The rockefeller university

We describe a Turkish patient with tyrosine kinase 2 deficiency who suffered from disseminated Bacille Calmette-Guerin infection, neurobrucellosis, and cutaneous herpes zoster infection. Tyrosine kinase 2 deficiency should be considered in patients susceptible to herpes viruses and intramacrophage pathogens even in the absence of atopy, high serum IgE, and staphylococcal disease. (J Pediatr 2012; 160:1055-7)

The molecular determinants of spleen organogenesis and the etiology of isolated congenital asplenia (ICA), a life-threatening human condition, are unknown. We previously reported that Pbx1 deficiency causes organ growth defects including asplenia. Here, we show that mice with splenic mesenchyme-specific Pbx1 inactivation exhibit hyposplenia. Moreover, the loss of Pbx causes downregulation of Nkx2-5 and derepression of p15Ink4b in spleen mesenchymal progenitors, perturbing the cell cycle. Removal of p15Ink4b in Pbx1 spleen-specific mutants partially rescues spleen growth. By whole-exome sequencing of a multiplex kindred with ICA, we identify a heterozygous missense mutation (P236H) in NKX2-5 showing reduced transactivation in vitro. This study establishes that a Pbx/Nkx2-5/p15 regulatory module is essential for spleen development.

Results are presented from a search for large, extra spatial dimensions in events with either two isolated muons or two isolated electrons. The data are from proton-proton interactions at root s = 7 TeV collected with the CMS detector at the LHC. The size of the data sample corresponds to an integrated luminosity of approximately 2 fb(-1). The observed dimuon and dielectron mass spectra are found to be consistent with standard-model expectations. Depending on the number of extra dimensions, the 95% confidence level limits from the combined mu mu and ee channels range from M-s > 2.4 TeV to M-s > 3.8 TeV, where M-s characterizes the scale for the onset of quantum gravity. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.

Background. Natural killer (NK) cells are an important component of the innate immune defense against viruses, including hepatitis C virus (HCV). The cell culture system using HCV-permissive Huh-7.5 cells make studies on interaction of NK cells and HCV-infected target cells possible. We used this system to characterize interactions of HCV-infected Huh-7.5 cells and NK cells from healthy controls and patients with acute HCV infection. Methods. IFN alpha- and IL-2 stimulated NK cells were cultured with HCV-infected hepatoma cells and subsequently analyzed (for degranulation and cytokine production) via multicolour flow cytometry. Luciferase assyas have been used to study inhibition of HCV replication. Further, PBMC from patients with acute hepatitis C as well as HCV-infected Huh7.5 cells have been analyzed via flow cytometry for expression of NK cell receptors and ligands, respectively. Results. After interferon (IFN) alpha stimulation, NK cells from healthy controls and patients with acute hepatitis C efficiently recognized both HCV-infected and uninfected hepatoma cells. Subsequent dissection of receptor-ligand interaction revealed a dominant role for DNAM-1 and a complementary contribution of NKG2D for NK cell activation in this setting. Furthermore, IFN-alpha-stimulated NK cells effectively inhibited HCV replication in a DNAM-1-dependent manner. Conclusions. Human NK cells recognize HCV-infected hepatoma cells after IFN-alpha stimulation in a DNAM-1-dependent manner. Furthermore, interaction of IFN-alpha-stimulated NK cells with HCV-infected hepatoma cells efficiently reduced HCV replication. This study opens up future studies of NK cell interaction with HCV-infected hepatocytes to gain further insight into the pathogenesis of human HCV infection and the therapeutic effects of IFN-alpha.

Experiential factors shape the neural circuits underlying social and emotional behavior from the prenatal period to the end of life. These factors include both incidental influences, such as early adversity, and intentional influences that can be produced in humans through specific interventions designed to promote prosocial behavior and well-being. Here we review important extant evidence in animal models and humans. Although the precise mechanisms of plasticity are still not fully understood, moderate to severe stress appears to increase the growth of several sectors of the amygdala, whereas the effects in the hippocampus and prefrontal cortex tend to be opposite. Structural and functional changes in the brain have been observed with cognitive therapy and certain forms of meditation and lead to the suggestion that well-being and other prosocial characteristics might be enhanced through training.

Our understanding of current treatments for depression, and the development of more specific therapies, is limited by the complexity of the circuits controlling mood and the distributed actions of antidepressants. Although the therapeutic efficacy of serotonin-specific reuptake inhibitors (SSRIs) is correlated with increases in cortical activity, the cell types crucial for their action remain unknown. Here we employ bacTRAP translational profiling to show that layer 5 corticostriatal pyramidal cells expressing p11 (S100a10) are strongly and specifically responsive to chronic antidepressant treatment. This response requires p11 and includes the specific induction of Htr4 expression. Cortex-specific deletion of p11 abolishes behavioral responses to SSRIs, but does not lead to increased depression-like behaviors. Our data identify corticostriatal projection neurons as critical for the response to antidepressants, and suggest that the regulation of serotonergic tone in this single cell type plays a pivotal role in antidepressant therapy.

We present the results of a search for dark matter production in the monojet signature. We analyze a sample of Tevatron p (p) over bar collisions at root s = 1.96 TeV corresponding to an integrated luminosity of 6.7 fb(-1) recorded by the CDF II detector. In events with large missing transverse energy and one energetic jet, we find good agreement between the standard model prediction and the observed data. We set 90% confidence level upper limits on the dark matter production rate. The limits are translated into bounds on nucleon-dark matter scattering rates which are competitive with current direct detection bounds on spin-independent interaction below a dark matter candidate mass of 5 GeV/c(2), and on spin-dependent interactions up to masses of 200 GeV/c(2).

The telomere end-protection problem is defined by the aggregate of DNA damage signaling and repair pathways that require repression at telomeres. To define the end-protection problem, we removed the whole shelterin complex from mouse telomeres through conditional deletion of TRF1 and TRF2 in nonhomologous end-joining (NHEJ) deficient cells. The data reveal two DNA damage response pathways not previously observed upon deletion of individual shelterin proteins. The shelterin-free telomeres are processed by microhomology-mediated alternative-NHEJ when Ku70/80 is absent and are attacked by nucleolytic degradation in the absence of 53BP1. The data establish that the end-protection problem is specified by six pathways [ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3 related) signaling, classical-NHEJ, alt-NHEJ, homologous recombination, and resection] and show how shelterin acts with general DNA damage response factors to solve this problem.

Decoding post-transcriptional regulatory programs in RNA is a critical step towards the larger goal of developing predictive dynamical models of cellular behaviour. Despite recent efforts(1-3), the vast landscape of RNA regulatory elements remains largely uncharacterized. A long-standing obstacle is the contribution of local RNA secondary structure to the definition of interaction partners in a variety of regulatory contexts, including-but not limited to-transcript stability(3), alternative splicing(4) and localization(3). There are many documented instances where the presence of a structural regulatory element dictates alternative splicing patterns (for example, human cardiac troponin T) or affects other aspects of RNA biology(5). Thus, a full characterization of post-transcriptional regulatory programs requires capturing information provided by both local secondary structures and the underlying sequence(3,6). Here we present a computational framework based on context-free grammars(3,7) and mutual information(2) that systematically explores the immense space of small structural elements and reveals motifs that are significantly informative of genome-wide measurements of RNA behaviour. By applying this framework to genome-wide human mRNA stability data, we reveal eight highly significant elements with substantial structural information, for the strongest of which we show a major role in global mRNA regulation. Through biochemistry, mass spectrometry and in vivo binding studies, we identified human HNRPA2B1 (heterogeneous nuclear ribonucleoprotein A2/B1, also known as HNRNPA2B1) as the key regulator that binds this element and stabilizes a large number of its target genes. We created a global post-transcriptional regulatory map based on the identity of the discovered linear and structural cis-regulatory elements, their regulatory interactions and their target pathways. This approach could also be used to reveal the structural elements that modulate other aspects of RNA behaviour.

Intraprotein side chain contacts can couple the evolutionary process of amino acid substitution at one position to that at another. This coupling, known as residue coevolution, may vary in strength. Conserved contacts thus not only define 3-dimensional protein structure, but also indicate which residue-residue interactions are crucial to a protein's function. Therefore, prediction of strongly coevolving residue-pairs helps clarify molecular mechanisms underlying function. Previously, various coevolution detectors have been employed separately to predict these pairs purely from multiple sequence alignments, while disregarding available structural information. This study introduces an integrative framework that improves the accuracy of such predictions, relative to previous approaches, by combining multiple coevolution detectors and incorporating structural contact information. This framework is applied to the ABC-B and ABC-C transporter families, which include the drug exporter P-glycoprotein involved in multidrug resistance of cancer cells, as well as the CFTR chloride channel linked to cystic fibrosis disease. The predicted coevolving pairs are further analyzed based on conformational changes inferred from outward- and inward-facing transporter structures. The analysis suggests that some pairs coevolved to directly regulate conformational changes of the alternating-access transport mechanism, while others to stabilize rigid-body-like components of the protein structure. Moreover, some identified pairs correspond to residues previously implicated in cystic fibrosis.