The rockefeller university

Genetic susceptibility and environmental factors (such as stress) can interact to affect the likelihood of developing a mood disorder. Stress-induced changes in the hippocampus have been implicated in mood disorders, and mutations in several genes have now been associated with increased risk, such as brain-derived neurotrophic factor (BDNF). The hippocampus has important anatomical subdivisions, and pyramidal neurons of the vulnerable CA3 region show significant remodeling after chronic stress, but the mechanisms underlying their unique plasticity remain unknown. This study characterizes stress-induced changes in the in vivo translating mRNA of this cell population using a CA3-specific enhanced green fluorescent protein (EGFP) reporter fused to the L10a large ribosomal subunit (EGFPL10a). RNA-sequencing after isolation of polysome-bound mRNAs allows for cell-type-specific, genome-wide characterization of translational changes after stress. The data demonstrate that acute and chronic stress produce unique translational profiles and that the stress history of the animal can alter future reactivity of CA3 neurons. CA3-specific EGFPL10a mice were then crossed to the stress-susceptible BDNF Val66Met mouse line to characterize how a known genetic susceptibility alters both baseline translational profiles and the reactivity of CA3 neurons to stress. Not only do Met allele carriers exhibit distinct levels of baseline translation in genes implicated in ion channel function and cytoskeletal regulation, but they also activate a stress response profile that is highly dissimilar from wild-type mice. Closer examination of genes implicated in the mechanisms of neuroplasticity, such as the NMDA and AMPA subunits and the BDNF pathway, reveal how wild-type mice upregulate many of these genes in response to stress, but Met allele carriers fail to do so. These profiles provide a roadmap of stress-induced changes in a genetically homogenous population of hippocampal neurons and illustrate the profound effects of gene-environment interactions on the translational profile of these cells.

Elevated body mass index (BMI) is associated with increased multi-morbidity and mortality. The investigation of the relationship between BMI and brain organization has the potential to provide new insights relevant to clinical and policy strategies for weight control. Here, we quantified the association between increasing BMI and the functional organization of resting-state brain networks in a sample of 496 healthy individuals that were studied as part of the Human Connectome Project. We demonstrated that higher BMI was associated with changes in the functional connectivity of the default-mode network (DMN), central executive network (CEN), sensorimotor network (SMN), visual network (VN), and their constituent modules. In siblings discordant for obesity, we showed that person-specific factors contributing to obesity are linked to reduced cohesiveness of the sensory networks (SMN and VN). We conclude that higher BMI is associated with widespread alterations in brain networks that balance sensory-driven (SMN, VN) and internally guided (DMN, CEN) states which may augment sensory-driven behavior leading to overeating and subsequent weight gain. Our results provide a neurobiological context for understanding the association between BMI and brain functional organization while accounting for familial and person-specific influences.

Depression is a mental disorder associated with environmental, genetic and psychological factors. Recent studies indicate that chronic neuro-inflammation may affect brain physiology and alter mood and behavior. Consumption of a high-fat diet leads to obesity and chronic systemic inflammation. The gut micro biota mediates many effects of a high-fat diet on human physiology and may also influence the mood and behavior of the host. We review here recent studies suggesting the existence of a link between obesity, the gut microbiota and depression, focusing on the mechanisms underlying the effects of a high-fat diet on chronic inflammation and brain physiology. This body of research suggests that modulating the composition of the gut microbiota using prebiotics and probiotics may produce beneficial effects on anxiety and depression. (C) 2017 Elsevier Inc. All rights reserved.

Purpose: The purpose of this study was to compare the maternal and neonatal outcomes among laboring women permitted ad lib oral intake with those permitted nothing by mouth except for ice chips. Design: This was a quantitative retrospective observational cross-sectional study. Sample: The initial data set consisted of all closed medical records for 2,817 women who were admitted to a suburban community hospital in the northeastern United States between January 2008 and December 2012. Some subjects' records were missing either covariate data or outcomes data, resulting in final sample sizes of 2,797 women (for comparison across covariates) and 2,784 women (for comparison across outcomes). Methods: A deidentified limited data set was extracted from the electronic health record for descriptive and inferential comparisons between groups. Demographics and maternal comorbidities present on admission were compared between groups before data analysis. Outcome comparisons were obtained with traditional between-groups analysis and propensity score matching. Results: The groups were found to be sufficiently equivalent for comparison. The group permitted nothing by mouth was significantly more likely to have unplanned cesarean section births than the group permitted ad lib oral intake. There were no significant differences in unplanned maternal ICU admissions postpartum, in neonate condition as determined by Apgar scores, or in the need for a higher level of care. Allowing women ad lib oral intake during labor caused no increase in morbidity, and there were no mortalities in either group. Conclusion: Allowing women ad lib oral intake during labor does not increase adverse maternal or neonatal outcomes. It stands to reason that allowing such intake could increase patient satisfaction. Further study is needed to determine what types of food and drink are most beneficial as well as what types are preferred.

HIV infection has long been known to result in dementia and other forms of neurocognitive deficits. The rate of HIV-associated dementia is decreasing, while mild forms of neurological impairments increase. Treatment of HIV infection has advanced, and patients are living longer, and are thus at a greater risk of cognitive decline. The HIV aging cohort is susceptible to neurocognitive impairment from other medical conditions that have a compounding effect on cognitive decline. The diagnosis of HIV-associated neurocognitive disorders involves identifying neurological dysfunction and then determining that HIV is the most probable cause. Implications for practice include early control of HIV replication and treatment of comorbid diseases.

Transcriptional pausing by RNA polymerases (RNAPs) is a key mechanism to regulate gene expression in all kingdoms of life and is a prerequisite for transcription termination. The essential bacterial transcription factor NusA stimulates both pausing and termination of transcription, thus playing a central role. Here, wereport single-particle electron cryo-microscopy reconstructions of NusA bound to paused E. coli RNAP elongation complexes with and without a pause-enhancing hairpin in the RNA exit channel. The structures reveal four interactions between NusA and RNAP that suggest how NusA stimulates RNA folding, pausing, and termination. An asymmetric translocation intermediate of RNA and DNA converts the active site of the enzyme into an inactive state, providing a structural explanation for the inhibition of catalysis. Comparing RNAP at different stages of pausing provides insights on the dynamic nature of the process and the role of NusA as a regulatory factor.

Gram-positive bacteria homeostasis and antibiotic resistance mechanisms are dependent on the intricate architecture of the cell wall, where amidated peptidoglycan plays an important role. The amidation reaction is carried out by the bi-enzymatic complex MurT-GatD, for which biochemical and structural information is very scarce. In this work, we report the first crystal structure of the glutamine amidotransferase member of this complex, GatD from Staphylococcus aureus, at 1.85 angstrom resolution. A glutamine molecule is found close to the active site funnel, hydrogen-bonded to the conserved R128. In vitro functional studies using H-1-NMR spectroscopy showed that S. aureus MurT-GatD complex has glutaminase activity even in the absence of lipid II, the MurT substrate. In addition, we produced R128A, C94A and H189A mutants, which were totally inactive for glutamine deamidation, revealing their essential role in substrate sequestration and catalytic reaction. GatD from S. aureus and other pathogenic bacteria share high identity to enzymes involved in cobalamin biosynthesis, which can be grouped in a new sub-family of glutamine amidotransferases. Given the ubiquitous presence of GatD, these results provide significant insights into the molecular basis of the so far undisclosed amidation mechanism, contributing to the development of alternative therapeutics to fight infections.

A statistical combination of several searches for the electroweak production of charginos and neutralinos is presented. All searches use proton-proton collision data at A root s = 13 TeV, recorded with the CMS detector at the LHC in 2016 and corresponding to an integrated luminosity of 35.9 fb(-1). In addition to the combination of previous searches, a targeted analysis requiring three or more charged leptons (electrons or muons) is presented, focusing on the challenging scenario in which the difference in mass between the two least massive neutralinos is approximately equal to the mass of the Z boson. The results are interpreted in simplified models of chargino-neutralino or neutralino pair production. For chargino-neutralino production, in the case when the lightest neutralino is massless, the combination yields an observed (expected) limit at the 95% confidence level on the chargino mass of up to 650 (570) GeV, improving upon the individual analysis limits by up to 40 GeV. If the mass difference between the two least massive neutralinos is approximately equal to the mass of the Z boson in the chargino-neutralino model, the targeted search requiring three or more leptons obtains observed and expected exclusion limits of around 225 GeV on the second neutralino mass and 125 GeV on the lightest neutralino mass, improving the observed limit by about 60 GeV in both masses compared to the previous CMS result. In the neutralino pair production model, the combined observed (expected) exclusion limit on the neutralino mass extends up to 650-750 (550-750) GeV, depending on the branching fraction assumed. This extends the observed exclusion achieved in the individual analyses by up to 200 GeV. The combined result additionally excludes some intermediate gaps in the mass coverage of the individual analyses.

Src family kinases (SFKs) coordinate the initiating and propagating activation signals in platelets, but it remains unclear how they are regulated. Here, we show that ablation of C-terminal Src kinase (Csk) and receptor-like protein tyrosine-phosphatase CD148 in mice results in a dramatic increase in platelet SFK activity, demonstrating that these proteins are essential regulators of platelet reactivity. Paradoxically, Csk/CD148-deficient mice exhibit reduced in vivo and ex vivo thrombus formation and increased bleeding following injury rather than a prothrombotic phenotype. This is a consequence of multiple negative feedback mechanisms, including downregulation of the immunoreceptor tyrosine-based activation motif (ITAM)- and hemi-ITAM-containing receptors glycoprotein VI (GPVI)-Fc receptor (FcR) gamma-chain and CLEC-2, respectively and upregulation of the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing receptor G6b-B and its interaction with the tyrosine phosphatases Shp1 and Shp2. Results from an analog-sensitive Csk mouse model demonstrate the unconventional role of SFKs in activating ITIM signaling. This study establishes Csk and CD148 as critical molecular switches controlling the thrombotic and hemostatic capacity of platelets and reveals cell-intrinsic mechanisms that prevent pathological thrombosis from occurring.

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.