The rockefeller university

A search for heavy resonances decaying to a pair of Z bosons is performed using data collected with the CMS detector at the LHC. Events are selected by requiring two oppositely charged leptons (electrons or muons), consistent with the decay of a Z boson, and large missing transverse momentum, which is interpreted as arising from the decay of a second Z boson to two neutrinos. The analysis uses data from proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to an integrated luminosity of 35.9 fb(-1). The hypothesis of a spin-2 bulk graviton (X) decaying to a pair of Z bosons is examined for 600 <= m(X) <= 2500 GeV and upper limits at 95% confidence level are set on the product of the production cross section and branching fraction of X -> ZZ ranging from 100 to 4 fb. For bulk graviton models characterized by a curvature scale parameter (k) over tilde = 0.5 in the extra dimension, the region nix < 800 GeV is excluded, providing the most stringent limit reported to date. Variations of the model considering the possibility of a wide resonance produced exclusively via gluon-gluon fusion or q<(q)over bar> annihilation are also examined.

The transfer of genomic information from DNA to mRNA to protein usually occurs with high fidelity, but can also be subverted by a programmed RNA sequence alteration termed 'RNA editing', involving deamination of adenosine to inosine (decoded as guanosine), or of cytosine to uracil. These sequence changes can lead to cellular heterogeneity by generating variable sets of transcripts within otherwise identical cells. Recent studies have demonstrated that editing is most prevalent in cells and tissues with high propensity for plasticity. Within those, RNA editing reproducibly targets transcripts of related function, altering the outcomes of entire pathways at once. In ongoing work, changes in patterns of editing have been correlated with neuronal disease pathogenesis, suggesting that RNA editing harbors diagnostic potential.

We proposed two hypotheses to explain why food chains are longer in pelagic than terrestrial ecosystems: greater trophic efficiency of pelagic animal taxa at lower trophic levels and a higher pelagic biomass production rate at lower trophic levels because of smaller pelagic body masses. Giacomini favored the former, invoking in support the energetic equivalence hypothesis. We reply that the energetic equivalence hypothesis does not describe populations at differing trophic levels and so does not refute a significant role for body-mass dependence in explaining faster trophic transfer in pelagic ecosystems. Metabolic scaling as body mass to the exponent 1/4, widely accepted, remains important for trophic dynamic models. We suggest a likelihood method to compare the two hypotheses on the basis of models of whole-ecosystem energetics.

Alzheimer's disease (AD) is a progressive degenerative neurological disorder affecting nearly one in nine elderly people in the United States. Population studies have shown that an inheritance of the apolipoprotein E (APOE) variant APOE4 allele increases the risk of developing AD, whereas APOE2 homozygotes are protected from late-onset AD. It was hypothesized that expression of the "protective"APOE2 variant by genetic modification of the central nervous system (CNS) of APOE4 homozygotes could reverse or prevent progressive neurologic damage. To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of delivery to the CNS of nonhuman primates of AAVrh.10hAPOE2-HA, an AAVrh.10 serotype coding for an HA-tagged human APOE2 cDNA sequence, were evaluated. To evaluate the route of delivery that achieves the widest extent of APOE2 expression in the CNS, the expression of APOE2 in the CNS was evaluated 2 months following vector administration for APOE2 DNA, mRNA, and protein. Finally, using conventional toxicology assays, the safety of the best route of delivery was assessed. The data demonstrated that while all three routes are capable of mediating ApoE2 expression in AD relevant regions, intracisternal delivery of AAVrh.10hAPOE2-HA safely mediated wide distribution of ApoE2 with the least invasive surgical intervention, thus providing the optimal strategy to deliver vector-mediated human APOE2 to the CNS.

Sequence-specific pausing by RNA polymerase (RNAP) during transcription plays crucial and diverse roles in gene expression. In bacteria, RNA structures are thought to fold within the RNA exit channel of the RNAP and can increase pause lifetimes significantly. The biophysical mechanism of pausing is uncertain. We used single-particle cryo-EM to determine structures of paused complexes, including a 3.8-angstrom structure of an RNA hairpin-stabilized, paused RNAP that coordinates RNA folding in the his operon attenuation control region of E. coli. The structures revealed a half-translocated pause state (RNA post-translocated, DNA pre-translocated) that can explain transcriptional pausing and a global conformational change of RNAP that allosterically inhibits trigger loop folding and can explain pause hairpin action. Pause hairpin interactions with the RNAP RNA exit channel suggest how RNAP guides the formation of nascent RNA structures.

The Caenorhabditis elegans cell lineage is nearly invariant. Whether this stereotyped cell division pattern promotes reproducibility in cell shapes/positions is not generally known, as manual spatiotemporal cell-shape/position alignments are labor-intensive, and fully-automated methods are not described. Here, we report automated algorithms for spatiotemporal alignments of C. elegans embryos from pre-morphogenesis to motor-activity initiation. We use sparsely-labeled green-fluorescent nuclei and a pan-nuclear red-fluorescent reporter to register consecutive imaging time points and compare embryos. Using our method, we monitor early assembly of the nerve-ring (NR) brain neuropil. While NR pioneer neurons exhibit reproducible growth kinetics and axon positions, cell-body placements are variable. Thus, pioneer-neuron axon locations, but not cell-body positions, are under selection. We also show that anterior NR displacement in cam-1/ROR Wnt-receptor mutants is not an early NR assembly defect. Our results demonstrate the utility of automated spatiotemporal alignments of C. elegans embryos, and uncover key principles guiding nervous-system development in this animal.

Most humans are exposed to Tropheryma whipplei (Tw). Whipple's disease (WD) strikes only a small minority of individuals infected with Tw (<0.01%), whereas asymptomatic chronic carriage is more common (<25%). We studied a multiplex kindred, containing four WD patients and five healthy Tw chronic carriers. We hypothesized that WD displays autosomal dominant (AD) inheritance, with age-dependent incomplete penetrance. We identified a single very rare non-synonymous mutation in the four patients: the private R98W variant of IRF4, a transcription factor involved in immunity. The five Tw carriers were younger, and also heterozygous for R98W. We found that R98W was loss-of-function, modified the transcriptome of heterozygous leukocytes following Tw stimulation, and was not dominant-negative. We also found that only six of the other 153 known non-synonymous IRF4 variants were loss-of-function. Finally, we found that IRF4 had evolved under purifying selection. AD IRF4 deficiency can underlie WD by haploinsufficiency, with age-dependent incomplete penetrance.

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.

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.

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.