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This paper presents a measurement of the underlying event activity in proton-proton collisions at a center-of-mass energy of 13TeV, performed using inclusive Z boson production events collected with the CMS experiment at the LHC. The analyzed data correspond to an integrated luminosity of 2.1 fb(-1). The underlying event activity is quantified in terms of the charged particle multiplicity, as well as of the scalar sum of the charged particles' transverse momenta in different topological regions defined with respect to the Z boson direction. The distributions are unfolded to the stable particle level and compared with predictions from various Monte Carlo event generators, as well as with similar CDF and CMS measurements at center-of-mass energies of 1.96 and 7TeV respectively.

The process pp -> pl(+)l(-)p(()*()), with l(+)l(-) a muon or an electron pair produced at midrapidity with mass larger than 110 GeV, has been observed for the first time at the LHC in pp collisions at root s = 13 TeV. One of the two scattered protons is measured in the CMS-TOTEM precision proton spectrometer (CT-PPS), which operated for the first time in 2016. The second proton either remains intact or is excited and then dissociates into a low-mass state p*, which is undetected. The measurement is based on an integrated luminosity of 9.4 fb(-1) collected during standard, high-luminosity LHC operation. A total of 12 mu(+)/mu(-) and 8 e(+)e(-) pairs with m(l(+)l(-)) > 110 GeV, and matching forward proton kinematics, are observed, with expected backgrounds of 1.49 +/- 0.07 (stat) +/- 0.53 (syst) and 2.36 +/- 0.09 (stat) +/- 0.47(syst), respectively. This corresponds to an excess of more than five standard deviations over the expected background. The present result constitutes the first observation of proton-tagged gamma gamma collisions at the electroweak scale. This measurement also demonstrates that CT-PPS performs according to the design specifications.

Purpose of reviewSeveral anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs.Recent findingsPhase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile. Single bNAb infusions led to significant, but transient, decline in viremia with selection of escape variants. A single bNAb also delayed viral rebound in ART-treated participants who discontinued ART. Importantly, in-vivo efficacy was related to antibody potency and to the level of preexisting resistance. Studies in animal models showed that bNAbs can clear HIV-infected cells and modulate host immune responses. These findings suggest that bNAbs may target the latent HIV reservoir in humans and could contribute to long-term remission of HIV-1 infection.SummarybNAbs may offer advantages over traditional ART for both the prevention and treatment of HIV-1 infection. In addition, bNAbs may target the latent viral reservoir. bNAb combinations and bNAbs engineered for prolonged half-life and increased potency are currently undergoing clinical evaluation.

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

Tetraploid cells, which are most commonly generated by errors in cell division, are genomically unstable and have been shown to promote tumorigenesis. Recent genomic studies have estimated that similar to 40% of all solid tumors have undergone a genome-doubling event during their evolution, suggesting a significant role for tetraploidy in driving the development of human cancers. To safeguard against the deleterious effects of tetraploidy, non-transformed cells that fail mitosis and become tetraploid activate both the Hippo and p53 tumor suppressor pathways to restrain further proliferation. Tetraploid cells must therefore overcome these antiproliferative barriers to ultimately drive tumor development. However, the genetic routes through which spontaneously arising tetraploid cells adapt to regain proliferative capacity remain poorly characterized. Here, we conducted a comprehensive gain-offunction genome-wide screen to identify microRNAs (miRNAs) that are sufficient to promote the proliferation of tetraploid cells. Our screen identified 23 miRNAs whose overexpression significantly promotes tetraploid proliferation. The vast majority of these miRNAs facilitate tetraploid growth by enhancing mitogenic signaling pathways (e.g., miR-191-3p); however, we also identified several miRNAs that impair the p53/p21 pathway (e.g., miR-523-3p), and a single miRNA (miR-24-3p) that potently inactivates the Hippo pathway via down-regulation of the tumor suppressor gene NF2. Collectively, our data reveal several avenues through which tetraploid cells may regain the proliferative capacity necessary to drive tumorigenesis.

Addictive diseases, including addiction to alcohol, pose massive public health costs. Addiction is a chronic relapsing disease caused by both the direct effects induced by drugs and persistent neuroadaptations at the molecular, cellular, and behavioral levels. These drug-type specific neuroadaptations are brought on largely by the reinforcing effects of drugs on the central nervous system and environmental stressors. Results from animal experiments have demonstrated important interactions between alcohol and stressresponsive systems. Addiction to specific drugs such as alcohol, psychostimulants, and opioids shares some common direct or downstream effects on the brain's stress-responsive systems, including arginine vasopressin and its V1b receptors, dynorphin and the kappa-opioid receptors, pro-opiomelanocortin/beta-endorphin and the mu-opioid receptors, and the endocannabinoids. Further study of these systems through laboratory-based and translational research could lead to the discovery of novel treatment targets and the early optimization of interventions (for example, combination) for the pharmacologic therapy of alcoholism.

Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid N-arachidonoylethanolamine (anandamide; AEA). Mice deficient in leptin exhibited elevated hypothalamic AEA levels and reductions in FAAH activity while leptin administration to WT mice reduced AEA content and increased FAAH activity. Following high fat diet exposure, mice developed resistance to the effects of leptin administration on hypothalamic AEA content and FAAH activity. At a functional level, pharmacological inhibition of FAAH was sufficient to prevent leptin-mediated effects on body weight and food intake. Using a novel knock-in mouse model recapitulating a common human polymorphism (FAAH C385A; rs324420), which reduces FAAH activity, we investigated whether human genetic variance in FAAH affects leptin sensitivity. While WT (CC) mice were sensitive to leptin-induced reductions in food intake and body weight gain, low-expressing FAAH (AA) mice were unresponsive. These data demonstrate that FAAH activity is required for leptin's hypophagic effects and, at a translational level, suggest that a genetic variant in the FAAH gene contributes to differences in leptin sensitivity in human populations.

All primates communicate. To dissect the neural circuits of social communication, we used fMRI to map non- human primate brain regions for social perception, second- person (interactive) social cognition, and orofacial movement generation. Face perception, second- person cognition, and face motor networks were largely non- overlapping and acted as distinct functional units rather than an integrated feedforward- processing pipeline. Whereas secondperson context selectively engaged a region of medial prefrontal cortex, production of orofacial movements recruited distributed subcortical and cortical areas in medial and lateral frontal and insular cortex. These areas exhibited some specialization, but not dissociation, of function along the mediolateral axis. Production of lipsmack movements recruited areas including putative homologs of Broca's area. These findings provide a new view of the neural architecture for social communication and suggest expressive orofacial movements generated by lateral premotor cortex as a putative evolutionary precursor to human speech.

Liver organogenesis requires complex cell-cell interactions between hepatic endoderm cells and adjacent cell niches. Endothelial cells are key players for endoderm hepatic fate decision. We previously demonstrated that the endothelial cell niche promotes hepatic specification of mouse embryonic stem cell(ESC)-derived endoderm through dual repression of Wnt and Notch pathways in endoderm cells. In the present study, we dissected further the mechanisms by which endothelial cells trigger endoderm hepatic specification. Using our previously established in vitro mouse ESC system mimicking the early hepatic specification process, endoderm cells were purified and co-cultured with endothelial cells to induce hepatic specification. The comparison of transcriptome profiles between hepatic endoderm cells isolated from co-cultures and endoderm cells cultured alone revealed that VEGF signaling instructs hepatic specification of endoderm cells through endothelial VEGFR2 activation. Additionally, epigenetic mark inhibition assays upon co-cultures uncovered that histone acetylation and DNA methylation promote hepatic specification while histone methylation inhibits it. This study provides an efficient 2D platform modelling the endothelial cell niche crosstalk with endoderm, and reveals mechanisms by which endothelial cells promote hepatic specification of mouse ESC-derived endoderm cells through endothelial VEGFR2 activation and endoderm epigenetic modifications.

Depressive disorders constitute a set of debilitating diseases with psychological, societal, economic and humanitarian consequences for millions of people worldwide. Scientists are beginning to understand the reciprocal communication between the brain and the rest of the body in the etiology of these diseases. In particular, scientists have noted a connection between depressive disorders, which are primarily seen as brain-based, and, insulin resistance (IR), a modifiable metabolic inflammatory state that is typically seen as peripheral. We highlight evidence showing how treating IR, with drugs or behavioral interventions, may ameliorate or possibly prevent, depressive disorders and their long-term consequences at various stages of the life course. This article is part of the Special Issue entitled 'Metabolic Impairment as Risk Factors for Neurodegenerative Disorders. (C) 2017 Elsevier Ltd. All rights reserved.