The rockefeller university

Serine is both a proteinogenic amino acid and the source of one-carbon units essential for de novo purine and deoxythymidine synthesis. In the canonical pathway of glucose-derived serine synthesis, Homo sapiens phosphoglycerate dehydrogenase (PHGDH) catalyzes the first, rate-limiting step. Genetic loss of PHGDH is toxic toward PHGDH-overexpressing breast cancer cell lines even in the presence of exogenous serine. Here, we used a quantitative high-throughput screen to identify small-molecule PHGDH inhibitors. These compounds reduce the production of glucose-derived serine in cells and suppress the growth of PHGDH-dependent cancer cells in culture and in orthotopic xenograft tumors. Surprisingly, PHGDH inhibition reduced the incorporation into nucleotides of one-carbon units from glucose-derived and exogenous serine. We conclude that glycolytic serine synthesis coordinates the use of one-carbon units from endogenous and exogenous serine in nucleotide synthesis, and we suggest that one-carbon unit wasting thus may contribute to the efficacy of PHGDH inhibitors in vitro and in vivo.

Developmental specification of germ cells lies at the heart of inheritance, as germ cells contain all of the genetic and epigenetic information transmitted between generations. The critical developmental event distinguishing germline from somatic lineages is the differentiation of primordial germ cells (PGCs)(1,2), precursors of sex-specific gametes that produce an entire organism upon fertilization. Germ cells toggle between uni- and pluripotent states as they exhibit their own 'latent' form of pluripotency. For example, PGCs express a number of transcription factors in common with embryonic stem (ES) cells, including OCT4 (encoded by Pou5f1), SOX2, NANOG and PRDM14 (refs 2-4). A biochemical mechanism by which these transcription factors converge on chromatin to produce the dramatic rearrangements underlying ES-cell-and PGC-specific transcriptional programs remains poorly understood. Here we identify a novel co-repressor protein, CBFA2T2, that regulates pluripotency and germline specification in mice. Cbfa2t2(-/-) mice display severe defects in PGC maturation and epigenetic reprogramming. CBFA2T2 forms a biochemical complex with PRDM14, a germline-specific transcription factor. Mechanistically, CBFA2T2 oligomerizes to form a scaffold upon which PRDM14 and OCT4 are stabilized on chromatin. Thus, in contrast to the traditional 'passenger' role of a co-repressor, CBFA2T2 functions synergistically with transcription factors at the crossroads of the fundamental developmental plasticity between uni- and pluripotency.

A search for a Higgs boson with suppressed couplings to fermions, h(f), assumed to be the neutral, lower-mass partner of the Higgs boson discovered at the Large Hadron Collider, is reported. Such a Higgs boson could exist in extensions of the standard model with two Higgs doublets, and could be produced via p (p) over bar -> H(+/-)h(f) -> W*h(f)h(f) -> 4 gamma + X where H (+/-) is a charged Higgs boson. This analysis uses all events withat least three photons in the final state from proton-antiproton collisions at a center-of-mass energy of 1.96 TeV collected by the Collider Detector at Fermilab, corresponding to an integrated luminosity of 9.2 fb(-1). No evidence of a signal is observed in the data. Values of Higgs-boson masses between 10 and 100 GeV/c(2) are excluded at 95% Bayesian credibility.

This report describes a male child with a history of poor feeding and swallowing problems, hypotonia, mild bilateral sensorineural hearing loss, cerebral cortical agenesis, cardiac defects, cyanotic episodes triggered by specific movement, dysmorphic features, and developmental delays. Analysis by CytoScan HD array identified a 12.1 Mb interstitial deletion of 7q22.1q31.1 (98,779,628-110,868,171). Wepresent a comprehensive review of the literature surrounding intermediate 7q deletions that overlap with this child's deletion, and an analysis of candidate genes in the deleted region. (C) 2016 Wiley Periodicals, Inc.

Staphylococcus haemolyticus is one of the most common pathogens associated with medical-device related infections, but its molecular epidemiology is poorly explored. In the current study, we aimed to better understand the genetic mechanisms contributing to S. haemolyticus diversity in the hospital environment and their impact on the population structure and clinical relevant phenotypic traits. The analysis of a representative S. haemolyticus collection by multilocus sequence typing (MLST) has identified a single highly prevalent and diverse genetic lineage of nosocomial S. haemolyticus clonal complex (CC) 29 accounting for 91% of the collection of isolates disseminated worldwide. The examination of the sequence changes at MLST loci during clonal diversification showed that recombination had a higher impact than mutation in shaping the S. haemolyticus population. Also, we ascertained that another mechanism contributing significantly to clonal diversification and adaptation was mediated by insertion sequence (IS) elements. We found that all nosocomial S. haemolyticus, belonging to different STs, were rich in IS1272 copies, as determined by Southern hybridization of macrorestriction patterns. In particular, we observed that the chromosome of a S. haemolyticus strain within CC29 was highly unstable during serial growth in vitro which paralleled with IS1272 transposition events and changes in clinically relevant phenotypic traits namely, mannitol fermentation, susceptibility to beta-lactams, biofilm formation and hemolysis. Our results suggest that recombination and IS transposition might be a strategy of adaptation, evolution and pathogenicity of the major S. haemolyticus prevalent lineage in the hospital environment.

While engagement of the inhibitory Fc gamma-receptor (Fc gamma R) IIB is an absolute requirement for in vivo antitumor activity of agonistic mouse anti-CD40 monoclonal antibodies (mAbs), a similar requirement for human mAbs has been disputed. By using a mouse model humanized for its Fc gamma Rs and CD40, we revealed that Fc gamma RIIB engagement is essential for the activity of human CD40 mAbs, while engagement of the activating Fc gamma RIIA inhibits this activity. By engineering Fc variants with selective enhanced binding to Fc gamma RIIB, but not to Fc gamma RIIA, significantly improved antitumor immunity was observed. These findings highlight the necessity of optimizing the Fc domain for this class of therapeutic antibodies by using appropriate preclinical models that accurately reflect the unique affinities and cellular expression of human Fc gamma R.

A surveillance study in 1996 identified the USA100 clone (ST5/SCCmecII)-also known as the "New York/Japan" clone-as the most prevalent MRSA causing infections in 12 New York City hospitals. Here we update the epidemiology of MRSA in seven of the same hospitals eighteen years later in 2013/14. Most of the current MRSA isolates (78 of 121) belonged to the MRSA clone USA300 (CC8/SCCmecIV) but the USA100 clone-dominant in the 1996 survey-still remained the second most frequent MRSA (25 of the 121 isolates) causing 32% of blood stream infections. The USA300 clone was most common in skin and soft tissue infections (SSTIs) and was associated with 84.5% of SSTIs compared to 5% caused by the USA100 clone. Our data indicate that by 2013/14, the USA300 clone replaced the New York/Japan clone as the most frequent cause of MRSA infections in hospitals in Metropolitan New York. In parallel with this shift in the clonal type of MRSA, there was also a striking change in the types of MRSA infections from 1996 to 2014.

During the 1980s, the North Sea plankton community underwent a well-documented ecosystem regime shift, including both spatial changes (northward species range shifts) and temporal changes (increases in the total abundances of warmer water species). This regime shift has been attributed to climate change. Plankton provide a link between climate and higher trophic-level organisms, which can forage on large spatial and temporal scales. It is therefore important to understand not only whether climate change affects purely spatial or temporal aspects of plankton dynamics, but also whether it affects spatiotemporal aspects such as metapopulation synchrony. If plankton synchrony is altered, higher trophic-level feeding patterns may be modified. A second motivation for investigating changes in synchrony is that the possibility of such alterations has been examined for few organisms, in spite of the fact that synchrony is ubiquitous and of major importance in ecology. This study uses correlation coefficients and spectral analysis to investigate whether synchrony changed between the periods 1959-1980 and 1989-2010. Twenty-three plankton taxa, sea surface temperature (SST), and wind speed were examined. Results revealed that synchrony in SST and plankton was altered. Changes were idiosyncratic, and were not explained by changes in abundance. Changes in the synchrony of Calanus helgolandicus and Para-pseudocalanus spp appeared to be driven by changes in SST synchrony. This study is one of few to document alterations of synchrony and climate-change impacts on synchrony. We discuss why climate-change impacts on synchrony may well be more common and consequential than previously recognized.

The importance of TANK binding kinase-1 (TBK1), a multimeric kinase that modulates inflammation and autophagy, in human health has been highlighted for the first time by the recent discoveries of mutations in TBK1 that underlie amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), normal tension glaucoma (NTG) or childhood herpes simplex encephalitis (HSE). Gain-of-function of TBK1 are associated with NTG, whereas loss-of-function mutations result in ALS/FTD or in HSE. In light of these new findings, we review the role of TBK1 in these seemingly unrelated, yet allelic diseases, and discuss the role of TBK1 in neuroinflammatory diseases. This discovery has the potential to significantly increase our understanding of the molecular basis of these poorly understood diseases.

Uveal melanomas are molecularly distinct from cutaneous melanomas and lack mutations in BRAF, NRAS, KIT, and NF1. Instead, they are characterized by activating mutations in GNAQ and GNA11, two highly homologous alpha subunits of G(alpha q/11) heterotrimeric G proteins, and in PLCB4 (phospholipase C beta 4), the downstream effector of G(alpha q) signaling(1-3). We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ, GNA11, and PLCB4 but in 0 of 127 samples that harbored mutations in these genes. The Leu129Gln CysLT(2)R mutant protein constitutively activates endogenous G(alpha q) and is unresponsive to stimulation by leukotriene. Expression of Leu129Gln CysLT(2)R in melanocytes enforces expression of a melanocyte-lineage signature, drives phorbol ester-independent growth in vitro, and promotes tumorigenesis in vivo. Our findings implicate CYSLTR2 as a uveal melanoma oncogene and highlight the critical role of G(alpha q) signaling in uveal melanoma pathogenesis.