Subfamily-Specific Adaptations in the Structures of Two Penicillin-Binding Proteins from Mycobacterium tuberculosis

Beta-lactam antibiotics target penicillin-binding proteins including several enzyme classes essential for bacterial cell-wall homeostasis. To better understand the functional and inhibitor-binding specificities of penicillin-binding proteins from the pathogen, Mycobacterium tuberculosis, we carried out structural and phylogenetic analysis of two predicted D,D-carboxypeptidases, Rv2911 and Rv3330. Optimization of Rv2911 for crystallization using directed evolution and the GFP folding reporter method yielded a soluble quadruple mutant. Structures of optimized Rv2911 bound to phenylmethylsulfonyl fluoride and Rv3330 bound to meropenem show that, in contrast to the nonspecific inhibitor, meropenem forms an extended interaction with the enzyme along a conserved surface. Phylogenetic analysis shows that Rv2911 and Rv3330 belong to different clades that emerged in Actinobacteria and are not represented in model organisms such as Escherichia coli and Bacillus subtilis. Clade-specific adaptations allow these enzymes to fulfill distinct physiological roles despite strict conservation of core catalytic residues. The characteristic differences include potential protein-protein interaction surfaces and specificity-determining residues surrounding the catalytic site. Overall, these structural insights lay the groundwork to develop improved beta-lactam therapeutics for tuberculosis

The factor structure of the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen distinct populations

There is considerable evidence that self-criticism plays a major role in the vulnerability to and recovery from psychopathology. Methods to measure this process, and its change over time, are therefore important for research in psychopathology and well-being. This study examined the factor structure of a widely used measure, the Forms of Self-Criticising/Attacking & Self-Reassuring Scale in thirteen nonclinical samples (N = 7510) from twelve different countries: Australia (N = 319), Canada (N = 383), Switzerland (N = 230), Israel (N = 476), Italy (N = 389), Japan (N = 264), the Netherlands (N = 360), Portugal (N = 764), Slovakia (N = 1326), Taiwan (N = 417), the United Kingdom 1 (N = 1570), the United Kingdom 2 (N = 883), and USA (N = 331). This study used more advanced analyses than prior reports: a bifactor item-response theory model, a two-tier item-response theory model, and a non-parametric item-response theory (Mokken) scale analysis. Although the original three-factor solution for the FSCRS (distinguishing between Inadequate-Self, Hated-Self, and Reassured-Self) had an acceptable fit, two-tier models, with two general factors (Self-criticism and Self-reassurance) demonstrated the best fit across all samples. This study provides preliminary evidence suggesting that this two-factor structure can be used in a range of nonclinical contexts across countries and cultures. Inadequate-Self and Hated-Self might not by distinct factors in nonclinical samples. Future work may benefit from distinguishing between self-correction versus shame-based self-criticism.Peer reviewe

TIA1 Mutations in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Promote Phase Separation and Alter Stress Granule Dynamics.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are age-related neurodegenerative disorders with shared genetic etiologies and overlapping clinical and pathological features. Here we studied a novel ALS/FTD family and identified the P362L mutation in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1). Subsequent genetic association analyses showed an increased burden of TIA1 LCD mutations in ALS patients compared to controls (p = 8.7 × 1

A process model of natural attenuation in drainage from a historic mining district

A process model was used to better understand the controls on the chemical evolution of drainage in a historic mining district. At the Pecos Mine Operable Unit, New Mexico, drainage near the waste rock pile is acidic (pH varies from 3.0--5.0) and carries high concentrations of Zn, Al, Cu and Pb. As drainage flows toward the Pecos River, pH increases to greater than 7 and heavy metal content decreases. A process model of natural attenuation in this drainage shows the main controls on pH are reaction with a local bedrock that contains limestone, and concurrent mixing with tributary streams. Models that account for both calcite dissolution and mixing reproduce the observed decrease in aqueous metal concentrations with increasing pH. Contaminant concentrations attenuate primarily via two distinct pathways: Al, Cu, Fe and Pb precipitate directly from solution, whereas Zn, Mg, Mn and SO{sub 4} concentrations decrease primarily through dilution. Additionally, Pb adsorbs to precipitating hydroxide surfaces

Bose-Einstein Correlations of Three Charged Pions in Hadronic Z^0 Decays

Bose-Einstein Correlations (BEC) of three identical charged pions were studied in 4 x 10^6 hadronic Z^0 decays recorded with the OPAL detector at LEP. The genuine three-pion correlations, corrected for the Coulomb effect, were separated from the known two-pion correlations by a new subtraction procedure. A significant genuine three-pion BEC enhancement near threshold was observed having an emitter source radius of r_3 = 0.580 +/- 0.004 (stat.) +/- 0.029 (syst.) fm and a strength of \lambda_3 = 0.504 +/- 0.010 (stat.) +/- 0.041 (syst.). The Coulomb correction was found to increase the \lambda_3 value by \~9% and to reduce r_3 by ~6%. The measured \lambda_3 corresponds to a value of 0.707 +/- 0.014 (stat.) +/- 0.078 (syst.) when one takes into account the three-pion sample purity. A relation between the two-pion and the three-pion source parameters is discussed.Comment: 19 pages, LaTeX, 5 eps figures included, accepted by Eur. Phys. J.

Antiviral treatment with valacyclovir reduces virus shedding in saliva of Antarctic expeditioners

IntroductionReactivation of herpes viruses, such as Epstein–Barr virus (EBV), herpes simplex virus 1 (HSV1), and varicella zoster virus (VZV), increases in astronauts during spaceflight, compared with their preflight and postflight levels. Reactivations can increase the risk of associated clinical conditions, such as herpes zoster, chronic neuropathic pain, vision loss, stroke, cognitive impairment, and cold sores. Furthermore, continued viral shedding for longer periods after space travel may increase the risk of viral transmission to uninfected crew contacts, including, but not limited to, the immunocompromised and newborn infants. Thus, it is essential to develop spaceflight countermeasures to prevent herpes viral reactivations to ensure the health of crewmembers and their contacts. One such countermeasure is the prophylactic administration of an antiviral drug (valacyclovir) against the alpha herpesviruses (VZV and HSV1). To determine the effectiveness of this countermeasure, we studied the shedding of EBV, VZV, and HSV1 in Antarctic expeditioners, who have similar salivary viral shedding patterns during winter-over to astronauts during long spaceflights.MethodsThe efficacy of this antiviral drug as a countermeasure was determined using three major parameters in the saliva of expeditioners during winter-over with and without administration of this drug: (i) viral load and frequency, (ii) physiological stress biomarkers [i.e., levels of cortisol, dehydroepiandrosterone (DHEA), and amylase), and (iii) immune markers (i.e., inflammatory cytokines)]. Thirty-two volunteers from two Antarctic stations (McMurdo and South Pole) participated in this study. Participants were randomly assigned to either the treatment group (valacyclovir HCl: 1 g/day) or placebo group (oyster calcium: 500mg/day). ResultsViral shedding of EBV reduced significantly (> 24-fold) in the treatment group compared with the placebo group. HSV1 was also reduced by more than fivefold, but this was not statistically significant. No VZV shedding was observed in any of the participants. In the placebo group 50% of the saliva samples had measurable viral DNA (EBV, HSV1, or both), compared with 19% of the treatment group. There was no significant change in the ratio of cortisol to DHEA or levels of alpha-amylase, indicating that physiological stress was similar between the groups. No difference was detected in levels of salivary cytokines, except IL-10, which was found in significantly lower levels in the treatment group. DiscussionThese data indicate that valacyclovir is a safe and successful intervention to reduce EBV and HSV1 shedding in individuals subjected to extreme environments and stressors

Measurement of the production of a W boson in association with a charm quark in pp collisions at √s = 7 TeV with the ATLAS detector

The production of a W boson in association with a single charm quark is studied using 4.6 fb−1 of pp collision data at s√ = 7 TeV collected with the ATLAS detector at the Large Hadron Collider. In events in which a W boson decays to an electron or muon, the charm quark is tagged either by its semileptonic decay to a muon or by the presence of a charmed meson. The integrated and differential cross sections as a function of the pseudorapidity of the lepton from the W-boson decay are measured. Results are compared to the predictions of next-to-leading-order QCD calculations obtained from various parton distribution function parameterisations. The ratio of the strange-to-down sea-quark distributions is determined to be 0.96+0.26−0.30 at Q 2 = 1.9 GeV2, which supports the hypothesis of an SU(3)-symmetric composition of the light-quark sea. Additionally, the cross-section ratio σ(W + +c¯¯)/σ(W − + c) is compared to the predictions obtained using parton distribution function parameterisations with different assumptions about the s−s¯¯¯ quark asymmetry

Search for Higgs Bosons in e+e- Collisions at 183 GeV

The data collected by the OPAL experiment at sqrts=183 GeV were used to search for Higgs bosons which are predicted by the Standard Model and various extensions, such as general models with two Higgs field doublets and the Minimal Supersymmetric Standard Model (MSSM). The data correspond to an integrated luminosity of approximately 54pb-1. None of the searches for neutral and charged Higgs bosons have revealed an excess of events beyond the expected background. This negative outcome, in combination with similar results from searches at lower energies, leads to new limits for the Higgs boson masses and other model parameters. In particular, the 95% confidence level lower limit for the mass of the Standard Model Higgs boson is 88.3 GeV. Charged Higgs bosons can be excluded for masses up to 59.5 GeV. In the MSSM, mh > 70.5 GeV and mA > 72.0 GeV are obtained for tan{beta}>1, no and maximal scalar top mixing and soft SUSY-breaking masses of 1 TeV. The range 0.8 < tanb < 1.9 is excluded for minimal scalar top mixing and m{top} < 175 GeV. More general scans of the MSSM parameter space are also considered.Comment: 49 pages. LaTeX, including 33 eps figures, submitted to European Physical Journal