The rockefeller university

Multidrug-resistant bacteria pose a major threat to effective antibiotics and alternatives to fight multidrug-resistant pathogens are needed. We synthetized molybdenum oxide (MoO3) nanoparticles (NP) and determined their antibacterial activity against 39 isolates: (i) eight Staphylococcus aureus, including representatives of methicillin-resistant S. aureus epidemic clones; (ii) six enterococci, including vancomycin-resistant isolates; and (iii) 25 Gram-negative isolates (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Acinetobacter baumannii, Enterobacter cloacae), including extended spectrum beta-lactamases and carbapenemases producers. All isolates showed a MoO3 NP MIC of 700-800 mg l(-1). MoO3 NP produced a clear inhibition zone for S. aureus and all Gram-negative isolates at concentrations >= 25 mg ml(-1) and >= 50 mg ml(-1) for enterococci. When the NP solutions were adjusted to pH similar to 7, the biocidal activity was completely abolished. MoO3 NP create an acidic pH and show a universal antimicrobial activity against susceptible and resistant isolates belonging to the most relevant bacterial species responsible for hospital-acquired infections.

Approximately 75% of breast cancers are estrogen receptor alpha (ER alpha)-positive and are treatable with endocrine therapies, but often patients develop lethal resistant disease. Frequent mutations (10-40%) in the ligand-binding domain (LBD) codons in the gene encoding ER alpha (ESR1) have been identified, resulting in ligand-independent, constitutively active receptors. In addition, ESR1 chromosomal translocations can occur, resulting in fusion proteins that lack the LBD and are entirely unresponsive to all endocrine treatments. Thus, identifying coactivators that bind to these mutant ERa proteins may offer new therapeutic targets for endocrine-resistant cancer. To define coactivator candidate targets, a proteomics approach was performed profiling proteins recruited to the two most common ER alpha LBD mutants, Y537S and D538G, and an ESR1-YAP1 fusion protein. These mutants displayed enhanced coactivator interactions as compared to unliganded wild-type ER alpha. Inhibition of these coactivators decreased the ability of ESR1 mutants to activate transcription and promote breast cancer growth in vitro and in vivo. Thus, we have identified specific coactivators that may be useful as targets for endocrine-resistant breast cancers.

In experimental cultures, when bacteria are mixed with lytic ( virulent) bacteriophage, bacterial cells resistant to the phage commonly emerge and become the dominant population of bacteria. Following the ascent of resistant mutants, the densities of bacteria in these simple communities become limited by resources rather than the phage. Despite the evolution of resistant hosts, upon which the phage cannot replicate, the lytic phage population is most commonly maintained in an apparently stable state with the resistant bacteria. Several mechanisms have been put forward to account for this result. Here we report the results of population dynamic/evolution experiments with a virulent mutant of phage Lambda, lambda(VIR), and Escherichia coli in serial transfer cultures. We show that, following the ascent of lambda(VIR) resistant bacteria, lambda(VIR) is maintained in the majority of cases in maltose-limited minimal media and in all cases in nutrient-rich broth. Using mathematical models and experiments, we show that the dominant mechanism responsible for maintenance of lambda(VIR) in these resource-limited populations dominated by resistant E. coli is a high rate of either phenotypic or genetic transition from resistance to susceptibility-a hitherto undemonstrated mechanism we term "leaky resistance." We discuss the implications of leaky resistance to our understanding of the conditions for the maintenance of phage in populations of bacteria-their "existence conditions."

This paper reviews early evidence for the existence of rapid, non-genomic effects of estrogens on neurons, and, further, proposes that these rapid effects are often synergistic with later, genomic effects. Finally, suggestions about potential molecular mechanisms underlying the rapid effects of estrogens are offered. A mechanistic step we propose to be common among rapid estrogenic actions includes membrane ER's binding to histamine, and NMDA receptors and subsequent dimerization, and clustering (respectively) in a manner that enhances histamine and NMDA actions.

Objective To measure the association of preconception health insurance status with preconception health among women in New York City, and examine whether this association is modified by race/ethnicity. Methods Using data from the New York City Pregnancy Risk Assessment Monitoring System 2009-2011 (n = 3929), we created a "Preconception Health Score" (PHS) capturing modifiable behaviors, healthcare services utilization, pregnancy intention, and timely entry into prenatal care. We then built multivariable logistic regression models to measure the association of PHS with health insurance status and race/ethnicity. Results We found PHS to be higher among women with private insurance (7.3 +/- 0.07) or public insurance (6.3 +/- 0.08) before pregnancy than no insurance (5.9 +/- 0.09) (p < .001). However, when stratified by race/ethnicity, the positive association of PHS with insurance was absent in the non-white population. Conclusions for Practice Having health insurance during the pre-pregnancy period is associated with greater health among white women, but not among black or Hispanic women in NYC.

Alzheimer's disease (AD) represents a major healthcare burden with no effective treatment. The glutamate modulator, riluzole, was shown to reverse many AD-related gene expression changes and improve cognition in aged rats. However, riluzole's effect on amyloid beta (A beta) pathology, a major histopathological hallmark of AD, remains unclear. 5XFAD transgenic mice, which harbor amyloid beta precursor protein (APP) and presenilin mutations and exhibit early A beta accumulation, were treated with riluzole from 1 to 6 months of age. Riluzole significantly enhanced cognition and reduced A beta 42, A beta 40, A beta oligomers levels, and A beta plaque load in 5XFAD mice. RNA-Sequencing showed that riluzole reversed many gene expression changes observed in the hippocampus of 5XFAD mice, predominantly in expression of canonical gene markers for microglia, specifically disease-associated microglia (DAM), as well as neurons and astrocytes. Central to the cognitive improvements observed, riluzole reversed alterations in NMDA receptor subunits gene expression, which are essential for learning and memory. These data demonstrate that riluzole exerts a disease modifying effect in an A beta mouse model of early-onset familial AD.

The initial fitness benefits of group living are considered to be the greatest hurdle to the evolution of sociality(1), and evolutionary theory predicts that these benefits need to arise at very small group sizes(2). Such benefits are thought to emerge partly from scaling effects that increase efficiency as group size increases(3-5). In social insects and other taxa, the benefits of group living have been proposed to stem from division of labour(5-8), which is characterized by between-individual variability and within-individual consistency (specialization) in task performance. However, at the onset of sociality groups were probably small and composed of similar individuals with potentially redundant-rather than complementary-function(1). Self-organization theory suggests that division of labour can emerge even in relatively small, simple groups(9-10). However, empirical data on the effects of group size on division of labour and on fitness remain equivocal(6). Here we use long-term automated behavioural tracking in clonal ant colonies, combined with mathematical modelling, to show that increases in the size of social groups can generate division of labour among extremely similar workers, in groups as small as six individuals. These early effects on behaviour were associated with large increases in homeostasis-the maintenance of stable conditions in the colony(11)-and per capita fitness. Our model suggests that increases in homeostasis are primarily driven by increases in group size itself, and to a smaller extent by a higher division of labour. Our results indicate that division of labour, increased homeostasis and higher fitness can emerge naturally in social groups that are small and homogeneous, and that scaling effects associated with increasing group size can thus promote social cohesion at the incipient stages of group living.

Advanced, metastatic melanomas frequently grow in subcutaneous tissues and portend a poor prognosis. Though subcutaneous tissues are largely composed of adipocytes, the mechanisms by which adipocytes influence melanoma are poorly understood. Using in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. Additionally, adipocytes directly transfer lipids to melanoma cells, which alters tumor cell metabolism. Adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAF(V600E) in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. Pharmacologic blockade of FATPs with the small-molecule inhibitor Lipofermata abrogates lipid transport into melanoma cells and reduces melanoma growth and invasion. These data demonstrate that stromal adipocytes can drive melanoma progression through FATP lipid transporters and represent a new target aimed at interrupting adipocyte-melanoma cross-talk. SIGNIFICANCE: We demonstrate that stromal adipocytes are donors of lipids that mediate melanoma progression. Adipocyte-derived lipids are taken up by FATP proteins that are aberrantly expressed in melanoma. Inhibition of FATPs decreases melanoma lipid uptake, invasion, and growth. We provide a mechanism for how stromal adipocytes drive tumor progression and demonstrate a novel microenvironmental therapeutic target. (c) 2018 AACR.

Results are reported from a search for physics beyond the standard model in proton-proton collisions at a center-of-mass energy of root s=13TeV. The search uses a signature of a single lepton, large jet and bottom quark jet multiplicities, and high sum of large-radius jet masses, without any requirement on the missing transverse momentum in an event. The data sample corresponds to an integrated luminosity of 35.9 fb(-1) recorded by the CMS experiment at the LHC. No significant excess beyond the prediction from standard model processes is observed. The results are interpreted in terms of upper limits on the production cross section for R-parity violating supersymmetric extensions of the standard model using a benchmark model of gluino pair production, in which each gluino decays promptly via (g) over tilde -> tbs. Gluinos with a mass below 1610 GeV are excluded at 95% confidence level. (c) 2018 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (https://urldefense.proofpoint.com/v2/url?u=http-3A__creativecommons.org_licenses_by_4.0_&d=DwIDaQ&c=JeTkUgVztGMmhKYjxsy2rfoWYibK1YmxXez1G3oNStg&r=bWJiylK2oqB9vBxAFHE1PJcvSYL9TVkBaaVMsMDsLbs&m=VTpB_Xwivicryu99yNeoC2h8JMzHG23s6l8sMqCuZ4o&s=BNICcpZRv1cFogMPWOdQrUGkJAUcABVqQ0cOTBHqGcU&e=). Funded by SCOAP(3).