generate outward-facing gradients. We measure LPA gradients across the margins of melanomas in vivo, confirming the physiological importance of our results. We conclude that LPA chemotaxis provides a strong drive for melanoma cells to invade outwards. Cells create their own gradients by acting as a sink, breaking down locally present LPA, and thus forming a gradient that is low in the tumour and high in the surrounding areas. The key step is not acquisition of sensitivity to the chemoattractant, but rather the tumour growing to break down enough LPA to form a gradient. Thus the stimulus that drives cell dispersal is not the presence of LPA itself, but the self-generated, outward-directed gradient. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001966 Autophagy and Its Effects: Making Sense of Double-Edged Swords Andrew Thorburn info:doi/10.1371/journal.pbio.1001967 2014-10-14T21:00:00Z 2014-10-14T21:00:00Z
by Andrew Thorburn
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001967 The Chromatin Assembly Factor 1 Promotes Rad51-Dependent Template Switches at Replication Forks by Counteracting D-Loop Disassembly by the RecQ-Type Helicase Rqh1 Violena Pietrobon et al. info:doi/10.1371/journal.pbio.1001968 2014-10-14T21:00:00Z 2014-10-14T21:00:00Z
by Violena Pietrobon, Karine Fréon, Julien Hardy, Audrey Costes, Ismail Iraqui, Françoise Ochsenbein, Sarah A.E. Lambert
 At blocked replication forks, homologous recombination mediates the nascent strands to switch template in order to ensure replication restart, but faulty template switches underlie genome rearrangements in cancer cells and genomic disorders. Recombination occurs within DNA packaged into chromatin that must first be relaxed and then restored when recombination is completed. The chromatin assembly factor 1, CAF-1, is a histone H3-H4 chaperone involved in DNA synthesis-coupled chromatin assembly during DNA replication and DNA repair. We reveal a novel chromatin factor-dependent step during replication-coupled DNA repair: Fission yeast CAF-1 promotes Rad51-dependent template switches at replication forks, independently of the postreplication repair pathway. We used a physical assay that allows the analysis of the individual steps of template switch, from the recruitment of recombination factors to the formation of joint molecules, combined with a quantitative measure of the resulting rearrangements. We reveal functional and physical interplays between CAF-1 and the RecQ-helicase Rqh1, the BLM homologue, mutations in which cause Bloom's syndrome, a human disease associating genome instability with cancer predisposition. We establish that CAF-1 promotes template switch by counteracting D-loop disassembly by Rqh1. Consequently, the likelihood of faulty template switches is controlled by antagonistic activities of CAF-1 and Rqh1 in the stability of the D-loop. D-loop stabilization requires the ability of CAF-1 to interact with PCNA and is thus linked to the DNA synthesis step. We propose that CAF-1 plays a regulatory role during template switch by assembling chromatin on the D-loop and thereby impacting the resolution of the D-loop. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001968 Correction: Root System Architecture from Coupling Cell Shape to Auxin Transport The PLOS Biology Staff info:doi/10.1371/journal.pbio.1001984 2014-10-10T21:00:00Z 2014-10-10T21:00:00Z
by The PLOS Biology Staff
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001984 The KRÜPPEL-Like Transcription Factor DATILÓGRAFO Is Required in Specific Cholinergic Neurons for Sexual Receptivity in Drosophila Females Joseph Moeller Schinaman et al. info:doi/10.1371/journal.pbio.1001964 2014-10-07T21:00:00Z 2014-10-07T21:00:00Z
by Joseph Moeller Schinaman, Rachel Lynn Giesey, Claudia Mieko Mizutani, Tamas Lukacsovich, Rui Sousa-Neves
 Courtship is a widespread behavior in which one gender conveys to the other a series of cues about their species identity, gender, and suitability as mates. In many species, females decode these male displays and either accept or reject them. Despite the fact that courtship has been investigated for a long time, the genes and circuits that allow females to generate these mutually exclusive responses remain largely unknown. Here, we provide evidence that the Krüppel-like transcription factor datilógrafo (dati) is required for proper locomotion and courtship acceptance in adult Drosophila females. dati mutant females are completely unable to decode male courtship and almost invariably reject males. Molecular analyses reveal that dati is broadly expressed in the brain and its specific removal in excitatory cholinergic neurons recapitulates the female courtship behavioral phenotype but not the locomotor deficits, indicating that these are two separable functions. Clonal analyses in female brains identified three discrete foci where dati is required to generate acceptance. These include neurons around the antennal lobe, the lateral horn, and the posterior superior lateral protocerebrum. Together, these results show that dati is required to organize and maintain a relatively simple excitatory circuit in the brain that allows females to either accept or reject courting males. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001964 The "Balance of Nature"—Evolution of a Panchreston Daniel Simberloff info:doi/10.1371/journal.pbio.1001963 2014-10-07T21:00:00Z 2014-10-07T21:00:00Z
by Daniel Simberloff
 The earliest concept of a balance of nature in Western thought saw it as being provided by gods but requiring human aid or encouragement for its maintenance. With the rise of Greek natural philosophy, emphasis shifted to traits gods endowed species with at the outset, rather than human actions, as key to maintaining the balance. The dominance of a constantly intervening God in the Middle Ages lessened interest in the inherent features of nature that would contribute to balance, but the Reformation led to renewed focus on such features, particularly traits of species that would maintain all of them but permit none to dominate nature. Darwin conceived of nature in balance, and his emphasis on competition and frequent tales of felicitous species interactions supported the idea of a balance of nature. But Darwin radically changed its underlying basis, from God to natural selection. Wallace was perhaps the first to challenge the very notion of a balance of nature as an undefined entity whose accuracy could not be tested. His skepticism was taken up again in the 20th century, culminating in a widespread rejection of the idea of a balance of nature by academic ecologists, who focus rather on a dynamic, often chaotic nature buffeted by constant disturbances. The balance-of-nature metaphor, however, lives on in large segments of the public, representing a fragile aspect of nature and biodiversity that it is our duty to protect. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001963 Centromere-Independent Accumulation of Cohesin at Ectopic Heterochromatin Sites Induces Chromosome Stretching during Anaphase Raquel A. Oliveira et al. info:doi/10.1371/journal.pbio.1001962 2014-10-07T21:00:00Z 2014-10-07T21:00:00Z
by Raquel A. Oliveira, Shaila Kotadia, Alexandra Tavares, Mihailo Mirkovic, Katherine Bowlin, Christian S. Eichinger, Kim Nasmyth, William Sullivan
 Pericentric heterochromatin, while often considered as "junk" DNA, plays important functions in chromosome biology. It contributes to sister chromatid cohesion, a process mediated by the cohesin complex that ensures proper genome segregation during nuclear division. Long stretches of heterochromatin are almost exclusively placed at centromere-proximal regions but it remains unclear if there is functional (or mechanistic) importance in linking the sites of sister chromatid cohesion to the chromosomal regions that mediate spindle attachment (the centromere). Using engineered chromosomes in Drosophila melanogaster, we demonstrate that cohesin enrichment is dictated by the presence of heterochromatin rather than centromere proximity. This preferential accumulation is caused by an enrichment of the cohesin-loading factor (Nipped-B/NIPBL/Scc2) at dense heterochromatic regions. As a result, chromosome translocations containing ectopic pericentric heterochromatin embedded in euchromatin display additional cohesin-dependent constrictions. These ectopic cohesion sites, placed away from the centromere, disjoin abnormally during anaphase and chromosomes exhibit a significant increase in length during anaphase (termed chromatin stretching). These results provide evidence that long stretches of heterochromatin distant from the centromere, as often found in many cancers, are sufficient to induce abnormal accumulation of cohesin at these sites and thereby compromise the fidelity of chromosome segregation. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001962 In TFIIH, XPD Helicase Is Exclusively Devoted to DNA Repair Jochen Kuper et al. info:doi/10.1371/journal.pbio.1001954 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by Jochen Kuper, Cathy Braun, Agnes Elias, Gudrun Michels, Florian Sauer, Dominik R. Schmitt, Arnaud Poterszman, Jean-Marc Egly, Caroline Kisker
 The eukaryotic XPD helicase is an essential subunit of TFIIH involved in both transcription and nucleotide excision repair (NER). Mutations in human XPD are associated with several inherited diseases such as xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy. We performed a comparative analysis of XPD from Homo sapiens and Chaetomium thermophilum (a closely related thermostable fungal orthologue) to decipher the different molecular prerequisites necessary for either transcription or DNA repair. In vitro and in vivo assays demonstrate that mutations in the 4Fe4S cluster domain of XPD abrogate the NER function of TFIIH and do not affect its transcriptional activity. We show that the p44-dependent activation of XPD is promoted by the stimulation of its ATPase activity. Furthermore, we clearly demonstrate that XPD requires DNA binding, ATPase, and helicase activity to function in NER. In contrast, these enzymatic properties are dispensable for transcription initiation. XPD helicase is thus exclusively devoted to NER and merely acts as a structural scaffold to maintain TFIIH integrity during transcription. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001954 Resolving the Flap over Bird Wrists Robin Meadows info:doi/10.1371/journal.pbio.1001958 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by Robin Meadows
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001958 New Developmental Evidence Clarifies the Evolution of Wrist Bones in the Dinosaur–Bird Transition João Francisco Botelho et al. info:doi/10.1371/journal.pbio.1001957 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by João Francisco Botelho, Luis Ossa-Fuentes, Sergio Soto-Acuña, Daniel Smith-Paredes, Daniel Nuñez-León, Miguel Salinas-Saavedra, Macarena Ruiz-Flores, Alexander O. Vargas
 From early dinosaurs with as many as nine wrist bones, modern birds evolved to develop only four ossifications. Their identity is uncertain, with different labels used in palaeontology and developmental biology. We examined embryos of several species and studied chicken embryos in detail through a new technique allowing whole-mount immunofluorescence of the embryonic cartilaginous skeleton. Beyond previous controversy, we establish that the proximal–anterior ossification develops from a composite radiale+intermedium cartilage, consistent with fusion of radiale and intermedium observed in some theropod dinosaurs. Despite previous claims that the development of the distal–anterior ossification does not support the dinosaur–bird link, we found its embryonic precursor shows two distinct regions of both collagen type II and collagen type IX expression, resembling the composite semilunate bone of bird-like dinosaurs (distal carpal 1+distal carpal 2). The distal–posterior ossification develops from a cartilage referred to as "element x," but its position corresponds to distal carpal 3. The proximal–posterior ossification is perhaps most controversial: It is labelled as the ulnare in palaeontology, but we confirm the embryonic ulnare is lost during development. Re-examination of the fossil evidence reveals the ulnare was actually absent in bird-like dinosaurs. We confirm the proximal–posterior bone is a pisiform in terms of embryonic position and its development as a sesamoid associated to a tendon. However, the pisiform is absent in bird-like dinosaurs, which are known from several articulated specimens. The combined data provide compelling evidence of a remarkable evolutionary reversal: A large, ossified pisiform re-evolved in the lineage leading to birds, after a period in which it was either absent, nonossified, or very small, consistently escaping fossil preservation. The bird wrist provides a modern example of how developmental and paleontological data illuminate each other. Based on all available data, we introduce a new nomenclature for bird wrist ossifications. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001957 Differentially Timed Extracellular Signals Synchronize Pacemaker Neuron Clocks Ben Collins et al. info:doi/10.1371/journal.pbio.1001959 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by Ben Collins, Harris S. Kaplan, Matthieu Cavey, Katherine R. Lelito, Andrew H. Bahle, Zhonghua Zhu, Ann Marie Macara, Gregg Roman, Orie T. Shafer, Justin Blau
 Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001959 Contact-Mediated Inhibition Between Oligodendrocyte Progenitor Cells and Motor Exit Point Glia Establishes the Spinal Cord Transition Zone Cody J. Smith et al. info:doi/10.1371/journal.pbio.1001961 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by Cody J. Smith, Angela D. Morris, Taylor G. Welsh, Sarah Kucenas
 Rapid conduction of action potentials along motor axons requires that oligodendrocytes and Schwann cells myelinate distinct central and peripheral nervous system (CNS and PNS) domains along the same axon. Despite the importance of this arrangement for nervous system function, the mechanisms that establish and maintain this precise glial segregation at the motor exit point (MEP) transition zone are unknown. Using in vivo time-lapse imaging in zebrafish, we observed that prior to myelination, oligodendrocyte progenitor cells (OPCs) extend processes into the periphery via the MEP and immediately upon contact with spinal motor root glia retract back into the spinal cord. Characterization of the peripheral cell responsible for repelling OPC processes revealed that it was a novel, CNS-derived population of glia we propose calling MEP glia. Ablation of MEP glia resulted in the absence of myelinating glia along spinal motor root axons and an immediate breach of the MEP by OPCs. Taken together, our results identify a novel population of CNS-derived peripheral glia located at the MEP that selectively restrict the migration of OPCs into the periphery via contact-mediated inhibition. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001961 Social Network Analysis Shows Direct Evidence for Social Transmission of Tool Use in Wild Chimpanzees Catherine Hobaiter et al. info:doi/10.1371/journal.pbio.1001960 2014-09-30T21:00:00Z 2014-09-30T21:00:00Z
by Catherine Hobaiter, Timothée Poisot, Klaus Zuberbühler, William Hoppitt, Thibaud Gruber
 Social network analysis methods have made it possible to test whether novel behaviors in animals spread through individual or social learning. To date, however, social network analysis of wild populations has been limited to static models that cannot precisely reflect the dynamics of learning, for instance, the impact of multiple observations across time. Here, we present a novel dynamic version of network analysis that is capable of capturing temporal aspects of acquisition—that is, how successive observations by an individual influence its acquisition of the novel behavior. We apply this model to studying the spread of two novel tool-use variants, "moss-sponging" and "leaf-sponge re-use," in the Sonso chimpanzee community of Budongo Forest, Uganda. Chimpanzees are widely considered the most "cultural" of all animal species, with 39 behaviors suspected as socially acquired, most of them in the domain of tool-use. The cultural hypothesis is supported by experimental data from captive chimpanzees and a range of observational data. However, for wild groups, there is still no direct experimental evidence for social learning, nor has there been any direct observation of social diffusion of behavioral innovations. Here, we tested both a static and a dynamic network model and found strong evidence that diffusion patterns of moss-sponging, but not leaf-sponge re-use, were significantly better explained by social than individual learning. The most conservative estimate of social transmission accounted for 85% of observed events, with an estimated 15-fold increase in learning rate for each time a novice observed an informed individual moss-sponging. We conclude that group-specific behavioral variants in wild chimpanzees can be socially learned, adding to the evidence that this prerequisite for culture originated in a common ancestor of great apes and humans, long before the advent of modern humans. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001960 Correction: Transport of Fibroblast Growth Factor 2 in the Pericellular Matrix Is Controlled by the Spatial Distribution of Its Binding Sites in Heparan Sulfate The PLOS BIOLOGY Staff info:doi/10.1371/journal.pbio.1001976 2014-09-26T21:00:00Z 2014-09-26T21:00:00Z
by The PLOS BIOLOGY Staff
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001976 A Vesicular Protein Important for Puberty Caitlin Sedwick info:doi/10.1371/journal.pbio.1001953 2014-09-23T21:00:00Z 2014-09-23T21:00:00Z
by Caitlin Sedwick
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001953 Variable Combinations of Specific Ephrin Ligand/Eph Receptor Pairs Control Embryonic Tissue Separation Nazanin Rohani et al. info:doi/10.1371/journal.pbio.1001955 2014-09-23T21:00:00Z 2014-09-23T21:00:00Z
by Nazanin Rohani, Andrea Parmeggiani, Rudolf Winklbauer, François Fagotto
 Ephrins and Eph receptors are involved in the establishment of vertebrate tissue boundaries. The complexity of the system is puzzling, however in many instances, tissues express multiple ephrins and Ephs on both sides of the boundary, a situation that should in principle cause repulsion between cells within each tissue. Although co-expression of ephrins and Eph receptors is widespread in embryonic tissues, neurons, and cancer cells, it is still unresolved how the respective signals are integrated into a coherent output. We present a simple explanation for the confinement of repulsion to the tissue interface: Using the dorsal ectoderm–mesoderm boundary of the Xenopus embryo as a model, we identify selective functional interactions between ephrin–Eph pairs that are expressed in partial complementary patterns. The combined repulsive signals add up to be strongest across the boundary, where they reach sufficient intensity to trigger cell detachments. The process can be largely explained using a simple model based exclusively on relative ephrin and Eph concentrations and binding affinities. We generalize these findings for the ventral ectoderm–mesoderm boundary and the notochord boundary, both of which appear to function on the same principles. These results provide a paradigm for how developmental systems may integrate multiple cues to generate discrete local outcomes. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001955 Bind and Separate: How Ephrins and Their Receptors Create Tissue Boundaries Richard Robinson info:doi/10.1371/journal.pbio.1001956 2014-09-23T21:00:00Z 2014-09-23T21:00:00Z
by Richard Robinson
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001956 Haploinsufficiency of Dmxl2, Encoding a Synaptic Protein, Causes Infertility Associated with a Loss of GnRH Neurons in Mouse Brooke Tata et al. info:doi/10.1371/journal.pbio.1001952 2014-09-23T21:00:00Z 2014-09-23T21:00:00Z
by Brooke Tata, Lukas Huijbregts, Sandrine Jacquier, Zsolt Csaba, Emmanuelle Genin, Vincent Meyer, Sofia Leka, Joelle Dupont, Perrine Charles, Didier Chevenne, Jean-Claude Carel, Juliane Léger, Nicolas de Roux
 Characterization of the genetic defects causing gonadotropic deficiency has made a major contribution to elucidation of the fundamental role of Kisspeptins and Neurokinin B in puberty onset and reproduction. The absence of puberty may also reveal neurodevelopmental disorders caused by molecular defects in various cellular pathways. Investigations of these neurodevelopmental disorders may provide information about the neuronal processes controlling puberty onset and reproductive capacity. We describe here a new syndrome observed in three brothers, which involves gonadotropic axis deficiency, central hypothyroidism, peripheral demyelinating sensorimotor polyneuropathy, mental retardation, and profound hypoglycemia, progressing to nonautoimmune insulin-dependent diabetes mellitus. High-throughput sequencing revealed a homozygous in-frame deletion of 15 nucleotides in DMXL2 in all three affected patients. This homozygous deletion was associated with lower DMXL2 mRNA levels in the blood lymphocytes of the patients. DMXL2 encodes the synaptic protein rabconnectin-3α, which has been identified as a putative scaffold protein for Rab3-GAP and Rab3-GEP, two regulators of the GTPase Rab3a. We found that rabconnectin-3α was expressed in exocytosis vesicles in gonadotropin-releasing hormone (GnRH) axonal extremities in the median eminence of the hypothalamus. It was also specifically expressed in cells expressing luteinizing hormone (LH) and follicle-stimulating hormone (FSH) within the pituitary. The conditional heterozygous deletion of Dmxl2 from mouse neurons delayed puberty and resulted in very low fertility. This reproductive phenotype was associated with a lower number of GnRH neurons in the hypothalamus of adult mice. Finally, Dmxl2 knockdown in an insulin-secreting cell line showed that rabconnectin-3α controlled the constitutive and glucose-induced secretion of insulin. In conclusion, this study shows that low levels of DMXL2 expression cause a complex neurological phenotype, with abnormal glucose metabolism and gonadotropic axis deficiency due to a loss of GnRH neurons. Our findings identify rabconectin-3α as a key controller of neuronal and endocrine homeostatic processes. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001952 Disentangling Human Tolerance and Resistance Against HIV Roland R. Regoes et al. the Swiss HIV Cohort Study info:doi/10.1371/journal.pbio.1001951 2014-09-16T21:00:00Z 2014-09-16T21:00:00Z
by Roland R. Regoes, Paul J. McLaren, Manuel Battegay, Enos Bernasconi, Alexandra Calmy, Huldrych F. Günthard, Matthias Hoffmann, Andri Rauch, Amalio Telenti, Jacques Fellay, the Swiss HIV Cohort Study
 In ecology, "disease tolerance" is defined as an evolutionary strategy of hosts against pathogens, characterized by reduced or absent pathogenesis despite high pathogen load. To our knowledge, tolerance has to date not been quantified and disentangled from host resistance to disease in any clinically relevant human infection. Using data from the Swiss HIV Cohort Study, we investigated if there is variation in tolerance to HIV in humans and if this variation is associated with polymorphisms in the human genome. In particular, we tested for associations between tolerance and alleles of the Human Leukocyte Antigen (HLA) genes, the CC chemokine receptor 5 (CCR5), the age at which individuals were infected, and their sex. We found that HLA-B alleles associated with better HIV control do not confer tolerance. The slower disease progression associated with these alleles can be fully attributed to the extent of viral load reduction in carriers. However, we observed that tolerance significantly varies across HLA-B genotypes with a relative standard deviation of 34%. Furthermore, we found that HLA-B homozygotes are less tolerant than heterozygotes. Lastly, tolerance was observed to decrease with age, resulting in a 1.7-fold difference in disease progression between 20 and 60-y-old individuals with the same viral load. Thus, disease tolerance is a feature of infection with HIV, and the identification of the mechanisms involved may pave the way to a better understanding of pathogenesis. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001951 Plant Ecological Strategies Shift Across the Cretaceous–Paleogene Boundary Benjamin Blonder et al. info:doi/10.1371/journal.pbio.1001949 2014-09-16T21:00:00Z 2014-09-16T21:00:00Z
by Benjamin Blonder, Dana L. Royer, Kirk R. Johnson, Ian Miller, Brian J. Enquist
 The Chicxulub bolide impact caused the end-Cretaceous mass extinction of plants, but the associated selectivity and ecological effects are poorly known. Using a unique set of North Dakota leaf fossil assemblages spanning 2.2 Myr across the event, we show among angiosperms a reduction of ecological strategies and selection for fast-growth strategies consistent with a hypothesized recovery from an impact winter. Leaf mass per area (carbon investment) decreased in both mean and variance, while vein density (carbon assimilation rate) increased in mean, consistent with a shift towards "fast" growth strategies. Plant extinction from the bolide impact resulted in a shift in functional trait space that likely had broad consequences for ecosystem functioning. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001949 A Plant's Guide to Surviving the Chicxulub Impact Jonathan M. Chase info:doi/10.1371/journal.pbio.1001948 2014-09-16T21:00:00Z 2014-09-16T21:00:00Z
by Jonathan M. Chase
 http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001948 A Trihelix DNA Binding Protein Counterbalances Hypoxia-Responsive Transcriptional Activation in Arabidopsis Beatrice Giuntoli et al. info:doi/10.1371/journal.pbio.1001950 2014-09-16T21:00:00Z 2014-09-16T21:00:00Z
by Beatrice Giuntoli, Seung Cho Lee, Francesco Licausi, Monika Kosmacz, Teruko Oosumi, Joost T. van Dongen, Julia Bailey-Serres, Pierdomenico Perata
 Transcriptional activation in response to hypoxia in plants is orchestrated by ethylene-responsive factor group VII (ERF-VII) transcription factors, which are stable during hypoxia but destabilized during normoxia through their targeting to the N-end rule pathway of selective proteolysis. Whereas the conditionally expressed ERF-VII genes enable effective flooding survival strategies in rice, the constitutive accumulation of N-end-rule–insensitive versions of the Arabidopsis thaliana ERF-VII factor RAP2.12 is maladaptive. This suggests that transcriptional activation under hypoxia that leads to anaerobic metabolism may need to be fine-tuned. However, it is presently unknown whether a counterbalance of RAP2.12 exists. Genome-wide transcriptome analyses identified an uncharacterized trihelix transcription factor gene, which we named HYPOXIA RESPONSE ATTENUATOR1 (HRA1), as highly up-regulated by hypoxia. HRA1 counteracts the induction of core low oxygen-responsive genes and transcriptional activation of hypoxia-responsive promoters by RAP2.12. By yeast-two-hybrid assays and chromatin immunoprecipitation we demonstrated that HRA1 interacts with the RAP2.12 protein but with only a few genomic DNA regions from hypoxia-regulated genes, indicating that HRA1 modulates RAP2.12 through protein–protein interaction. Comparison of the low oxygen response of tissues characterized by different levels of metabolic hypoxia (i.e., the shoot apical zone versus mature rosette leaves) revealed that the antagonistic interplay between RAP2.12 and HRA1 enables a flexible response to fluctuating hypoxia and is of importance to stress survival. In Arabidopsis, an effective low oxygen-sensing response requires RAP2.12 stabilization followed by HRA1 induction to modulate the extent of the anaerobic response by negative feedback regulation of RAP2.12. This mechanism is crucial for plant survival under suboptimal oxygenation conditions. The discovery of the feedback loop regulating the oxygen-sensing mechanism in plants opens new perspectives for breeding flood-resistant crops. http://www.plosbiology.org/article/info%3Adoi%2F10.1371%2Fjournal.pbio.1001950


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NEW YORK (AP) -- Branden Frazier scored all 22 of his points in the second half as Fordham got its first conference win of the season Wednesday night against George Mason 76-70.
RICHMOND, Va.


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Home » Ink Appointment Plugin
Nowadays people are accustomed to booking things online. When they browse any service enabled website which is related to beauty like in a spa/salon, food like in restaurant, clinics etc. People enjoy booking appointment instantly from anywhere in the world just by few clicks on the websites. On the other hand, if you are running an independent business and wants to excel in reaping profits for your business then you should prioritize giving more ease-implemented serviceability to your customer. So taking this factor in mind, giving facility to your users in booking an appointment for the services online is now and then trend.
Business website that provides exclusive and distinct services should provide a portal that gives more ease to their customers to book an appointment according to their suitable date and time, it would become simpler for them to access your services, simultaneously easier for you to manage long customer list who have previously accessed your services and the one who want to access ahead in time. Additionally it generates a professional business image and give 24/7 facility to your customer to book an appointment online through any web accessible devices.
This tutorial is going to enlighten you about one of the Flubers Ink Appointment plugin which facilitates your customer to do online booking for the multiple services offered by your venture. It provides an easy gateway for payment transaction with the help of PayPal.
As I have mentioned above this plugin is for business-oriented website and is an ideal way to accomplish an online appointment booking for your customers, now I will speak more in-depth about it. This is a widgetized plugin and you can easily integrate it with any of the WordPress websites. It has inbuilt opt-in form which can be used as an appointment form to display all the services offered by you, where your customers will fill their details, choose the particular service and book an appointment session according to their suitable time slot at a specified date. Subsequently, your customers can pay via PayPal or pay cash later according to the payment mode you will activate on your website. As soon as the customer completes the appointment booking, their booking detail will be stored in your WordPress dashboard and can be visible to you. Thereafter you can confirm customers booking and once the appointment is confirmed the customer will be notified via email.
One of the major advantages of integrating online appointment booking to your website is, it will not let your any customer to go off from your reach, you can re-communicate with them if you have drop communicating mistakenly. Additionally, it saves your's customer time from filling the client information form manually and submitting it to counter from where you will gather the client's information and fixed their appointment, you can utilize this time in other organization's activities rather than hang up with collecting forms and scheduling appointments, make a database and then updating it frequently. Instead Ink Appointment plugin has inbuilt database in the dashboard that retrieves the client's information and you just have to confirm the appointments, keep the record secured and confidential and review your customer with upcoming appointments and sessions.
You can install the Ink Appointment plugin on your dashboard very easily with any of the InkThemes, although I have implemented it with Colorway theme. Simply follow the steps given below:
First off, install any suitable theme on your dashboard for e.g. Colorway theme.
Go to Dashboard -> Appearance -> Themes -> Add New -> Install Themes.
colorway theme
Install the Colorway theme and activate it.
Under the Dashboard choose Plugins option.
Dashboard -> Plugins -> Add New
After that a page will appear with the heading Install Plugins option.
Go to Upload option, click on it.
In the next step, select the Ink Appointment plugin zip file from the desktop and upload it.
After uploading the file, click on the Install Now button.
ink appointment plugin
Click on Activate Plugin option to activate the plugin on your website, you can see the Ink Appointment plugin icon under your dashboard. See the image for reference:
Ink appointment plugin icon
It has some of the basic inbuilt features that help you to customize your services according to your website niche.
Create Appointments:
It allows you to create your desired services specifying date, timing and pricing detail to display in the appointment form on your website. Follow these steps to create your services to display them on your website:
Go to Dashboard -> Appointments icon -> Create Appointments.
After that Create New Service page will appear. Enter the name of your service and its price and then click on Add New Service button. If you want to add multiple services repeat the above step for the same. See below the screenshot:
ink appointment create service
In the next step, set the date slot and time slot of your services. Just click on the Add Date Slot button to mention the dates and Add Time Slot button to mention the time duration in which the services will be available for customers.
Drag and drop Ink Appointment Widget on any of the sidebar widget according to your requirement, follow the steps: Go to Dashboard -> Appearance -> Widgets.
Visit your website where you can see an appointment form. Your Customers can fill the details in the form and book the appointment. See below the screenshot:appointment form image
This feature allows, displaying all the transaction details of your customers on the WordPress dashboard. To view the customer's transaction details follow these steps:
Dashboard -> Appointments -> Payment Details -> Payment Transaction Details.
The customers will be able to book their appointment for a particular service by selecting the desired services from the drop down menu at a particular time; only one appointment can be booked. If a customer wants to book appointment for more than one service then he/she will have to follow the same procedure. Once the appointment is confirmed, the customer will be notified by the email. All the appointment details will be stored in the admin dashboard. To view the details on dashboard follow these steps:
Dashboard -> Appointments -> Booked Appointments -> View All Recent Appointments/View All Past Appointments.
This feature is meant to customize the appointment form on your site according to your website niche.
ink appointment payment setting
The Ink Appointment plugin provides three payment modes through which you can personalize your customer with the required option they want to pay through. It has following three options:
PayPal: When you set this option in Payment Mode field, you can receive customer's payment through their PayPal account.
PayPal Sandbox: It is used in the testing process. Here admin can check whether the money transaction is occurring correctly or not.
Pay Cash Later: If you want your customer to pay cash after accessing your services, set Payment mode field as Pay Cash Later.
To set the Payment mode, follow these steps: Go to Dashboard -> Appointments -> Settings -> Payment Setting -> Payment Mode, select one of the options from the drop-down list and then click on Save All Changes button to save the changes .ink appointment payment modeIn addition Ink appointment plugin provides facility to the admin to set the currency according to their respective countries. It provides 24 options of various countries and its currencies.
To set the currency option follow these steps:
Dashboard -> Appointments -> Settings -> Manage Currency -> Set Default Currency. See the screenshot below.
Last but not least Ink Appointment plugin will customize your appointment form on your website and enhance the functionality of your appointment form. Additionally, it will give ease to your customers to book appointments directly from your website from anywhere in the world without any constraints. It will provide clutter-free management to your customer's record.
If you have any queries regarding the Ink Appointment plugin, do write it down in the comment form. We'll feel happy in helping you in any of the way.


text:
Outfitting fans since 1999.
Main Content
Your daughter's charming personality is always winning fans over at the ballpark. Now being the most adorable little girl in the stadium will be a walk in the park when your little Giants fan supports Tim Lincecum in this tee by Majestic. It features a team wordmark logo across the chest with Lincecum's name and number printed on the back. With an allover girly pink body, your baseball princess will certainly have a grand slam look full of cuteness for the big game.
- 100% Cotton fabric
- Imported
- Lightweight ribbed T-shirt
- Officially licensed Giants tee
- Rib-knit collar
- Screen print graphics
- Tagless collar
Shop early for holidays and birthdays with our 365 Day No-Hassle Return Policy! Because we stand behind the quality of our products, you can return any item in original condition for up to a full year from the purchase date. We want you and your gift recipients to love what you ordered, but if not, we make returns easy for you.
Special event items are produced by manufacturers only after the outcome of a game or event. These are advanced sale items and will ship immediately after they are received in our warehouse.
Manufacturer direct items are shipped directly from the manufacturer. These items are not available for international or expedited shipping.
Customized items can be personalized with options such as your name, your favorite number, and/or designs. Some options may be limited by league rules.


text:
You can register to WVYSL recreational soccer programs either online or by mail.
Please refer to seasonal programs offered by WVYSL
- Spring: Mid-March to May/June
- Summer: June to early August
- Fall: Mid-August to early/mid-November
- Winter (Indoor): Early/mid December to late February
To Register Online
- Click here for online registration - You will be sent to a Blue Sombrero site. If the hyperlink does not work, copy and paste: https://sports.bluesombrero.com/Default.aspx?tabid=316356
To Register by Mail
- Complete the CYSA Membership Form (1601) – Please state which program you are registering for on the top of the form.
- Complete the volunteer form
- Check should be payable to WVYSL for the amount of registration, plus volunteer opt-out fee (if applicable).
- Mail them to WVYSL, P.O. Box 10087, San Jose, CA 95157
Contact rec@wvysl for questions.


text:
Dream Dictionary
Welcome to Dream Dictionary!
Whether the sand you dreamed of was on a beach, in your food or in your shoes, it is warning you to be wary of a new acquaintance who will try to exploit you.
Dream Decoding 101
Take our crash course in dream interpretation!
Bedside Notes
Print this notepaper to jot down dream details before they fade away.
Need help?
Step-by-step instructions for using Dream Dictionary


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After Congress passed a bill last year to prevent anyone convicted of domestic violence from possessing a gun, few realized that hundreds of police officers could end up losing their weapons. As a result, dozens of police departments nationwide have had to lay off or transfer hundreds of officers with domestic violence convictions. Now, infuriated police groups stand ready to change the law.
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GUEST: PAM COUKOS, the public policy director for the National Coalition Against Domestic Violence.


text:
" I don't spin to do fancy tricks,
I don't spin to be the best,
I spin my ropes and spheres and sticks,
To abide the tide within my chest.
I don't spin to be known as cool,
I don't spin for fame or glory,
I spin for king as well as fool,
to share the essence of my story.
I don't spin just to teach,
I don't spin to perform,
I spin to reach,
I spin to grow, to surrender and transform,
I spin to expand the shapes that grow,
In the corners of my mind,
To lead them in an ancient dance,
Older than mankind.
I spin like tiny molecules,
Like giant planets round the sun,
I spin for the unseen force between,
That gathers us and makes us one.
I spin during the night,
I spin during the day,
I spin like everything in sight,
Because I know no other way… "
Thom Thumb
- 22 notes
- 24.September.2012
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