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A search is presented for the production of a Higgs boson in association with a single top quark, based on data collected in 2016 by the CMS experiment at the LHC at a center-of-mass energy of 13 TeV, which corresponds to an integrated luminosity of 35.9 fb(-1). The production cross section for this process is highly sensitive to the absolute values of the top quark Yukawa coupling, y(t); the Higgs boson coupling to vector bosons, g(HVV); and, uniquely, their relative sign. Analyses using multilepton signatures, targeting H -> WW, H -> tau tau, and H -> ZZ decay modes, and signatures with a single lepton and a b (b) over bar pair, targeting the H -> b (b) over bar decay, are combined with a reinterpretation of a measurement in the H -> gamma gamma channel to constrain y(t). For a standard model-like value of g(HVV), the data favor positive values of y(t) and exclude values of y(t) below about -0.9y(t)(SM).

In this issue of Neuron, Du et al. (2019) demonstrate that the bicistronic CACNA1A gene encodes a transcription factor alpha 1ACT, mutations in which are associated with SCA6, that controls expression of genes important for cerebellar Purkinje cell development and excitability. Reduction of alpha 1ACT in the adult is well tolerated, suggesting a potential new therapy for SCA6.

Army ants are among the top arthropod predators and considered keystone species in tropical ecosystems. During daily mass raids with many thousand workers, army ants hunt live prey, likely exerting strong top-down control on prey species. Many tropical sites exhibit a high army ant species diversity (>20 species), suggesting that sympatric species partition the available prey niches. However, whether and to what extent this is achieved has not been intensively studied yet. We therefore conducted a large-scale diet survey of a community of surface-raiding army ants at La Selva Biological Station in Costa Rica. We systematically collected 3,262 prey items from eleven army ant species (genera Eciton, Nomamyrmex and Neivamyrmex). Prey items were classified as ant prey or non-ant prey. The prey nearly exclusively consisted of other ants (98%), and most booty was ant brood (87%). Using morphological characters and DNA barcoding, we identified a total of 1,103 ant prey specimens to the species level. One hundred twenty-nine ant species were detected among the army ant prey, representing about 30% of the known local ant diversity. Using weighted bipartite network analyses, we show that prey specialization in army ants is unexpectedly high and prey niche overlap very small. Besides food niche differentiation, we uncovered a spatiotemporal niche differentiation in army ant raid activity. We discuss competition-driven multidimensional niche differentiation and predator-prey arms races as possible mechanisms underlying prey specialization in army ants. By combining systematic prey sampling with species-level prey identification and network analyses, our integrative approach can guide future research by portraying how predator-prey interactions in complex communities can be reliably studied, even in cases where morphological prey identification is infeasible.

Objective: Insulin resistance (IR) is a metabolic dysfunction often co-morbid with major depressive disorder (MDD). The paths to development of MDD remain largely unspecified, highlighting a need for identification of risk factors. Here, we tested whether specific subscales of childhood trauma as well as family history of type-2 diabetes (Fam-Hx-Dm2) are risk factors for development of metabolic dysfunction and severity of depressive symptoms. Research design and methods: We used a sample of 45 adults suffering from MDD that was well-characterized for insulin resistance and sensitivity as assessed by measures of fasting plasma glucose (FPG) plasma insulin (FPI) levels, body mass index (BMI), weight, homeostasis model assessment of insulin sensitivity (HOMA), Matsuda index as well as both glucose and insulin responses to oral glucose challenges, Severity of depressive symptoms was assessed with the Hamilton Depression Rating Scale (HDRS-21). Physical, sexual and emotional abuse as well as physical and emotional neglect were assessed with the Childhood Trauma Questionnaire. First-or second-degree relatives with type-2 diabetes defined fam-Hx-DM2. Results: Individuals reporting higher rates of emotional abuse were more likely to have greater IR as showed by elevated FPI levels and HOMA. No association was found with any of the other subscales of childhood trauma (e.g., physical abuse). Similarly, Fam-Hx-DM2 was associated with greater degree of IR as shown by elevated FPI, HOMA, but also FPG, weight and BMI. Moreover, we report a relationship and interaction between Fam-Hx-DM2 and emotional abuse on severity of depressive symptoms. Specifically, emotional abuse and Fam-HX-DM2 predicted severity of depressive symptoms at HDRS-21. Also, severity of depressive symptoms was greater with higher reported rates of emotional abuse but only in patients with negative Fam-HX-Dm2. Individuals reporting higher emotional abuse and negative Fam-Hx-Dm2 also showed higher FPG levels. Conversely, individuals reporting higher emotional abuse and positive Fam-Hx-Dm2 showed higher FPI levels. This data suggest that Fam-Hx-Dm2 may define two different metabolic endophenotypes. Conclusions: Our findings suggest that Fam-HX-DM2 and emotional abuse represent separate risk factors for developing metabolic dysfunction (i.e.: IR) in patients suffering from MDD, and that the effects of emotional abuse on psychiatric illness may depend upon the personal characteristics, including Farn-Hx-DM2.

The precise control of CRISPR-Cas9 activity is required for a number of genome engineering technologies. Here, we report a generalizable platform that provided the first synthetic small-molecule inhibitors of Streptococcus pyogenes Cas9 (SpCas9) that weigh <500 Da and are cell permeable, reversible, and stable under physiological conditions. We developed a suite of high-throughput assays for SpCas9 functions, including a primary screening assay for SpCas9 binding to the protospacer adjacent motif, and used these assays to screen a structurally diverse collection of natural-product-like small molecules to ultimately identify compounds that disrupt the SpCas9-DNA interaction. Using these synthetic anti-CRISPR small molecules, we demonstrated dose and temporal control of SpCas9 and catalytically impaired SpCas9 technologies, including transcription activation, and identified a pharmacophore for SpCas9 inhibition using structure-activity relationships. These studies establish a platform for rapidly identifying synthetic, miniature, cell-permeable, and reversible inhibitors against both SpCas9 and next-generation CRISPR-associated nucleases.

Associative learning of food cues that link location in space to food availability guides feeding behavior in mammals. However, the function of specific neurons that are elements of the higher-order, cognitive circuitry controlling feeding behavior is largely unexplored. Here, we report that hippocampal dopamine 2 receptor (hD2R) neurons are specifically activated by food and that both acute and chronic modulation of their activity reduces food intake in mice. Upstream projections from the lateral entorhinal cortex (LEC) to the hippocampus activate hD2R cells and can also decrease food intake. Finally, activation of hD2R neurons interferes with the encoding of a spatial memory linking food to a specific location via projections from the hippocampus to the septal area. Altogether these data describe a previously unidentified LEC > hippocampus > septal higher-order circuit that regulates feeding behavior.

Charm production in charged current deep inelastic scattering has been measured for the first time in e(+/-)p collisions, using data collected with the ZEUS detector at HERA, corresponding to an integrated luminosity of 358 pb(-1). Results are presented separately for e(+)p and e(-)p scattering at a centre-of-mass energy of root s = 318 GeV within a kinematic phase-space region of 200 GeV2 < Q(2) < 60000 GeV2 and y < 0.9, where Q(2) is the squared four-momentum transfer and y is the inelasticity. The measured cross sections of electroweak charm production are consistent with expectations from the Standard Model within the large statistical uncertainties.

Mycolic acids are the signature lipid of mycobacteria and constitute an important physical component of the cell wall, a target of mycobacterium-specific antibiotics and a mediator of Mycobacterium tuberculosis pathogenesis. Mycolic acids are synthesized in the cytoplasm and are thought to be transported to the cell wall as a trehalose ester by the MmpL3 transporter, an antibiotic target for M. tuberculosis. However, the mechanism by which mycolate synthesis is coupled to transport, and the full MmpL3 transport machinery, is unknown. Here, we identify two new components of the MmpL3 transport machinery in mycobacteria. The protein encoded by MSMEG_0736/Rv0383c is essential for growth of Mycobacterium smegmatis and M. tuberculosis and is anchored to the cytoplasmic membrane, physically interacts with and colocalizes with MmpL3 in growing cells, and is required for trehalose monomycolate (TMM) transport to the cell wall. In light of these findings, we propose MSMEG_0736/Rv0383c be named "TMM transport factor A", TtfA. The protein encoded by MSMEG_5308 also interacts with the MmpL3 complex but is nonessential for growth or TMM transport. However, MSMEG_5308 accumulates with inhibition of MmpL3-mediated TMM transport and stabilizes the MmpL3/TtfA complex, indicating that it may stabilize the transport system during stress. These studies identify two new components of the mycobacterial mycolate transport machinery, an emerging antibiotic target in M. tuberculosis. IMPORTANCE The cell envelope of Mycobacterium tuberculosis, the bacterium that causes the disease tuberculosis, is a complex structure composed of abundant lipids and glycolipids, including the signature lipid of these bacteria, mycolic acids. In this study, we identified two new components of the transport machinery that constructs this complex cell wall. These two accessory proteins are in a complex with the MmpL3 transporter. One of these proteins, TtfA, is required for mycolic acid transport and cell viability, whereas the other stabilizes the MmpL3 complex. These studies identify two new components of the essential cell envelope biosynthetic machinery in mycobacteria.

Cyclic GMP-AMP synthase (cGAS) is the primary sensor for aberrant intracellular dsDNA producing the cyclic dinucleotide cGAMP, a second messenger initiating cytokine production in subsets of myeloid lineage cell types. Therefore, inhibition of the enzyme cGAS may act anti-inflammatory. Here we report the discovery of human-cGAS-specific small-molecule inhibitors by high-throughput screening and the targeted medicinal chemistry optimization for two molecular scaffolds. Lead compounds from one scaffold co-crystallize with human cGAS and occupy the ATP- and GTP-binding active site. The specificity and potency of these drug candidates is further documented in human myeloid cells including primary macrophages. These novel cGAS inhibitors with cell-based activity will serve as probes into cGAS-dependent innate immune pathways and warrant future pharmacological studies for treatment of cGAS-dependent inflammatory diseases.