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Stress plays a substantial role in shaping behavior and brain function, often with lasting effects. How these lasting effects occur in the context of a fixed postmitotic neuronal genome has been an enduring question for the field. Synaptic plasticity and neurogenesis have provided some of the answers to this question, and more recently epigenetic mechanisms have come to the fore. The exploration of epigenetic mechanisms recently led us to discover that a single acute stress can regulate the expression of retrotransposons in the rat hippocampus via an epigenetic mechanism. We propose that this response may represent a genomic stress response aimed at maintaining genomic and transcriptional stability in vulnerable brain regions such as the hippocampus. This finding and those of other researchers have made clear that retrotransposons and the genomic plasticity they permit play a significant role in brain function during stress and disease. These observations also raise the possibility that the transposome might have adaptive functions at the level of both evolution and the individual organism.

Cardiovascular disease is the most common cause of death worldwide, and hypertension is the major risk factor(1). Mendelian hypertension elucidates mechanisms of blood pressure regulation. Here we report six missense mutations in PDE3A (encoding phosphodiesterase 3A) in six unrelated families with mendelian hypertension and brachydactyly type E (HTNB)(2). The syndrome features brachydactyly type E (BDE), severe salt-independent but age-dependent hypertension, an increased fibroblast growth rate, neurovascular contact at the rostral-ventrolateral medulla, altered baroreflex blood pressure regulation and death from stroke before age 50 years when untreated(3,4). In vitro analyses of mesenchymal stem cell-derived vascular smooth muscle cells (VSMCs) and chondrocytes provided insights into molecular pathogenesis. The mutations increased protein kinase A-mediated PDE3A phosphorylation and resulted in gain of function, with increased cAMP-hydrolytic activity and enhanced cell proliferation. Levels of phosphorylated VASP were diminished, and PTHrP levels were dysregulated. We suggest that the identified PDE3A mutations cause the syndrome. VSMC-expressed PDE3A deserves scrutiny as a therapeutic target for the treatment of hypertension.

Central memory T (T-CM) cells in lymph nodes (LNs) and resident memory T (T-RM) cells in peripheral tissues have distinct roles in protective immunity(1-5). Both are generated after primary infections, but their clonal origins have been unclear. To address this question, we immunized mice through the skin with a protein antigen, a chemical hapten, or a non-replicating poxvirus. We then analyzed antigen-activated T cells from different tissues using high-throughput sequencing (HIS) of the gene encoding the T cell receptor (TCR) beta-chain (Trb, also known as Tcrb) using CDR3 sequences to simultaneously track thousands of unique T cells(6). For every abundant T-RM cell clone generated in the skin, an abundant T-CM cell clone bearing the identical TCR was present in the LNs. Thus, antigen-reactive skin T-RM and LN T-CM cell clones were derived from a common naive T cell precursor after skin immunization, generating overlapping TCR repertoires. Although they bore the same TCR, T-RM cells mediated rapid contact hypersensitivity(7) responses, whereas T-CM cells mediated delayed and attenuated responses. Studies in human subjects confirmed the generation of skin T-RM cells in allergic contact dermatitis. Thus, immunization through skin simultaneously generates skin T-RM and LN T-CM cells in similar numbers from the same naive T cells.

The first measurement of the cross section ratio sigma(t (t) over barb (b) over bar)/sigma(t (t) over bar jj) is presented using a data sample corresponding to an integrated luminosity of 19.6 fb(-1) collected in pp collisions at root s = 8 TeV with the CMS detector at the LHC. Events with two leptons (e or mu) and four reconstructed jets, including two identified as b quark jets, in the final state are selected. The ratio is determined for a minimum jet transverse momentum p(T) of both 20 and 40 GeV/c. The measured ratio is 0.022 +/- 0.003 (stat) +/- 0.005 (syst) for p(T) > 20GeV/c. The absolute cross sections sigma(t (t) over barb (b) over bar) and sigma(t (t) over bar jj) are also measured. The measured ratio for p(T) > 40 GeV/c is compatible with a theoretical quantum chromodynamics calculation at next-to-leading order. (C) 2015 CERN for the benefit of the CMS Collaboration. Published by Elsevier B.V.

The hormone leptin plays a key role in energy homeostasis, and the absence of either leptin or its receptor (LepR) leads to severe obesity and metabolic disorders. To avoid indirect effects and to address the cell-intrinsic role of leptin signaling in the immune system, we conditionally targeted LepR in T cells. In contrast with pleiotropic immune disorders reported in obese mice with leptin or LepR deficiency, we found that LepR deficiency in CD4(+) T cells resulted in a selective defect in both autoimmune and protective Th17 responses. Reduced capacity for differentiation toward a Th17 phenotype by lepr-deficient T cells was attributed to reduced activation of the STAT3 and its downstream targets. This study establishes cell-intrinsic roles for LepR signaling in the immune system and suggests that leptin signaling during T cell differentiation plays a crucial role in T cell peripheral effector function.

A search is performed for a vector-like heavy T quark that is produced in pairs and that decays to a top quark and a Higgs boson. The data analysed correspond to an integrated luminosity of 19.7 fb(-1) collected with the CMS detector in proton-proton collisions at root s = 8TeV. For T quarks with large mass values the top quarks and Higgs bosons can have significant Lorentz boosts, so that their individual decay products often overlap and merge. Methods are applied to resolve the substructure of such merged jets. Upper limits on the production cross section of a T quark with mass between 500 and 1000 GeV/c(2) are derived. If the T quark decays exclusively to tH, the observed (expected) lower limit on the mass of the T quark is 745 (773) GeV/c(2) at 95% confidence level. For the first time an algorithm is used for tagging boosted Higgs bosons that is based on a combination of jet substructure information and b tagging.

Social insects present highly interesting and experimentally amenable systems for the study of disease transmission because they naturally live in dense groups of frequently interacting individuals. Using experimental inoculations of five trypanosomatid strains into groups of its natural host, the bumblebee Bombus terrestris, we investigate the effects of the initial parasite strain distribution across group members on the establishment and transmission success of the different strains to new hosts. For a given number of parasite strains circulating within a host group, transmission to new hosts was increased when the strains were initially inoculated as mixed infections (as opposed to separate single infections), presumably because mixed infections generally favored fast replicating strains. In contrast, separate single infections reduced transmission at least in part through a precedence effect, whereby weak strains appeared to persist by making their host unavailable to superinfection. These results suggest that host groups could benefit from 'compartmentalizing' infections by different parasite strains across different group members, which might be achieved in social insects, for example, by division of labor. (C) 2015 Elsevier B.V. All rights reserved.

Background: Invasive infections of the central nervous system (CNS) or digestive tract caused by commensal fungi of the genus Candida are rare and life-threatening. The known risk factors include acquired and inherited immunodeficiencies, with patients often displaying a history of multiple infections. Cases of meningoencephalitis, colitis, or both caused by Candida species remain unexplained. Objective: We studied 5 previously healthy children and adults with unexplained invasive disease of the CNS, digestive tract, or both caused by Candida species. The patients were aged 39, 7, 17, 37, and 26 years at the time of infection and were unrelated, but each was born to consanguineous parents of Turkish (2 patients), Iranian, Moroccan, or Pakistani origin. Meningoencephalitis was reported in 3 patients, meningoencephalitis associated with colitis was reported in a fourth patient, and the fifth patient had colitis only. Methods: Inherited caspase recruitment domain family, member 9 (CARD9) deficiency was recently reported in otherwise healthy patients with other forms of severe disease caused by Candida, Trichophyton, Phialophora, and Exophiala species, including meningoencephalitis but not colitis caused by Candida and Exophiala species. Therefore we sequenced CARD9 in the 5 patients. Results: All patients were found to be homozygous for rare and deleterious mutant CARD9 alleles: R7OW and Q289* for the 3 patients with Candida albicans induced meningoencephalitis, R35Q for the patient with meningoencephalitis and colitis caused by Candida glabrata, and Q295* for the patient with Candida albicans induced colitis. Regardless of their levels of mutant CARD9 protein, the patients' monocyte-derived dendritic cells responded poorly to CARD9-dependent fungal agonists (curdlan, heat-killed Calbicans, Saccharomyces cerevisiae, and Exophiala dermatitidis). Conclusion: Invasive infections of the CNS or digestive tract caused by Candida species in previously healthy children and even adults might be caused by inherited CARD9 deficiency.