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A search for heavy resonances with masses above 1 TeV, decaying to final states containing a vector boson and a Higgs boson, is presented. The search considers hadronic decays of the vector boson, and Higgs boson decays to b quarks. The decay products are highly boosted, and each collimated pair of quarks is reconstructed as a single, massive jet. The analysis is performed using a data sample collected in 2016 by the CMS experiment at the LHC in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The data are consistent with the background expectation and are used to place limits on the parameters of a theoretical model with a heavy vector triplet. In the benchmark scenario with mass-degenerate W' and Z' bosons decaying predominantly to pairs of standard model bosons, for the first time heavy resonances for masses as high as 3.3 TeV are excluded at 95% confidence level, setting the most stringent constraints to date on such states decaying into a vector boson and a Higgs boson.

Infections due to non-tuberculous mycobacteria species are problematic for immunodeficient individuals. Mendelian susceptibility to mycobacterial diseases (MSMD) defines a group of genetic defects affecting cellular interactions and the interferon (IFN)-gamma pathway. Patients with MSMD may present with a disseminated infection resulting from the Bacillus Calmette-Guerin vaccine, Mycobacterium tuberculosis complex, environmental nontuberculous mycobacteria or Salmonella species. Atypical mycobacterial infections and deficient granuloma or giant cell formation are important indicators for MSMD, especially in patients with a family history of parental consanguineous marriage. Herein we report the case of a boy with an IL-12R beta 1 defect who presented with massive intra-abdominal lymphadenopathy due to Mycobacterium intracellulare infection. The patient was born to consanguineous parents, both heterozygous for the IL-12R beta 1 defect mutation. Debulking surgery was planned in order to decrease the abdominal mass, but could not be performed due to a high risk of fatal outcomes. He has been receiving linezolid, levofloxacin, azithromycin, rifabutin and IFN-gamma therapy for the past 14 months. At follow-up, the patient showed significant clinical improvement and weight gain.

The Rho GTPase Rac1 activates the WAVE regulatory complex (WRC) to drive Arp2/3 complex-mediated actin polymerization, which underpins diverse cellular processes. Here we report the structure of a WRC-Rac1 complex determined by cryo-electron microscopy. Surprisingly, Rac1 is not located at the binding site on the Sra1 subunit of the WRC previously identified by mutagenesis and biochemical data. Rather, it binds to a distinct, conserved site on the opposite end of Sra1. Biophysical and biochemical data on WRC mutants confirm that Rac1 binds to both sites, with the newly identified site having higher affinity and both sites required for WRC activation. Our data reveal that the WRC is activated by simultaneous engagement of two Rac1 molecules, suggesting a mechanism by which cells may sense the density of active Rac1 at membranes to precisely control actin assembly.

Pontocerebellar hypoplasia (PCH) represents a group of recessive developmental disorders characterized by impaired growth of the pons and cerebellum, which frequently follows a degenerative course. Currently, there are 10 partially overlapping clinical subtypes and 13 genes known mutated in PCH. Here, we report biallelic TBC1D23 mutations in six individuals from four unrelated families manifesting a non-degenerative form of PCH. In addition to reduced volume of pons and cerebellum, affected individuals had microcephaly, psychomotor delay, and ataxia. In zebrafish, tbc1d23 morphants replicated the human phenotype showing hindbrain volume loss. TBC1D23 localized at the trans-Golgi and was regulated by the small GTPases Arl1 and Arl8, suggesting a role in trans-Golgi membrane trafficking. Altogether, this study provides a causative link between TBC1D23 mutations and PCH and suggests a less severe clinical course than other PCH subtypes.

Replicative helicases in all cell types are hexameric rings that unwind DNA by steric exclusion in which the helicase encircles the tracking strand only and excludes the other strand from the ring. This mode of translocation allows helicases to bypass blocks on the strand that is excluded from the central channel. Unlike other replicative helicases, eukaryotic CMG helicase partially encircles duplex DNA at a forked junction and is stopped by a block on the non-tracking (lagging) strand. This report demonstrates that Mcm10, an essential replication protein unique to eukaryotes, binds CMG and greatly stimulates its helicase activity in vitro. Most significantly, Mcm10 enables CMG and the replisome to bypass blocks on the non-tracking DNA strand. We demonstrate that bypass occurs without displacement of the blocks and therefore Mcm10 must isomerize the CMG-DNA complex to achieve the bypass function.

As a behavioral neuroscientist and neuroendocrinologist, Randall Sakai appreciated the extensive and complex interactions between the brain and the body as exemplified by his seminal studies on the regulation of salt appetite and the brain and body effects in the Visible Burrow System. He applied state-of-the-art methods to probe underlying mechanisms. Randall's view of science will live on in the influence he had on his many colleagues who were also his friends! (C) 2016 Published by Elsevier Inc.

The term 'stress' - coined in 1936 - has many definitions, but until now has lacked a theoretical foundation. Here we present an information-theoretic approach - based on the 'free energy principle' - defining the essence of stress; namely, uncertainty. We address three questions: What is uncertainty? What does it do to us? What are our resources to master it? Mathematically speaking, uncertainty is entropy or 'expected surprise'. The 'free energy principle' rests upon the fact that self-organizing biological agents resist a tendency to disorder and must therefore minimize the entropy of their sensory states. Applied to our everyday life, this means that we feel uncertain, when we anticipate that outcomes will turn out to be something other than expected - and that we are unable to avoid surprise. As all cognitive systems strive to reduce their uncertainty about future outcomes, they face a critical constraint: Reducing uncertainty requires cerebral energy. The characteristic of the vertebrate brain to prioritize its own high energy is captured by the notion of the 'selfish brain'. Accordingly, in times of uncertainty, the selfish brain demands extra energy from the body. If, despite all this, the brain cannot reduce uncertainty, a persistent cerebral energy crisis may develop, burdening the individual by 'allostatic load' that contributes to systemic and brain malfunction (impaired memory, atherogenesis, diabetes and subsequent cardio- and cerebrovascular events). Based on the basic tenet that stress originates from uncertainty, we discuss the strategies our brain uses to avoid surprise and thereby resolve uncertainty. (C) 2017 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Venom peptide toxins such as conotoxins play a critical role in the characterization of nicotinic acetylcholine receptor (nAChR) structure and function and have potential as nervous system therapeutics as well. However, the lack of solved structures of conotoxins bound to nAChRs and the large size of these peptides are barriers to their computational docking and design. We addressed these challenges in the context of the alpha 4 beta 2 nAChR, a widespread ligand-gated ion channel in the brain and a target for nicotine addiction therapy, and the 19-residue conotoxin alpha-GID that antagonizes it. We developed a docking algorithm, ToxDock, which used ensemble-docking and extensive conformational sampling to dock alpha-GID and its analogs to an alpha 4 beta 2 nAChR homology model. Experimental testing demonstrated that a virtual screen with ToxDock correctly identified three bioactive alpha-GID mutants (alpha-GID[A10V], alpha-GID[V13I], and alpha-GID[V13Y]) and one inactive variant (alpha-GID[A10Q]). Two mutants, alpha-GID[A10V] and alpha-GID[V13Y], had substantially reduced potency at the human alpha 7 nAChR relative to alpha-GID, a desirable feature for alpha-GID analogs. The general usefulness of the docking algorithm was highlighted by redocking of peptide toxins to two ion channels and a binding protein in which the peptide toxins successfully reverted back to near-native crystallographic poses after being perturbed. Our results demonstrate that ToxDock can overcome two fundamental challenges of docking large toxin peptides to ion channel homology models, as exemplified by the alpha-GID: alpha 4 beta 2 nAChR complex, and is extendable to other toxin peptides and ion channels. ToxDock is freely available at rosie.rosettacommons.org/tox_dock.

[No abstract available]

The mucus layer in the intestine affects several aspects of intestinal biology, encompassing physical, chemical protection, immunomodulation and growth, thus contributing to homeostasis. Mice with genetic inactivation of the Muc2 gene, encoding the MUC2 mucin, the major protein component of mucus, exhibit altered intestinal homeostasis, which is strictly dependent on the habitat, likely due to differing complements of intestinal microbes. Our previous work established that Muc2 deficiency was linked to low chronic inflammation resulting in tumor development in the small, large intestine including the rectum. Here, we report that inactivation of Muc2 alters metabolic pathways in the normal appearing mucosa of Muc2(-/-) mice. Comparative analysis of gene expression profiling of isolated intestinal epithelial cells (IECs) and the entire intestinal mucosa, encompassing IECs, immune and stromal cells underscored that more than 50% of the changes were common to both sets of data, suggesting that most alterations were IEC-specific. IEC-specific expression data highlighted perturbation of lipid absorption, processing and catabolism linked to altered Ppara signaling in IECs. Concomitantly, alterations of glucose metabolism induced expression of genes linked to de novo lipogenesis, a characteristic of tumor cells. Importantly, gene expression alterations characterizing Muc2(-/-) IECs are similar to those observed when analyzing the gene expression signature of IECs along the crypt-villus axis in WT B6 mice, suggesting that Muc2(-/-) IECs display a crypt-like gene expression signature. Thus, our data strongly suggest that decreased lipid metabolism, and alterations in glucose utilization characterize the crypt proliferative compartment, and may represent a molecular signature of pre-neoplastic lesions.