Cell-Envelope Remodeling as a Determinant of Phenotypic Antibacterial Tolerance in Mycobacterium tuberculosis

[Image: see text] The mechanisms that lead to phenotypic antibacterial tolerance in bacteria remain poorly understood. We investigate whether changes in NaCl concentration toward physiologically higher values affect antibacterial efficacy against Mycobacterium tuberculosis (Mtb), the causal agent of human tuberculosis. Indeed, multiclass phenotypic antibacterial tolerance is observed during Mtb growth in physiologic saline. This includes changes in sensitivity to ethionamide, ethambutol, d-cycloserine, several aminoglycosides, and quinolones. By employing organism-wide metabolomic and lipidomic approaches combined with phenotypic tests, we identified a time-dependent biphasic adaptive response after exposure of Mtb to physiological levels of NaCl. A first rapid, extensive, and reversible phase was associated with changes in core and amino acid metabolism. In a second phase, Mtb responded with a substantial remodelling of plasma membrane and outer lipid membrane composition. We demonstrate that phenotypic tolerance at physiological concentrations of NaCl is the result of changes in plasma and outer membrane lipid remodeling and not changes in core metabolism. Altogether, these results indicate that physiologic saline-induced antibacterial tolerance is kinetically coupled to cell envelope changes and demonstrate that metabolic changes and growth arrest are not the cause of phenotypic tolerance observed in Mtb exposed to physiologic concentrations of NaCl. Importantly, this work uncovers a role for bacterial cell envelope remodeling in antibacterial tolerance, alongside well-documented allterations in respiration, metabolism, and growth rate

Equilibria-based Probabilistic Model Checking for Concurrent Stochastic Games

Probabilistic model checking for stochastic games enables formal verification of systems that comprise competing or collaborating entities operating in a stochastic environment. Despite good progress in the area, existing approaches focus on zero-sum goals and cannot reason about scenarios where entities are endowed with different objectives. In this paper, we propose probabilistic model checking techniques for concurrent stochastic games based on Nash equilibria. We extend the temporal logic rPATL (probabilistic alternating-time temporal logic with rewards) to allow reasoning about players with distinct quantitative goals, which capture either the probability of an event occurring or a reward measure. We present algorithms to synthesise strategies that are subgame perfect social welfare optimal Nash equilibria, i.e., where there is no incentive for any players to unilaterally change their strategy in any state of the game, whilst the combined probabilities or rewards are maximised. We implement our techniques in the PRISM-games tool and apply them to several case studies, including network protocols and robot navigation, showing the benefits compared to existing approaches

Raman Study of Layered Breathing Kagome Lattice Semiconductor Nb3Cl8

Niobium chloride (Nb3Cl8) is a layered 2D semiconducting material with many exotic properties including a breathing kagome lattice, a topological flat band in its band structure, and a crystal structure that undergoes a structural and magnetic phase transition at temperatures below 90 K. Despite being a remarkable material with fascinating new physics, the understanding of its phonon properties is at its infancy. In this study, we investigate the phonon dynamics of Nb3Cl8 in bulk and few layer flakes using polarized Raman spectroscopy and density functional theory (DFT) analysis to determine the material's vibrational modes, as well as their symmetrical representations and atomic displacements. We experimentally resolved 12 phonon modes, 5 of which are A1g modes while the remaining 7 are Eg modes, which is in strong agreement with our DFT calculation. Layer-dependent results suggest that the Raman peak positions are mostly insensitive to changes in layer thickness, while peak intensity and FWHM are affected. Raman measurements as a function of excitation wavelength (473-785 nm) show a significant increase of the peak intensities when using a 473 nm excitation source, suggesting a near resonant condition. Temperature-dependent Raman experiments carried out above and below the transition temperature did not show any change in the symmetries of the phonon modes, suggesting that the structural phase transition is likely from the high temperature P3m1 phase to the low-temperature R3m phase. Magneto-Raman measurements carried out at 140 and 2 K between -2 to 2 T show that the Raman modes are not magnetically coupled. Overall, our study presented here significantly advances the fundamental understanding of layered Nb3Cl8 material which can be further exploited for future applications.Comment: 18 pages, 8 figures, 1 tabl

Carbonium vs. carbenium ion-like transition state geometries for carbocation cyclization – how strain associated with bridging affects 5-exo vs. 6-endo selectivity

Quantum chemical calculations are used to explore the origins of regioselectivity for proton-, Pt(II)- and Pd(II)-promoted cyclizations of 1,5-hexadienes, 5-aminoalkenes, and allylic acetimidates. The strain associated with achieving carbonium ion-like transition state geometries is shown to be a key factor in controlling 5-exo vs. 6-endo selectivity

Spanish medical students’ attitudes and views towards Mental Health and Psychiatry: a multicentric cross-sectional study.

Objective The aim of this study is to investigate the attitudes towards mental illness and psychiatry among fifth year Spanish medical students. Methods The study included 171 students from three medical schools located in different areas of Spain: Cádiz; UCA (n= 113), Madrid; San Pablo-CEU (n=22), and Barcelona; UAB (n=36). They responded, prior to their undergraduate medical course in psychiatry, to the AMI questionnaire to measure the attitudes towards mental illness and to Balon’s adapted questionnaire to investigate their view towards psychiatry. Results The students (93.4 %) had a positive attitude towards mental illness (AMI). Attitudes towards psychiatry were fairly positive with a few negative views, specifically regarding the role of psychiatrists (items 11 and 13) and the prestige of the specialty (item 16). There were some statistically significant differences between the three medical schools in the perception of psychiatry as a medical discipline. A better attitude towards mental illness was associated with a better view of the overall merits of psychiatry. Conclusions Findings suggest that Spanish medical students do not have a negative attitude towards mental illness and they have a good perception of psychiatry, although there are still some misconceptions about this specialty. These student’s attitudes could favor an appropriate management of patients suffering from mental illness

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

Cancer cells generate protons (H) that are extruded to the extracellular medium mainly via the Na/H exchanger 1 (NHE1), which regulates intracellular pH (pHi) and cell proliferation. In primary cultures of human ascites-derived ovarian cancer cells (haOC) we assayed whether NHE1 was required for pHi modulation and cell proliferation. Human ovary expresses NHE1, which is higher in haOC and A2780 (ovarian cancer cells) compared with HOSE cells (normal ovarian cells). Basal pHi and pHi recovery (following a NHCl pulse) was higher in haOC and A2780, compared with HOSE cells. Zoniporide (NHE1 inhibitor) caused intracellular acidification and pHi recovery was independent of intracellular buffer capacity, but reduced in NHE1 knockdown A2780 cells. Zoniporide reduced the maximal proliferation capacity, cell number, thymidine incorporation, and ki67 (marker of proliferation) fluorescence in haOC cells. SLC9A1 (for NHE1) amplification associated with lower overall patient survival. In conclusion, NHE1 is expressed in human ovarian cancer where it has a pro-proliferative role. Increased NHE1 expression and activity constitute an unfavourable prognostic factor in these patients

Validation of techniques to mitigate copper surface contamination in CUORE

In this article we describe the background challenges for the CUORE experiment posed by surface contamination of inert detector materials such as copper, and present three techniques explored to mitigate these backgrounds. Using data from a dedicated test apparatus constructed to validate and compare these techniques we demonstrate that copper surface contamination levels better than 10E-07 - 10E-08 Bq/cm2 are achieved for 238U and 232Th. If these levels are reproduced in the final CUORE apparatus the projected 90% C.L. upper limit on the number of background counts in the region of interest is 0.02-0.03 counts/keV/kg/y depending on the adopted mitigation technique.Comment: 10 pages, 6 figures, 6 table

SIVA UAV: A Case Study for the EMC Analysis of Composite Air Vehicles

[EN] The increased use of carbon-fiber composites in unmanned aerial vehicles is a challenge for their EMC assessment by numerical solvers. For accurate and reliable simulations, numerical procedures should be tested not only for individual components, but also within the framework of complete systems. With this aim, this paper presents a benchmark test case based on experimental measurements coming from direct-current injection tests in the SIVA unmanned air vehicle, reproduced by a numerical finite-difference-time-domain solver that employs a new subgridding scheme to treat lossy composite thin panels. Validation was undertaken by applying the feature selective validation method, which quantifies the agreement between experimental and numerical data.This work was supported by the Projects TEC2013-48414C3-{ 1,2,3}-R, TEC2016-79214-C3-{1,2,3}-R, and TEC2015-68766-REDC (Spanish MINECO, EU FEDER), P12-TIC-1442 (J. de Andalucia, Spain), Alhambra-UGRFDTD (AIRBUS DS), and by the CSIRC alhambra.ugr.es supercomputing center.Cabello, MR.; Fernández, S.; Pous, M.; Pascual-Gil, E.; Angulo, LD.; López, P.; Riu, PJ.... (2017). SIVA UAV: A Case Study for the EMC Analysis of Composite Air Vehicles. IEEE Transactions on Electromagnetic Compatibility. 59(4):1103-1113. https://doi.org/10.1109/TEMC.2017.2648507S1103111359