An interplay of multiple positive and negative factors governs methicillin resistance in Staphylococcus aureus

The development of resistance to β-lactam antibiotics has made Staphylococcus aureus a clinical burden on a global scale. MRSA (methicillin-resistant S. aureus) is commonly known as a superbug. The ability of MRSA to proliferate in the presence of β-lactams is attributed to the acquisition of mecA, which encodes the alternative penicillin binding protein, PBP2A, which is insensitive to the antibiotics. Most MRSA isolates exhibit low-level β-lactam resistance, whereby additional genetic adjustments are required to develop high-level resistance. Although several genetic factors that potentiate or are required for high-level resistance have been identified, how these interact at the mechanistic level has remained elusive. Here, we discuss the development of resistance and assess the role of the associated components in tailoring physiology to accommodate incoming mecA

Acid pH activation of the PmrA/PmrB two-component regulatory system of Salmonella enterica

Acid pH often triggers changes in gene expression. However, little is known about the identity of the gene products that sense fluctuations in extracytoplasmic pH. The Gram-negative pathogen Salmonella enterica serovar Typhimurium experiences a number of acidic environments both inside and outside animal hosts. Growth in mild acid (pH 5.8) promotes transcription of genes activated by the response regulator PmrA, but the signalling pathway(s) that mediates this response has thus far remained unexplored. Here we report that this activation requires both PmrA's cognate sensor kinase PmrB, which had been previously shown to respond to Fe(3+) and Al(3+), and PmrA's post-translational activator PmrD. Substitution of a conserved histidine or of either one of four conserved glutamic acid residues in the periplasmic domain of PmrB severely decreased or abolished the mild acid-promoted transcription of PmrA-activated genes. The PmrA/PmrB system controls lipopolysaccharide modifications mediating resistance to the antibiotic polymyxin B. Wild-type Salmonella grown at pH 5.8 were > 100 000-fold more resistant to polymyxin B than organisms grown at pH 7.7. Our results suggest that protonation of the PmrB periplasmic histidine and/or of the glutamic acid residues activate the PmrA protein, and that mild acid promotes cellular changes resulting in polymyxin B resistance

Proton Elastic and Inelastic Scattering at Intermediate Energies from Isotopes of Oxygen and 9-Be as Part of a Unified Study of These Nuclei

This work was supported by National Science Foundation Grants PHY 76-84033A01, PHY 78-22774, and Indiana Universit

Citizen Science 2.0 : Data Management Principles to Harness the Power of the Crowd

Citizen science refers to voluntary participation by the general public in scientific endeavors. Although citizen science has a long tradition, the rise of online communities and user-generated web content has the potential to greatly expand its scope and contributions. Citizens spread across a large area will collect more information than an individual researcher can. Because citizen scientists tend to make observations about areas they know well, data are likely to be very detailed. Although the potential for engaging citizen scientists is extensive, there are challenges as well. In this paper we consider one such challenge – creating an environment in which non-experts in a scientific domain can provide appropriate and accurate data regarding their observations. We describe the problem in the context of a research project that includes the development of a website to collect citizen-generated data on the distribution of plants and animals in a geographic region. We propose an approach that can improve the quantity and quality of data collected in such projects by organizing data using instance-based data structures. Potential implications of this approach are discussed and plans for future research to validate the design are described

Photo-production of Nucleon Resonances and Nucleon Spin Structure Function in the Resonance Region

The photo-production of nucleon resonances is calculated based on a chiral constituent quark model including both relativistic corrections H{rel} and two-body exchange currents, and it is shown that these effects play an important role. We also calculate the first moment of the nucleon spin structure function g1 (x,Q^2) in the resonance region, and obtain a sign-changing point around Q^2 ~ 0.27 {GeV}^2 for the proton.Comment: 23 pages, 5 figure

Coupled oscillators as models of phantom and scalar field cosmologies

We study a toy model for phantom cosmology recently introduced in the literature and consisting of two oscillators, one of which carries negative kinetic energy. The results are compared with the exact phase space picture obtained for similar dynamical systems describing, respectively, a massive canonical scalar field conformally coupled to the spacetime curvature, and a conformally coupled massive phantom. Finally, the dynamical system describing exactly a minimally coupled phantom is studied and compared with the toy model.Comment: 18 pages, LaTeX, to appear in Physical Review

Discovery of Human Signaling Systems: Pairing Peptides to G Protein-Coupled Receptors

The peptidergic system is the most abundant network of ligand-receptor-mediated signaling in humans. However, the physiological roles remain elusive for numerous peptides and more than 100 G protein-coupled receptors (GPCRs). Here we report the pairing of cognate peptides and receptors. Integrating comparative genomics across 313 species and bioinformatics on all protein sequences and structures of human class A GPCRs, we identify universal characteristics that uncover additional potential peptidergic signaling systems. Using three orthogonal biochemical assays, we pair 17 proposed endogenous ligands with five orphan GPCRs that are associated with diseases, including genetic, neoplastic, nervous and reproductive system disorders. We also identify additional peptides for nine receptors with recognized ligands and pathophysiological roles. This integrated computational and multifaceted experimental approach expands the peptide-GPCR network and opens the way for studies to elucidate the roles of these signaling systems in human physiology and disease. Video Abstract: Features learned from comparative sequence and structural analyses enabled prediction of peptide ligands for orphan GPCRs that, when coupled with functional validation, expose physiologically relevant signaling systems. © 2019 The Author(s

Why does fertilization reduce plant species diversity? Testing three competition-based hypotheses

1 Plant species diversity drops when fertilizer is added or productivity increases. To explain this, the total competition hypothesis predicts that competition above ground and below ground both become more important, leading to more competitive exclusion, whereas the light competition hypothesis predicts that a shift from below-ground to above-ground competition has a similar effect. The density hypothesis predicts that more above-ground competition leads to mortality of small individuals of all species, and thus a random loss of species from plots. 2 Fertilizer was added to old field plots to manipulate both below-ground and above-ground resources, while shadecloth was used to manipulate above-ground resources alone in tests of these hypotheses. 3 Fertilizer decreased both ramet density and species diversity, and the effect remained significant when density was added as a covariate. Density effects explained only a small part of the drop in diversity with fertilizer. 4 Shadecloth and fertilizer reduced light by the same amount, but only fertilizer reduced diversity. Light alone did not control diversity, as the light competition hypothesis would have predicted, but the combination of above-ground and below-ground competition caused competitive exclusion, consistent with the total competition hypothesis.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75695/1/j.1365-2745.2001.00662.x.pd

A consensus statement on detection of hippocampal sharp wave ripples and differentiation from other fast oscillations

Decades of rodent research have established the role of hippocampal sharp wave ripples (SPW-Rs) in consolidating and guiding experience. More recently, intracranial recordings in humans have suggested their role in episodic and semantic memory. Yet, common standards for recording, detection, and reporting do not exist. Here, we outline the methodological challenges involved in detecting ripple events and offer practical recommendations to improve separation from other high-frequency oscillations. We argue that shared experimental, detection, and reporting standards will provide a solid foundation for future translational discovery.This work was funded by K23NS104252 (A.A.L.) R01 MH117777 (E.B., J.W.R.) Whitehall Foundation (KH) 5F31NS120783-02 (Z.L.) 1U19NS104590 (A.L.) R01NS106611-02 (J.S., M.K.) MTEC-20-06-MOM013 (J.S., M.K.) 1U19NS107609-01 (I.S., J.L.) 1U19NS104590 (A.L., J.S.F., I.S.) 1U19NS107609 (E.A.B., J.W.R., J.J.L., I.S.) La Caixa LCF/PR/HR21/52410030 (A.N.O., L.dl.P) European Research Council Consolidator Grant 101001121 (B.P.S.) U.S.-Israel BSF grant 2017015 (RM)U01-NS113198 (J.J.) NSF CAREER IOS-1844935 (M.vdM.) 1R01NS121764-01 (B.L.M.) R01 MH122391 (G.B.) 30MH126483 (J.A.G.) Fondation pour la Recherche Médicale EQU202103012768 (M.Z.) 1R16-NS131108-01 (L.L.)