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A search for a new heavy particle decaying to a pair of vector bosons (WW or WZ) is presented using data from the CMS detector corresponding to an integrated luminosity of 35.9 fb(-1) collected in proton-proton collisions at a centre-of-mass energy of 13 TeV in 2016. One of the bosons is required to be a W boson decaying to e nu or mu nu, while the other boson is required to be reconstructed as a single massive jet with substructure compatible with that of a highly-energetic quark pair from a W or Z boson decay. The search is performed in the resonance mass range between 1.0 and 4.4 TeV. The largest deviation from the background-only hypothesis is observed for a mass near 1.4 TeV and corresponds to a local significance of 2.5 standard deviations. The result is interpreted as an upper bound on the resonance production cross section. Comparing the excluded cross section values and the expectations from theoretical calculations in the bulk graviton and heavy vector triplet models, spin-2 WW resonances with mass smaller than 1.07 TeV and spin-1 WZ resonances lighter than 3.05 TeV, respectively, are excluded at 95% confidence level.

A search for long-lived particles was performed with data corresponding to an integrated luminosity of 2.6 fb(-1) collected at a center-of-mass energy of 13 TeV by the CMS experiment in 2015. The analysis exploits two customized topological trigger algorithms, and uses the multiplicity of displaced jets to search for the presence of a signal decay occurring at distances between 1 and 1000 mm. The results can be interpreted in a variety of different models. For pair-produced long-lived particles decaying to two b quarks and two leptons with equal decay rates between lepton flavors, cross sections larger than 2.5 fb are excluded for proper decay lengths between 70-100 mm for a long-lived particle mass of 1130 GeV at 95% confidence. For a specific model of pair-produced, long-lived top squarks with R-parity violating decays to a b quark and a lepton, masses below 550-1130 GeV are excluded at 95% confidence for equal branching fractions between lepton flavors, depending on the squark decay length. This mass bound is the most stringent to date for top squark proper decay lengths greater than 3 mm. (C) 2018 The Author(s). Published by Elsevier B.V.

The lateral habenula (LHb) is a key brain region involved in the pathophysiology of depression. It is activated by stimuli associated with negative experiences and is involved in encoding aversive signals. Hyperactivity of LHb is found in both rodent models of depression and human patients with depression. However, little is known about the underlying molecular mechanisms. Here we show that in LHb neurons, p11, a multifunctional protein implicated in depression, is significantly upregulated by chronic restraint stress. Knockdown of p11 expression in LHb alleviates the stress-induced depression-like behaviors. Moreover, chronic restraint stress induces bursting action potentials in LHb neurons, which are abolished by p11 knockdown. Overexpression of p11 in dopamine D2 receptor-containing LHb neurons of control mice induces depression-like behaviors. These results have identified p11 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of depression.

Purpose: WST11 vascular targeted photodynan therapy (VTP) is a local ohlation approach relying upon rapid, free radical-mediated desiniction of tumor vasculature. A phase III trial showed that VIP significantly reduced disease progression when compared with active surveillance in patients with low-risk prostate cancer. The aim of this study was to identify a (huggable pathway that could be combined with VIP to improve its efficacy and applicability to higher risk prostate cancer tumors. Experimental Design: Transcriptome analysis of VIP-treated tumors (IN-CaP-AR xenografts) was used to identify a candidate pathway for combination therapy. The efficacy of the combination therapy was assessed in mice bearing INCaP-AR or VCaP tumors. Results: Gene set enrichment analysis identifies the enrichment of androgen-responsive gene sets within hours after VTP treatment, suggesting that the androgen receptor (AR) may be a viable target in combination with VIP. We tested this hypothesis in mice bearing LNCaP-AR xenograft tumors by using androgen deprivation therapy (ADT), degarelix, in combination with VIP. Compared with either AD'F or VII' alone, a single dose of degarelix in concert with VIP significantly inhibited tumor growth. A sharp decline in serum prostate-specific antigen (PSA) confirmed AR inhibition in this group. Tumors treated by VIP and degarelix displayed intense terminal deoxynucleotidyl transferase-mediated DUTP nick end labeling staining 7 days after treatment, supporting an increased apoptotic frequency underlying the effect on tumor inhibition. Conclusions: Improvement of local tumor control following androgen deprivation combined with VIP provides the rationale and preliminary protocol parameters for clinical trials in patients presented with locally advanced prostate cancer. (C) 2018 AACR.

A search for new physics using events containing an imbalance in transverse momentum and one or more energetic jets arising from initial-state radiation or the hadronic decay of W or Z bosons is presented. A data sample of proton-proton collisions at root s = 13 TeV, collected with the CMS detector at the LHC and corresponding to an integrated luminosity of 35.9 fb(-1), is used. The observed data are found to be in agreement with the expectation from standard model processes. The results are interpreted as limits on the dark matter production cross section in simplified models with vector, axial-vector, scalar, and pseudoscalar mediators. Interpretations in the context of fermion portal and nonthermal dark matter models are also provided. In addition, the results are interpreted in terms of invisible decays of the Higgs boson and set stringent limits on the fundamental Planck scale in the Arkani-Hamed, Dimopoulos, and Dvali model with large extra spatial dimensions.

Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a condition causing intense pelvic pain and urinary symptoms. While it is thought to affect millions of people and significantly impair quality of life, difficulty with diagnosis and a lack of reliably effective treatment options leave much progress to be made in managing this condition. We describe what is currently known about the immunological and neurological basis of this disease, focusing on the interactions between the immune and nervous system. Evidence for immune involvement in IC/BPS comes from its high co-occurrence with known autoimmune diseases, altered cytokine profiles, and immune cell infiltration in patients. These cytokines have the ability to cross-talk with the nervous system via NGF signaling, resulting in hyper-sensitization of pain receptors, causing them to release substance P and creating a positive feedback loop of neuroinflammation. While it seems that the crosstalk between the immune and nervous system in IC is understood, much of the information comes from studying other diseases or from animal models, and it remains to be confirmed in patients with the disease. Identifying biomarkers and confirming the mechanism of IC/BPS are ultimately important for selecting drug targets and for improving the lives of patients with this disease.

The function of proteins arises from cooperative interactions and rearrangements of their amino acids, which exhibit large-scale dynamical modes. Long-range correlations have also been revealed in protein sequences, and this has motivated the search for physical links between the observed genetic and dynamic cooperativity. We outline here a simplified theory of protein, which relates sequence correlations to physical interactions and to the emergence of mechanical function. Our protein is modeled as a strongly coupled amino acid network with interactions and motions that are captured by the mechanical propagator, the Green function. The propagator describes how the gene determines the connectivity of the amino acids and thereby, the transmission of forces. Mutations introduce localized perturbations to the propagator that scatter the force field. The emergence of function is manifested by a topological transition when a band of such perturbations divides the protein into subdomains. We find that epistasis-the interaction among mutations in the gene-is related to the nonlinearity of the Green function, which can be interpreted as a sum over multiple scattering paths. We apply this mechanical framework to simulations of protein evolution and observe long-range epistasis, which facilitates collective functional modes.

Differential production cross sections of prompt J/psi and psi(2S) charmonium and Upsilon(nS) (n = 1, 2, 3) bottomonium states are measured in proton-proton collisions at root s = 13 TeV, with data collected by the CMS detector at the LHC, corresponding to an integrated luminosity of 2.3 fb(-1) for the J/psi and 2.7 fb(-1) for the other mesons. The five quarkonium states are reconstructed in the dimuon decay channel, for dimuon rapidity vertical bar y vertical bar < 1.2. The double-differential cross sections for each state are measured as a function of y and transverse momentum, and compared to theoretical expectations. In addition, ratios are presented of cross sections for prompt psi(2S) to J/psi, Upsilon(2S) to Upsilon(1S), and Upsilon(3S) to Upsilon(1S) production. (C) 2018 The Author(s). Published by Elsevier B.V.

Modern biological techniques enable very dense genetic sampling of unfolding evolutionary histories, and thus frequently sample some genotypes multiple times. This motivates strategies to incorporate genotype abundance information in phylogenetic inference. In this article, we synthesize a stochastic process model with standard sequence-based phylogenetic optimality, and show that tree estimation is substantially improved by doing so. Our method is validated with extensive simulations and an experimental single-cell lineage tracing study of germinal center B cell receptor affinity maturation.

Apoptosis culminates in the activation of caspase-3, which plays an important role in implementing the cell death program. Here, we reveal a non-apoptotic role of caspase-3 as a key regulator of cell proliferation and organ size. Caspase-3 is specifically activated in the proliferating cells of the sebaceous gland, but does not instruct cell elimination. Deletion or chemical inhibition of caspase-3 diminishes cell proliferation, decreases cell number and reduces sebaceous gland size in vivo. Exploring the underlying mechanism, we demonstrate that a-catenin is cleaved by caspase-3, thus facilitating the activation and nuclear translocation of yes-associated protein (YAP), a vital regulator of organ size. Accordingly, activation of caspase-3 leads to YAP-dependent organ size augmentation. Finally, we show that X-linked inhibitor of apoptosis protein (XIAP) serves as an endogenous feedback antagonist for the caspase-3/YAP signaling module. Taken together, we report here a molecular mechanism wherein the apoptotic machinery is refocused to regulate cell proliferation and orchestrate organ size.