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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.

Cortical deep projection neurons (DPNs) are implicated in neurodevelopmental disorders. Although recent findings emphasize post-mitotic programs in projection neuron fate selection, the establishment of primate DPN identity during layer formation is not well understood. The subplate lies underneath the developing cortex and is a post-mitotic compartment that is transiently and disproportionately enlarged in primates in the second trimester. The evolutionary significance of subplate expansion, the molecular identity of its neurons, and its contribution to primate corticogenesis remain open questions. By modeling subplate formation with human pluripotent stem cells (hPSCs), we show that all classes of cortical DPNs can be specified from subplate neurons (SPNs). Post-mitotic WNT signaling regulates DPN class selection, and DPNs in the caudal fetal cortex appear to exclusively derive from SPNs. Our findings indicate that SPNs have evolved in primates as an important source of DPNs that contribute to cortical lamination prior to their known role in circuit formation.

DNA double-strand breaks repaired by non-homologous end joining display limited DNA end-processing and chromosomal mobility. By contrast, double-strand breaks undergoing homology-directed repair exhibit extensive processing and enhanced motion. The molecular basis of this movement is unknown. Here, using Xenopus laevis cell-free extracts and mammalian cells, we establish that nuclear actin, WASP, and the actin-nucleating ARP2/3 complex are recruited to damaged chromatin undergoing homology-directed repair. We demonstrate that nuclear actin polymerization is required for the migration of a subset of double-strand breaks into discrete sub-nuclear clusters. Actin-driven movements specifically affect double-strand breaks repaired by homology-directed repair in G2 cell cycle phase; inhibition of actin nucleation impairs DNA end-processing and homology-directed repair. By contrast, ARP2/3 is not enriched at double-strand breaks repaired by non-homologous end joining and does not regulate non-homologous end joining. Our findings establish that nuclear actin-based mobility shapes chromatin organization by generating repair domains that are essential for homology-directed repair in eukaryotic cells.

Background Phase III trials of long-acting injectable (LAI) PrEP, currently underway, have great potential for expanding the menu of HIV prevention options. Imagining a future in which multiple PrEP modalities are available to potential users of biomedical HIV prevention, we investigated which factors might help direct a patient-physician shared-decision making process to optimize the choice of biomedical HIV prevention method. Methods Participants (n = 105; ages 19-63; 46.7% men of color) were former participants in a PrEP demonstration project and had taken daily oral PrEP for >= 12 months. Participants were given information about LAI PrEP and asked whether they would be interested in switching from oral to LAI PrEP. Participants were also asked about specific pros/cons of LAI PrEP, PrEP attitudes and experiences, and personality factors. Results Two-thirds (66.7%) of current oral PrEP users would switch to LAI PrEP. Intention to switch was associated with product-level and psychosocial factors. Attitudes towards logistical factors (i.e. getting to regular clinic visits for recurring shots) featured more prominently than factors related to the physical experience of PrEP modality (i.e., concerns about injection pain) as motivators for switching. In a multivariate regression model, psychosocial factors including the emotional burden of daily pill taking, deriving a sense of responsibility from PrEP use, and self-identifying as an early adopter, were the strongest predictors of switching. Conclusions These data underscore the importance of attending not only to product-level factors, but also to the logistical and psychological experience of prevention methods for users. Findings have significant implications for the development of patient education materials and patient-provider shared decision aids.

Addition of beta-lactam antibiotics to growing cultures of bacteria inhibit synthesis of the bacterial cell wall peptidoglycan accompanied by killing (loss of viable titer) and lysis (physical disintegration) of the cells. However, it has also been well established that these antibiotics are not effective in killing non-growing or slow-growing bacteria and the mechanism of this "antibiotic tolerance" is not well understood. In this study, we report on the genetic basis and phenotypic properties of an antibiotic tolerant derivative of the methicillin susceptible S. aureus strain 27s. Cultures were exposed to "pulses" of high concentrations of oxacillin followed by outgrowth of the surviving bacteria. This procedure quickly selected for antibiotic tolerant mutants with an increased ability to survive antibiotic treatment without increase in the MIC value for the antibiotic. Such mutants also exhibited longer lag phase, decreased lysis, virtually no change in antibiotic susceptibilities, cross tolerance to D-cycloserine and vancomycin, and increase in biofilm formation in the presence of high concentrations of oxacillin. Whole genome sequencing showed that these altered properties were linked to mutations in the atl and gdpP genes.

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.

Many organisms possess multiple and often divergent actins whose regulation and roles are not understood in detail. For example, Chlamydomonas reinhardtii has both a conventional actin (IDA5) and a highly divergent one (NAP1); only IDA5 is expressed in normal proliferating cells. We showed previously that the drug latrunculin B (LatB) causes loss of filamentous (F-) IDA5 and strong upregulation of NAP1, which then provides essential actin function(s) by forming LatB-resistant F-NAP1. RNA-sequencing analyses now show that this up-regulation of NAP1 reflects a broad transcriptional response, much of which depends on three proteins (LAT1, LAT2, and LAT3) identified previously as essential for NAP1 transcription. Many of the LAT-regulated genes contain a putative cis-acting regulatory site, the "LRE motif." The LatB transcriptional program appears to be activated by loss of F-IDA5 and deactivated by formation of F-NAP1, thus forming an F-actin-dependent negative-feedback loop. Multiple genes encoding proteins of the ubiquitin-proteasome system are among those induced by LatB, resulting in rapid degradation of IDA5 (but not NAP1). Our results suggest that IDA5 degradation is functionally important because nonpolymerizable LatB-bound IDA5 interferes with the formation of F-NAP1. The genes for the actin-interacting proteins cofilin and profilin are also induced. Cofilin induction may further the clearance of IDA5 by promoting the scission of FIDA5, whereas profilin appears to function in protecting monomeric IDA5 from degradation. This multifaceted regulatory system allows rapid and quantitative turnover of F-actin in response to cytoskeletal perturbations and probably also maintains F-actin homeostasis under normal growth conditions.

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.

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.

DNA barcoding is both an important research and science education tool. The technique allows for quick and accurate species identification using only minimal amounts of tissue samples taken from any organism at any developmental phase. DNA barcoding has many practical applications including furthering the study of taxonomy and monitoring biodiversity. In addition to these uses, DNA barcoding is a powerful tool to empower, engage, and educate students in the scientific method while conducting productive and creative research. The study presented here provides the first assessment of Marine Park (Brooklyn, New York, USA) biodiversity using DNA barcoding. New York City citizen scientists (high school students and their teachers) were trained to identify species using DNA barcoding during a two-week long institute. By performing NCBI GenBank BLAST searches, students taxonomically identified 187 samples (1 fungus, 70 animals and 116 plants) and also published 12 novel DNA barcodes on GenBank. Students also identified 7 ant species and demonstrated the potential of DNA barcoding for identification of this especially diverse group when coupled with traditional taxonomy using morphology. Here we outline how DNA barcoding allows citizen scientists to make preliminary taxonomic identifications and contribute to modern biodiversity research.