Early molecular insights into thanatin analogues binding to A. baumannii LptA

The cationic antimicrobial ß-hairpin, thanatin, was recently developed into drug-like analogues active against carbapenem-resistant Enterobacteriaceae (CRE). The analogues represent new antibiotics with a novel mode of action targeting LptA in the periplasm and disrupting LPS transport. The compounds lose antimicrobial efficacy when the sequence identity to E. coli LptA falls below 70%. We wanted to test the thanatin analogues against LptA of a phylogenetic distant organism and investigate the molecular determinants of inactivity. Acinetobacter baumannii (A. baumannii) is a critical Gram-negative pathogen that has gained increasing attention for its multi-drug resistance and hospital burden. A. baumannii LptA shares 28% sequence identity with E. coli LptA and displays an intrinsic resistance to thanatin and thanatin analogues (MIC values > 32 μg/mL) through a mechanism not yet described. We investigated the inactivity further and discovered that these CRE- optimized derivatives can bind to LptA of A. baumannii in vitro, despite the high MIC values. Herein, we present a high-resolution structure of A. baumannii LptAm in complex with a thanatin derivative 7 and binding affinities of selected thanatin derivatives. Together, these data offer structural insights into why thanatin derivatives are inactive against A. baumannii LptA, despite binding events in vitro

Peptides in BioNMR Research

Heteronuclear NMR in combination with isotope labelling is used to study folding of polypeptides induced by metals in the case of metallothioneins, binding of the peptidic allosteric modulator ?-TIA to the human G-protein coupled ?1b adrenergic receptor, the development of therapeutic drugs that interfere with the biosynthesis of the outer membrane of Gram-negative bacteria, and a system in which protein assembly is induced upon peptide addition. NMR in these cases is used to derive precise structural data and to study the dynamics

Sexual harassment and eating disorders in female elite athletes - A controlled study

The aims were to examine the percentage of female elite athletes and controls reporting sexual harassment and abuse (SHAB), and whether a higher percentage of female athletes with eating disorders (ED) had experienced SHAB. A questionnaire was administered to the total population of female elite athletes (n=660) and controls (n=780) aged 15-39 years. SHAB were measured through 11 questions, ranging from light to severe SHAB. In addition, questions about dietary-, menstrual- and training history and the Eating Disorder Inventory were included. The response rate was 88% for athletes and 71% for controls. Athletes (n=121) and controls (n=81) classified as “at risk” for ED and non-ED controls participated in a clinical interview. A higher percentage of controls, compared with athletes reported experiences of SHAB in general (59% vs. 51%, p<0.001). A lower percentage of athletes had experienced SHAB in sports than outside sport (28% vs.39%, p<0.001). A higher percentage of ED athletes than non-ED athletes had experienced SHAB (66% vs.48%) (p<0.01), both inside sport and outside sport. In spite of the fact that a higher percentage of controls compared with athletes had experienced SHAB, it is necessary to formulate clear guidelines, set up educational workshops and implement intervention programs for both ED and SHAB in sport

Confidence interval estimation for the changepoint of treatment stratification in the presence of a qualitative covariate-treatment interaction

The goal in stratified medicine is to administer the \textquotedblbest\textquotedbl treatment to a patient. Not all patients might benefit from the same treatment; the choice of best treatment can depend on certain patient characteristics. In this article, it is assumed that a time-to-event outcome is considered as a patient-relevant outcome and a qualitative interaction between a continuous covariate and treatment exists, ie,~that patients with different values of one specific covariate should be treated differently. We suggest and investigate different methods for confidence interval estimation for the covariate value, where the treatment recommendation should be changed based on data collected in a randomized clinical trial. An adaptation of Fieller's theorem, the delta method, and different bootstrap approaches (normal, percentile-based, wild bootstrap) are investigated and compared in a simulation study. Extensions to multivariable problems are presented and evaluated. We observed appropriate confidence interval coverage following Fieller's theorem irrespective of sample size but at the cost of very wide or even infinite confidence intervals. The delta method and the wild bootstrap approach provided the smallest intervals but inadequate coverage for small to moderate event numbers, also depending on the location of the true changepoint. For the percentile-based bootstrap, wide intervals were observed, and it was slightly conservative regarding coverage, whereas the normal bootstrap did not provide acceptable results for many scenarios. The described methods were also applied to data from a randomized clinical trial comparing two treatments for patients with symptomatic, severe carotid artery stenosis, considering patient's age as predictive marker

Risk Estimation and Value-of-Information Analysis for Three Proposed Genetic Screening Programs for Chronic Beryllium Disease Prevention

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75032/1/0272-4332.00009.pd

Stress-Induced Subclinical Reactivation of Varicella Zoster Virus in Astronauts

After primary infection, varicella-zoster virus (VZV) becomes latent in ganglia. VZV reactivation occurs primarily in elderly individuals, organ transplant recipients, and patients with cancer and AIDS, correlating with a specific decline in cell-mediated immunity to VZV. VZV can also reactivate after surgical stress. To determine whether VZV can also reactivate after acute non-surgical stress, we examined total DNA extracted from 312 saliva samples of eight astronauts before, during and after space flight for VZV DNA by PCR: 112 samples were obtained 234 to 265 days before flight, 84 samples on days 2 through 13 of space flight, and 116 samples on days 1 through 15 after flight. Before space flight only one of the 112 saliva samples from a single astronaut was positive for VZV DNA. In contrast, during and after space flight, 61 of 200 (30%) saliva samples were positive in all 8 astronauts. No VZV DNA was detected in any of 88 saliva samples from 10 healthy control subjects. These data indicate that VZV can reactivate subclinically in healthy individuals after acute stress

Suppression of growth by multiplicative white noise in a parametric resonant system

The author studied the growth of the amplitude in a Mathieu-like equation with multiplicative white noise. The approximate value of the exponent at the extremum on parametric resonance regions was obtained theoretically by introducing the width of time interval, and the exponents were calculated numerically by solving the stochastic differential equations by a symplectic numerical method. The Mathieu-like equation contains a parameter $\alpha$ that is determined by the intensity of noise and the strength of the coupling between the variable and the noise. The value of $\alpha$ was restricted not to be negative without loss of generality. It was shown that the exponent decreases with $\alpha$, reaches a minimum and increases after that. It was also found that the exponent as a function of $\alpha$ has only one minimum at $\alpha \neq 0$ on parametric resonance regions of $\alpha = 0$. This minimum value is obtained theoretically and numerically. The existence of the minimum at $\alpha \neq 0$ indicates the suppression of the growth by multiplicative white noise.Comment: The title and the description in the manuscript are change