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A search for narrow, high-mass resonances decaying to electron or muon pairs has been performed using pp collision data collected at root s = 7 TeV by the CMS experiment in 2011. The data sample corresponds to an integrated luminosity of approximately 5 fb(-1). The event yields observed in the signal regions are consistent with predictions of the standard model backgrounds, and upper limits on the cross section times branching fraction for a resonance decaying to dileptons are extracted from a shape analysis of the dilepton invariant mass distribution. The resulting mass limits at 95% confidence level are 2330 GeV for the Z' in the Sequential Standard Model, 2000 GeV for the superstring-inspired Z'(psi) resonance, 890 (540) GeV for the Stueckelberg extension Z'(St) the mass parameter epsilon = 0.06 (0.04), and 2140 (1810) GeV for Kaluza-Klein gravitons with the coupling parameter k/(M) over bar (Pl) of 0.10 (0.05). These limits are the most stringent to date. (C) 2012 Elsevier B.V. All rights reserved.

Childhood herpes simplex virus-1 (HSV-1) encephalitis (HSE) may result from single-gene inborn errors of TLR3 immunity. TLR3-dependent induction of IFN-alpha/beta or IFN-lambda is crucial for protective immunity against primary HSV-1 infection in the central nervous system (CNS). We describe here two unrelated children with HSE carrying different heterozygous mutations (D50A and G159A) in TBK1, the gene encoding TANK-binding kinase 1, a kinase at the crossroads of multiple IFN-inducing signaling pathways. Both mutant TBK1 alleles are loss-of-function but through different mechanisms: protein instability (D50A) or a loss of kinase activity (G159A). Both are also associated with an autosomal-dominant (AD) trait but by different mechanisms: haplotype insufficiency (D50A) or negative dominance (G159A). A defect in polyinosinic-polycytidylic acid-induced TLR3 responses can be detected in fibroblasts heterozygous for G159A but not for D50A TBK1. Nevertheless, viral replication and cell death rates caused by two TLR3-dependent viruses (HSV-1 and vesicular stomatitis virus) were high in fibroblasts from both patients, and particularly so in G159A TBK1 fibroblasts. These phenotypes were rescued equally well by IFN-alpha 2b. Moreover, the IFN responses to the TLR3-independent agonists and viruses tested were maintained in both patients' peripheral blood mononuclear cells and fibroblasts. The narrow, partial cellular phenotype thus accounts for the clinical phenotype of these patients being limited to HSE. These data identify AD partial TBK1 deficiency as a new genetic etiology of childhood HSE, indicating that TBK1 is essential for the TLR3- and IFN-dependent control of HSV-1 in the CNS.

The genetic dissection of various human infectious diseases has led to the definition of inborn errors of human STAT1 immunity of four types, including (i) autosomal recessive (AR) complete STAT1 deficiency, (ii) AR partial STAT1 deficiency, (iii) autosomal dominant (AD) STAT1 deficiency, and (iv) AD gain of STAT1 activity. The two types of AR STAT1 defect give rise to a broad infectious phenotype with susceptibility to intramacrophagic bacteria (mostly mycobacteria) and viruses (herpes viruses at least), due principally to the impairment of IFN-gamma-mediated and IFN-alpha/beta-mediated immunity, respectively. Clinical outcome depends on the extent to which the STAT1 defect decreases responsiveness to these cytokines. AD STAT1 deficiency selectively predisposes individuals to mycobacterial disease, owing to the impairment of IFN-gamma-mediated immunity, as IFN-alpha/beta-mediated immunity is maintained. Finally, AD gain of STAT1 activity is associated with autoimmunity, probably owing to an enhancement of IFN-alpha/beta-mediated immunity. More surprisingly, it is also associated with chronic mucocutaneous candidiasis, through as yet undetermined mechanisms involving an inhibition of the development of IL-17-producing T cells. Thus, germline mutations in human STAT1 define four distinct clinical disorders. Various combinations of viral,mycobacterial and fungal infections are therefore allelic at the human STAT1 locus. These experiments of Nature neatly highlight the clinical and immunological impact of the human genetic dissection of infectious phenotypes.

Conventional assays of viral particle assembly and release are time consuming and laborious. We have developed an enzymatic virus-like particle (VLP) genesis assay that rapid and quantitative and is also versatile and applicable to diverse viruses including HIV-1 and Ebola virus. Using this assay, which has a dynamic range of several orders of magnitude, we show that the efficiency of VLP assembly and release, i.e., the fraction of the expressed protein that is assembled into extracellular particles, is dependent on the absolute level of expression of either HIV-1 Gag or Ebola virus VP40. We also demonstrate that the activity of the antiviral factor tetherin is dependent on the level of HIV-1 Gag expression and the numbers of VLPs generated, and appears to become saturated as these parameters are increased. (C) 2012 Elsevier Inc. All rights reserved.

The first measurement of the charged component of the underlying event using the novel "jet-area/median" approach is presented for proton-proton collisions at centre-of-mass energies of 0.9 and 7TeV. The data were recorded in 2010 with the CMS experiment at the LHC. A new observable, sensitive to soft particle production, is introduced and investigated inclusively and as a function of the event scale defined by the transverse momentum of the leading jet. Various phenomenological models are compared to data, with and without corrections for detector effects. None of the examined models describe the data satisfactorily.

Trypanosomatids represent the causative agents of major diseases in humans, livestock and plants, with inevitable suffering and economic hardship as a result. They are also evolutionarily highly divergent organisms, and the many unique aspects of trypanosome biology provide opportunities in terms of identification of drug targets, the challenge of exploiting these putative targets and, at the same time, significant scope for exploration of novel and divergent cell biology. We can estimate from genome sequences that the degree of divergence of trypanosomes from animals and fungi is extreme, with perhaps one third to one half of predicted trypanosome proteins having no known function based on homology or recognizable protein domains/architecture. Two highly important aspects of trypanosome biology are the flagellar pocket and the nuclear envelope, where in silico analysis clearly suggests great potential divergence in the proteome. The flagellar pocket is the sole site of endo- and exocytosis in trypanosomes and plays important roles in immune evasion via variant surface glycoprotein (VSG) trafficking and providing a location for sequestration of various invariant receptors. The trypanosome nuclear envelope has been largely unexplored but, by analogy with higher eukaryotes, roles in the regulation of chromatin and most significantly, in controlling VSG gene expression are expected. Here we discuss recent successful proteomics-based approaches towards characterization of the nuclear envelope and the endocytic apparatus, the identification of conserved and novel trypanosomatid-specific features, and the implications of these findings.

The Lambda b differential production cross section and the cross section ratio sigma((Lambda) over bar (b))/sigma(Lambda(b)) are measured as functions of transverse momentum p(T)(Lambda b) rapidity vertical bar y(Lambda b)vertical bar in pp collisions at root s = 7 TeV using data collected by the CMS experiment at the LHC. The measurements are based on Lambda(b) decays reconstructed in the exclusive final state J/psi Lambda, with the subsequent decays J/psi -> mu(+)mu(-) and Lambda -> p pi, using a data sample corresponding to an integrated luminosity of 1.9 fb(-1). The product sigma(Lambda(b)) x B(Lambda(b) -> J/psi Lambda) versus p(T)(Lambda b) falls faster than that of b mesons. The measured value of sigma(Lambda(b)) x B(Lambda(b) -> J/psi Lambda) for p(T)(Lambda b) > 10 GeV and vertical bar y(Lambda b)vertical bar < 2.0 is 1.16 +/- 0.06 +/- 0.12 nb, and the integrated sigma(<(Lambda)over bar>(b))/sigma(Lambda(b)) ratio is 1.02 +/- 0.07 +/- 0.09, where the uncertainties are statistical and systematic, respectively. (C) 2012 CERN. Published by Elsevier B.V. All rights reserved.

Mechanisms for the evolution of convergent behavioral traits are largely unknown. Vocal learning is one such trait that evolved multiple times and is necessary in humans for the acquisition of spoken language. Among birds, vocal learning is evolved in songbirds, parrots, and hummingbirds. Each time similar forebrain song nuclei specialized for vocal learning and production have evolved. This finding led to the hypothesis that the behavioral and neuroanatomical convergences for vocal learning could be associated with molecular convergence. We previously found that the neural activity-induced gene dual specificity phosphatase 1 (dusp1) was up-regulated in non-vocal circuits, specifically in sensory-input neurons of the thalamus and telencephalon; however, dusp1 was not up-regulated in higher order sensory neurons or motor circuits. Here we show that song motor nuclei are an exception to this pattern. The song nuclei of species from all known vocal learning avian lineages showed motor-driven up-regulation of dusp1 expression induced by singing. There was no detectable motor-driven dusp1 expression throughout the rest of the forebrain after non-vocal motor performance. This pattern contrasts with expression of the commonly studied activity-induced gene egr1, which shows motor-driven expression in song nuclei induced by singing, but also motor-driven expression in adjacent brain regions after non-vocal motor behaviors. In the vocal non-learning avian species, we found no detectable vocalizing-driven dusp1 expression in the forebrain. These findings suggest that independent evolutions of neural systems for vocal learning were accompanied by selection for specialized motor-driven expression of the dusp1 gene in those circuits. This specialized expression of dusp1 could potentially lead to differential regulation of dusp1-modulated molecular cascades in vocal learning circuits.

Clinical reports suggest a positive association between fat consumption and the incidence of hyperactivity, impulsivity and cognitive abnormalities. To investigate possible mechanisms underlying these disturbances under short-term conditions, we examined in Sprague-Dawley rats the influence of 7-day consumption of a high-fat diet (HFD) compared to chow on anxiety, novelty-seeking and exploratory behaviors and also on acetylcholine (ACh) neurotransmission that may mediate these behaviors. The HFD consumption, which elevated circulating fatty acids but produced no change in caloric intake or body weight, stimulated novelty-seeking and exploration in an open field, while reducing anxiety in an elevated plus maze. Using the Ellman assay to measure ACh esterase (AChE) activity that breaks down ACh, the second experiment showed HFD consumption to significantly reduce AChE activity in the frontal cortex, hypothalamus and midbrain. With measurements of [I-125]-epibatidine or [I-125]-bungarotoxin binding to nicotinic ACh receptors (nAChRs) containing beta 2 or alpha 7 subunits, respectively, the results also showed HFD consumption to increase both beta 2-nAChR binding in the medial prefrontal cortex and substantia nigra and alpha 7-nAChR binding in the lateral and ventromedial hypothalamus. When treated with an acute dose of the nicotinic antagonist, mecamylamine (0.5 mg/kg, sc), the HFD animals responded with significantly reduced exploratory and novelty-seeking behaviors, whereas the chow-consuming rats exhibited no response. These findings suggest that the exploratory and novelty-seeking behaviors induced by dietary fat may be mediated by enhanced nicotinic cholinergic activity, which is accompanied by increased density of beta 2-nAChRs in cortical and midbrain regions associated with impulsivity and locomotor activity and of alpha 7-nAChRs in hypothalamic regions associated with arousal and energy balance. 2012 Elsevier B.V. All rights reserved.