The rockefeller university

Glycogen synthase kinase 3 beta (GSK3 beta) is highly inactivated in epithelial cancers and is known to inhibit tumor migration and invasion. The zinc-finger-containing transcriptional repressor, Slug, represses E-cadherin transcription and enhances epithelial mesenchymal transition (EMT). In this study, we find that the GSK3 beta-pSer9 level is associated with the expression of Slug in non-small cell lung cancer. GSK3 beta-mediated phosphorylation of Slug facilitates Slug protein turnover. Proteomic analysis reveals that the carboxyl terminus of Hsc70-interacting protein (CHIP) interacts with wild-type Slug (wtSlug). Knockdown of CHIP stabilizes the wtSlug protein and reduces Slug ubiquitylation and degradation. In contrast, nonphosphorylatable Slug-4SA is not degraded by CHIP. The accumulation of nondegradable Slug may further lead to the repression of E-cadherin expression and promote cancer cell migration, invasion and metastasis. Our findings provide evidence of a de novo GSK3 beta-CHIP-Slug pathway that may be involved in the progression of metastasis in lung cancer.

In the rat, repeated brief exposures to novelty early in life can induce long-lasting enhancements in adult cognitive, social, emotional, and neuroendocrine function. Family-to-family variations in these intervention effects on adult offspring are predicted by the mother's ability to mount a rapid corticosterone (COAT) response to the onset of an acute stressor. Here, in Long-Evans rats, we investigated whether neonatal and adulthood novelty exposure, each individually and in combination, can enhance offspring hypothalamic-pituitary-adrenal (HPA) regulation. Using a 2 x 2 within-litter design, one half of each litter were exposed to a relatively novel non home environment for 3-min (Neo_Novel) daily during infancy (PND 1-21) and the other half of the litter remained in the home cage (Neo_Home); we further exposed half of these two groups to early adulthood (PND 54-63) novelty exposure in an open field and the remaining siblings stayed in their home cages. Two aspects of HPA regulation were assessed: the ability to maintain a low level of resting COAT (CORTB) and the ability to mount a large rapid CORT response (CORTE) to the onset of an acute stressor. Assessment of adult offspring's ability to regulate HPA regulation began at 370 days of age. We further investigated whether the novelty exposure effects on offspring HPA regulation are sensitive to the context of maternal HPA regulation by assessing maternal HPA regulation similarly beginning 7 days after her pups were weaned. We found that at the population level, rats receiving neonatal, but not early adulthood exposure or both, showed a greater rapid CORTE than their home-staying siblings. At the individual family level, these novelty effects are positively associated with maternal CORTE. These results suggest that early experience of novelty can enhance the offspring's ability to mount a rapid response to environmental challenge and the success of such early life intervention is critically dependent upon the context of maternal HPA regulation.

Previous studies produced evidence that mecA, the determinant of beta-lactam resistance in methicillin-resistant Staphylococcus aureus (MRSA), may have originated in the most primitive and widespread animal commensal species-Staphylococcus sciuri. But how the mecA homologue (mecA1/pbpD) was captured from S. sciuri into the staphylococcal cassette chromosome mec (SCCmec) has remained unclear. To understand the role of S. sciuri in the assembly of SCCmec, we screened 118 methicillin-susceptible S. sciuri isolates for SCCmec central elements-ccr and mec complex (ccrAB, ccrC, mecA, mecI and mecR1)-by dot-blot hybridization. In addition, isolates were typed by PFGE and the chromosomal proximity of SCCmec elements was determined by Southern hybridization. ccr typing was performed by nucleotide sequencing. ccrwere identified in 35% of the isolates (naEuroS=aEuroS41), represented by 24 PFGE types, but ccrC was not found. None of the isolates carried mecA or its regulators, but all isolates carried mecA1/pbpD. In the majority of isolates, ccr and mecA1 were located near orfX, the SCCmec integration site. Moreover, in 31% (naEuroS=aEuroS13) of the ccrAB-carrying strains, ccrAB, mecA1 and orfX colocalized in the chromosome. The nucleotide sequence of ccrA/ccrB was highly diverse, including ccr genes closely related (80%-97%) to those found in MRSA. Our results suggest that S. sciuri was a natural recipient and a rich reservoir of ccr for the assembly of SCCmec. The chromosomal location of mecA1, near orfX, the recognition site of ccr, was probably crucial for its mobilization out of S. sciuri species into SCCmec.

We present a measurement of the ratio of the top-quark branching fractions R = B(t -> Wb)/B(t -> Wq), where q represents any quark flavor, in events with two charged leptons, imbalance in total transverse energy, and at least two jets. The measurement uses proton-antiproton collision data at center-of-mass energy 1.96 TeV, corresponding to an integrated luminosity of 8.7 fb(-1) collected with the Collider Detector at Fermilab during Run II of the Tevatron. We measure R to be 0.87 +/- 0.07, and extract the magnitude of the top-bottom quark coupling to be |V-tb| 0.93 +/- 0.04, assuming three generations of quarks. Under these assumptions, a lower limit of |V-tb| > 0.85(0.87) at 95% (90%) credibility level is set.

A peaking structure in the J/psi phi mass spectrum near threshold is observed in B-+/- -> J/psi phi K-+/- decays, produced in pp collisions at root s = 7 TeV collected with the CMS detector at the LHC. The data sample, selected on the basis of the dimuon decay mode of the J/psi, corresponds to an integrated luminosity of 5.2 fb(-1). Fitting the structure to an S-wave relativistic Breit-Wigner lineshape above a three-body phase-space nonresonant component gives a signal statistical significance exceeding five standard deviations. The fitted mass and width values are m = 4148.0 +/- 2.4 (stat.) +/- 6.3 (syst.) MeV and Gamma = 28(-11)(+15) (stat.) +/- 19 (syst.) MeV, respectively. Evidence for an additional peaking structure at higher J/psi phi mass is also reported. (C) 2014 The Authors. Published by Elsevier B.V.

Only a small fraction of individuals exposed to Mycobacterium tuberculosis develop clinical tuberculosis (TB). Over the past century, epidemiological studies have shown that human genetic factors contribute significantly to this interindividual variability, and molecular progress has been made over the past decade for at least two of the three key TB-related phenotypes: (i) a major locus controlling resistance to infection with M. tuberculosis has been identified, and (ii) proof of principle that severe TB of childhood can result from single-gene inborn errors of interferon-g immunity has been provided; genetic association studies with pulmonary TB in adulthood have met with more limited success. Future genetic studies of these three phenotypes could consider subgroups of subjects defined on the basis of individual (e. g. age at TB onset) or environmental (e. g. pathogen strain) factors. Progress may also be facilitated by further methodological advances in human genetics. Identification of the human genetic variants controlling the various stages and forms of TB is critical for understanding TB pathogenesis. These findings should have major implications for TB control, in the definition of improved prevention strategies, the optimization of vaccines and clinical trials and the development of novel treatments aiming to restore deficient immune responses.

Recent studies have shown that the transcriptional functions of REST are much broader than repressing neuronal genes in non-neuronal systems. Whether REST occupies similar chromatin regions in different cell types and how it interacts with other transcriptional regulators to execute its functions in a context-dependent manner has not been adequately investigated. We have applied ChIP-seq analysis to identify the REST cistrome in human CD4+ T cells and compared it with published data from 15 other cell types. We found that REST cistromes were distinct among cell types, with REST binding to several tumor suppressors specifically in cancer cells, whereas 7% of the REST peaks in non-neuronal cells were ubiquitously called and <25% were identified for >= 5 cell types. Nevertheless, using a quantitative metric directly comparing raw ChIP-seq signals, we found the majority (similar to 80%) was shared by >= 2 cell types. Integration with RNA-seq data showed that REST binding was generally correlated with low gene expression. Close examination revealed that multiple contexts were correlated with reduced expression of REST targets, e. g., the presence of a cognate RE1 motif and cellular specificity of REST binding. These contexts were shown to play a role in differential corepressor recruitment. Furthermore, transcriptional outcome was highly influenced by REST cofactors, e. g., SIN3 and EZH2 co-occupancy marked higher and lower expression of REST targets, respectively. Unexpectedly, the REST cistrome in differentiated neurons exhibited unique features not observed in non-neuronal cells, e. g., the lack of RE1 motifs and an association with active gene expression. Finally, our analysis demonstrated how REST could differentially regulate a transcription network constituted of miRNAs, REST complex and neuronal factors. Overall, our findings of contexts playing critical roles in REST occupancy and regulatory outcome provide insights into the molecular interactions underlying REST's diverse functions, and point to novel roles of REST in differentiated neurons.

Results are reported from a search for supersymmetry in pp collisions at a center-of-mass energy of 8 TeV, based on events with a single isolated lepton (electron or muon) and multiple jets, at least two of which are identified as b jets. The data sample corresponds to an integrated luminosity of 19.3 fb(-1) recorded by the CMS experiment at the LHC in 2012. The search is motivated by supersymmetric models that involve strong-production processes and cascade decays of new particles. The resulting final states contain multiple jets as well as missing transverse momentum from weakly interacting particles. The event yields, observed across several kinematic regions, are consistent with the expectations from standard model processes. The results are interpreted in the context of simplified supersymmetric scenarios with pair production of gluinos, where each gluino decays to a top quark-antiquark pair and the lightest neutralino. For the case of decays via virtual top squarks, gluinos with a mass smaller than 1.26 TeV are excluded for low neutralino masses. (C) 2014 The Authors. Published by Elsevier B.V.

Primate lentiviruses exhibit narrow host tropism, reducing the occurrence of zoonoses but also impairing the development of optimal animal models of AIDS. To delineate the factors limiting cross-species HIV-1 transmission, we passaged a modified HIV-1 in pigtailed macaques that were transiently depleted of CD8(+) cells during acute infection. During adaptation over four passages in macaques, HIV-1 acquired the ability to antagonize the macaque restriction factor tetherin, replicated at progressively higher levels, and ultimately caused marked CD4(+) T cell depletion and AIDS-defining conditions. Transient treatment with an antibody to CD8 during acute HIV-1 infection caused rapid progression to AIDS, whereas untreated animals exhibited an elite controller phenotype. Thus, an adapted HIV-1 can cause AIDS in macaques, and stark differences in outcome can be determined by immunological perturbations during early infection.

Bacteriophage endolysins have shown great efficacy in killing Gram-positive bacteria. PlyC, a group C streptococcal phage lysin, represents the most efficient lysin characterized to date, with a remarkably high specificity against different streptococcal species, including the important pathogen Streptococcus pyogenes. However, PlyC is a unique lysin, in terms of both its high activity and structure (two distinct subunits). We sought to discover and characterize a phage lysin active against S. pyogenes with an endolysin architecture distinct from that of PlyC to determine if it relies on the same mechanism of action as PlyC. In this study, we identified and characterized an endolysin, termed PlyPy (phage lysin from S. pyogenes), from a prophage infecting S. pyogenes. By in silico analysis, PlyPy was found to have a molecular mass of 27.8 kDa and a pI of 4.16. It was active against a majority of group A streptococci and displayed high levels of activity as well as binding specificity against group B and C streptococci, while it was less efficient against other streptococcal species. PlyPy showed the highest activity at neutral pH in the presence of calcium and NaCl. Surprisingly, its activity was not affected by the presence of the group A-specific carbohydrate, while the activity of PlyC was partly inhibited. Additionally, PlyPy was active in vivo and could rescue mice from systemic bacteremia. Finally, we developed a novel method to determine the peptidoglycan bond cleaved by lysins and concluded that PlyPy exhibits a rare D-alanyl-L-alanine endopeptidase activity. PlyPy thus represents the first lysin characterized from Streptococcus pyogenes and has a mechanism of action distinct from that of PlyC.