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Super-enhancers (SEs) are clusters of enhancers that cooperatively assemble a high density of the transcriptional apparatus to drive robust expression of genes with prominent roles in cell identity. Here we demonstrate that the SE-enriched transcriptional coactivators BRD4 and MED1 form nuclear puncta at SEs that exhibit properties of liquid-like condensates and are disrupted by chemicals that perturb condensates. The intrinsically disordered regions (IDRs) of BRD4 and MED1 can form phase-separated droplets, and MED1-IDR droplets can compartmentalize and concentrate the transcription apparatus from nuclear extracts. These results support the idea that coactivators form phase-separated condensates at SEs that compartmentalize and concentrate the transcription apparatus, suggest a role for coactivator IDRs in this process, and offer insights into mechanisms involved in the control of key cell-identity genes.

A search is presented for a heavy resonance decaying into either a pair of Z bosons or a Z boson and a W boson (ZZ or WZ), with a Z boson decaying into a pair of neutrinos and the other boson decaying hadronically into two collimated quarks that are reconstructed as a highly energetic large-cone jet. The search is performed using the data collected with the CMS detector at the CERN LHC during 2016 in proton-proton collisions at a center-of-mass energy of 13 TeV, corresponding to a total integrated luminosity of 35.9 fb(-1). No excess is observed in data with regard to background expectations. Results are interpreted in scenarios of physics beyond the standard model. Limits at 95% confidence level on production cross sections are set at 0.9 fb (63 fb) for spin-1 W' bosons, included in the heavy vector triplet model, with mass 4.0 TeV (1.0 TeV), and at 0.5 fb (40 fb) for spin-2 bulk gravitons with mass 4.0 TeV (1.0 TeV). Lower limits are set on the masses of W' bosons in the context of two versions of the heavy vector triplet model of 3.1 TeV and 3.4 TeV, respectively.

Neurons in visual areas of the brain are generally characterized by the increase in firing rate that occurs when a stimulus is flashed on in the receptive field (RF). However, neurons also increase their firing rate when a stimulus is turned off. These "termination responses" or "after-discharges" that occur with flashed stimuli have been observed in area V1 and they may be important for vision as stimulus terminations have been shown to influence visual perception. The goal of the present study was to determine the strength of termination responses in the more natural situation in which eye movements move a stimulus out of an RF. We find that termination responses do occur in macaque V1 when termination results from a saccadic eye movement, but they are smaller in amplitude compared to flashed-off stimuli. Furthermore, there are termination responses even in the absence of visual stimulation. These findings demonstrate that termination responses are a component of naturalistic vision. They appear to be based on both visual and nonvisual signals in visual cortex. We speculate that the weakening of termination responses might be a neural correlate of saccadic suppression, the loss of perceptual sensitivity around the time of saccades.

Most breast cancer deaths are caused by metastasis and treatment options beyond radiation and cytotoxic drugs, which have severe side effects, and hormonal treatments, which are or become ineffective for many patients, are urgently needed. This study reanalyzed existing data from three genome-wide association studies (GWAS) using a novel computational biostatistics approach (muGWAS), which had been validated in studies of 600-2000 subjects in epilepsy and autism. MuGWAS jointly analyzes several neighboring single nucleotide polymorphisms while incorporating knowledge about genetics of heritable diseases into the statistical method and about GWAS into the rules for determining adaptive genome-wide significance. Results from three independent GWAS of 1000-2000 subjects each, which were made available under the National Institute of Health's "Up For A Challenge" (U4C) project, not only confirmed cell-cycle control and receptor/AKT signaling, but, for the first time in breast cancer GWAS, also consistently identified many genes involved in endo-/exocytosis (EEC), most of which had already been observed in functional and expression studies of breast cancer. In particular, the findings include genes that translocate (ATP8A1, ATP8B1, ANO4, ABCA1) and metabolize (AGPAT3, AGPAT4, DGKQ, LPPR1) phospholipids entering the phosphatidylinositol cycle, which controls EEC. These novel findings suggest scavenging phospholipids as a novel intervention to control local spread of cancer, packaging of exosomes (which prepare distant microenvironment for organ-specific metastases), and endocytosis of beta 1 integrins (which are required for spread of metastatic phenotype and mesenchymal migration of tumor cells). Beta-cyclodextrins (beta CD) have already been shown to be effective in in vitro and animal studies of breast cancer, but exhibits cholesterol-related ototoxicity. The smaller alpha-cyclodextrins (alpha CD) also scavenges phospholipids, but cannot fit cholesterol. An in-vitro study presented here confirms hydroxypropyl (HP)-alpha CD to be twice as effective as HP beta CD against migration of human cells of both receptor negative and estrogen-receptor positive breast cancer. If the previous successful animal studies with beta CDs are replicated with the safer and more effective alpha CDs, clinical trials of adjuvant treatment with alpha CDs are warranted. Ultimately, all breast cancer are expected to benefit from treatment with HP alpha CD, but women with triple-negative breast cancer (TNBC) will benefit most, because they have fewer treatment options and their cancer advances more aggressively.

Adipose tissue plays a central role in energy homeostasis and thermoregulation. It is composed of different types of adipocytes, as well as adipocyte precursors, immune cells, fibroblasts, blood vessels, and nerve projections. Although the molecular control of cell type specification and how these cells interact have been increasingly delineated, a more comprehensive understanding of these adipose-resident cells can be achieved by visualizing their distribution and architecture throughout the whole tissue. Existing immunohistochemistry and immunofluorescence approaches to analyze adipose histology rely on thin paraffin-embedded sections. However, thin sections capture only a small portion of tissue; as a result, the conclusions can be biased by what portion of tissue is analyzed. We have therefore developed an adipose tissue clearing technique, Adipo-Clear, to permit comprehensive three-dimensional visualization of molecular and cellular patterns in whole adipose tissues. Adipo-Clear was adapted from iDISCO/iDISCO+, with specific modifications made to completely remove the lipid stored in the tissue while preserving native tissue morphology. In combination with light-sheet fluorescence microscopy, we demonstrate here the use of the Adipo-Clear method to obtain high-resolution volumetric images of an entire adipose tissue.

The transverse momentum (p(T)) spectrum of prompt D-0 mesons and their antiparticles has been measured via the hadronic decay channels D-0 -> K- pi(+) and (D) over bar (0) -> K+ pi(-) in pp and PbPb collisions at a centre-of-mass energy of 5.02 TeV per nucleon pair with the CMS detector at the LHC. The measurement is performed in the D-0 meson p(T) range of 2-100GeV/c and in the rapidity range of vertical bar y vertical bar < 1. The pp (PbPb) dataset used for this analysis corresponds to an integrated luminosity of 27.4 pb(-1) (530 mu b(-1)). The measured D-0 meson p(T) spectrum in pp collisions is well described by perturbative QCD calculations. The nuclear modification factor, comparing D-0 meson yields in PbPb and pp collisions, was extracted for both minimum-bias and the 10% most central PbPb interactions. For central events, the D-0 meson yield in the PbPb collisions is suppressed by a factor of 5-6 compared to the pp reference in the p(T) range of 6-10GeV/c. For D-0 mesons in the high-p(T) range of 60-100GeV/c, a significantly smaller suppression is observed. The results are also compared to theoretical calculations. (C) 2018 The Author(s). Published by Elsevier B.V.

Specialized groups of neurons in the brain are key mediators of circadian rhythms, receiving daily environmental cues and communicating those signals to other tissues in the organism for entrainment and to organize circadian physiology. In Drosophila, the "circadian clock" is housed in seven neuronal clusters, which are defined by their expression of the main circadian proteins, Period, Timeless, Clock, and Cycle. These clusters are distributed across the fly brain and are thereby subject to the respective environments associated with their anatomical locations. While these core components are universally expressed in all neurons of the circadian network, additional regulatory proteins that act on these components are differentially expressed, giving rise to "local clocks" within the network that nonetheless converge to regulate coherent behavioral rhythms. In this review, we describe the communication between the neurons of the circadian network and the molecular differences within neurons of this network. We focus on differences in protein-expression patterns and discuss how such variation can impart functional differences in each local clock. Finally, we summarize our current understanding of how communication within the circadian network intersects with intracellular biochemical mechanisms to ultimately specify behavioral rhythms. We propose that additional efforts are required to identify regulatory mechanisms within each neuronal cluster to understand the molecular basis of circadian behavior.

Staphylococcus aureus is a major human pathogen with well-characterized bacteriophage contributions to its virulence potential. Recently, we identified plasmidial and episomal prophages in S. aureus strains using an extra-chromosomal DNA (exDNA) isolation and sequencing approach, uncovering the plasmidial phage phi BU01, which was found to encode important virulence determinants. Here, we expanded our extrachromosomal sequencing of S. aureus, selecting 15 diverse clinical isolates with known chromosomal sequences for exDNA isolation and next-generation sequencing. We uncovered the presence of additional episomal prophages in 5 of 15 samples, but did not identify any plasmidial prophages. exDNA isolation was found to enrich for circular prophage elements, and qPCR characterization of the strains revealed that such prophage enrichment is detectable only in exDNA samples and would likely be missed in whole-genome DNA preparations (e.g., detection of episomal prophages did not correlate with higher prophage excision rates nor higher excised prophage copy numbers in qPCR experiments using whole-genome DNA). In S. aureus MSSA476, we found that enrichment and excision of the prophage phi Sa4ms into the cytoplasm was temporal and that episomal prophage localization did not appear to be a precursor to lytic cycle replication, suggesting phi Sa4ms excision into the cytoplasm may be part of a novel lysogenic switch. For example, we show that phi Sa4ms excision alters the promoter and transcription of htrA(2), encoding a stress-response serine protease, and that alternative promotion of htrA(2) confers increased heat-stress survival in S. aureus COL. Overall, exDNA isolation and focused sequencing may offer a more complete genomic picture for bacterial pathogens, offering insights into important chromosomal dynamics likely missed with whole-genome DNA-based approaches.

Corticotropin-releasing factor receptors (CRFR1) contribute to stress-induced adaptations in hippocampal structure and function that can affect learning and memory processes. Our prior studies showed that female rats with elevated estrogens compared to males have more plasmalemmal CRFR1 in CA1 pyramidal cells, suggesting a greater sensitivity to stress. Here, we examined the distribution of hippocampal CRFR1 following chronic immobilization stress (CIS) in female and male rats using immuno-electron microscopy. Without stress, total CRFR1 dendritic levels were higher in females in CA1 and in males in the hilus; moreover, plasmalemmal CRFR1 was elevated in pyramidal cell dendrites in CA1 in females and in CA3 in males. Following CIS, near-plasmalemmal CRFR1 increased in CA1 pyramidal cell dendrites in males but not to levels of control or CIS females. In CA3 and the hilus, CIS decreased cytoplasmic and total CRFR1 in dendrites in males only. These results suggest that in naive rats, CRF could induce a greater activation of CA1 pyramidal cells in females than males. Moreover, after CIS, which leads to even greater sex differences in CRFR1 by trafficking it to different subcellular compartments, CRF could enhance activation of CA1 pyramidal cells in males but to a lesser extent than either unstressed or CIS females. Additionally, CA3 pyramidal cells and inhibitory interneurons in males have heightened sensitivity to CRF, regardless of stress state. These sex differences in CRFR1 distribution and trafficking in the hippocampus may contribute to reported sex differences in hippocampus-dependent learning processes in baseline conditions and following chronic stress. (C) 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

A search is presented for new physics in events with two low-momentum, oppositely charged leptons (electrons or muons) and missing transverse momentum in proton-proton collisions at a centre-of-mass energy of 13TeV. The data collected using the CMS detector at the LHC correspond to an integrated luminosity of 35.9 fb(-1). The observed event yields are consistent with the expectations from the standard model. The results are interpreted in terms of pair production of charginos and neutralinos ((chi) over tilde (+/-)(1) and (chi) over tilde (0)(2)) with nearly degenerate masses, as expected in natural supersymmetry models with light higgsinos, as well as in terms of the pair production of top squarks ((t) over tilde), when the lightest neutralino and the top squark have similar masses. At 95% confidence level, wino-like (chi) over tilde (+/-)(1)/(chi) over tilde (0)(2) masses are excluded up to 230GeVfor a mass difference of 20GeV relative to the lightest neutralino. In the higgsino-like model, masses are excluded up to 168GeV for the same mass difference. For (t) over tilde pair production, top squark masses up to 450GeVare excluded for a mass difference of 40GeV relative to the lightest neutralino. (C) 2018 The Author(s). Published by Elsevier B.V.