A natural histone H2A variant lacking the Bub1 phosphorylation site and regulated depletion of centromeric histone CENP-A foster evolvability in Candida albicans.

Eukaryotes have evolved elaborate mechanisms to ensure that chromosomes segregate with high fidelity during mitosis and meiosis, and yet specific aneuploidies can be adaptive during environmental stress. Here, we identify a chromatin-based system required for inducible aneuploidy in a human pathogen. Candida albicans utilizes chromosome missegregation to acquire tolerance to antifungal drugs and for nonmeiotic ploidy reduction after mating. We discovered that the ancestor of C. albicans and 2 related pathogens evolved a variant of histone 2A (H2A) that lacks the conserved phosphorylation site for kinetochore-associated Bub1 kinase, a key regulator of chromosome segregation. Using engineered strains, we show that the relative gene dosage of this variant versus canonical H2A controls the fidelity of chromosome segregation and the rate of acquisition of tolerance to antifungal drugs via aneuploidy. Furthermore, whole-genome chromatin precipitation analysis reveals that Centromere Protein A/ Centromeric Histone H3-like Protein (CENP-A/Cse4), a centromeric histone H3 variant that forms the platform of the eukaryotic kinetochore, is depleted from tetraploid-mating products relative to diploid parents and is virtually eliminated from cells exposed to aneuploidy-promoting cues. We conclude that genetically programmed and environmentally induced changes in chromatin can confer the capacity for enhanced evolvability via chromosome missegregation

Quality and Cost of Diabetes Mellitus Care in Community Health Centers in the United States

Objective To examine variations in the quality and cost of care provided to patients with diabetes mellitus by Community Health Centers (CHCs) compared to other primary care settings. Research Design and Methods We used data from the 2005–2008 Medical Expenditure Panel Survey (N = 2,108). We used two dependent variables: quality of care and ambulatory care expenditures. Our primary independent variable was whether the respondent received care in a Community Health Centers (CHCs) or not. We estimated logistic regression models to determine the probability of quality of care, and used generalized linear models with log link and gamma distribution to predict expenditures for CHC users compared to non-users of CHCs, conditional on patients with positive expenditures. Results Results showed that variations of quality between CHC users and non-CHC users were not statistically significant. Patients with diabetes mellitus who used CHCs saved payers and individuals approximately $1,656 in ambulatory care costs compared to non-users of CHCs. Conclusions These findings suggest an opportunity for policymakers to control costs for diabetes mellitus patients without having a negative impact on quality of care

Crew Exploration Vehicle Ascent Abort Coverage Analysis

An important element in the design of NASA's Crew Exploration Vehicle (CEV) is the consideration given to crew safety during various ascent phase failure scenarios. To help ensure crew safety during this critical and dynamic flight phase, the CEV requirements specify that an abort capability must be continuously available from lift-off through orbit insertion. To address this requirement, various CEV ascent abort modes are analyzed using 3-DOF (Degree Of Freedom) and 6-DOF simulations. The analysis involves an evaluation of the feasibility and survivability of each abort mode and an assessment of the abort mode coverage using the current baseline vehicle design. Factors such as abort system performance, crew load limits, thermal environments, crew recovery, and vehicle element disposal are investigated to determine if the current vehicle requirements are appropriate and achievable. Sensitivity studies and design trades are also completed so that more informed decisions can be made regarding the vehicle design. An overview of the CEV ascent abort modes is presented along with the driving requirements for abort scenarios. The results of the analysis completed as part of the requirements validation process are then discussed. Finally, the conclusions of the study are presented, and future analysis tasks are recommended

The Host Galaxy and Redshift of the Repeating Fast Radio Burst FRB 121102

The precise localization of the repeating fast radio burst (FRB 121102) has provided the first unambiguous association (chance coincidence probability $p\lesssim3\times10^{-4}$) of an FRB with an optical and persistent radio counterpart. We report on optical imaging and spectroscopy of the counterpart and find that it is an extended ($0.6^{\prime\prime}-0.8^{\prime\prime}$) object displaying prominent Balmer and [OIII] emission lines. Based on the spectrum and emission line ratios, we classify the counterpart as a low-metallicity, star-forming, $m_{r^\prime} = 25.1$ AB mag dwarf galaxy at a redshift of $z=0.19273(8)$, corresponding to a luminosity distance of 972 Mpc. From the angular size, the redshift, and luminosity, we estimate the host galaxy to have a diameter $\lesssim4$ kpc and a stellar mass of $M_*\sim4-7\times 10^{7}\,M_\odot$, assuming a mass-to-light ratio between 2 to 3$\,M_\odot\,L_\odot^{-1}$. Based on the H$\alpha$ flux, we estimate the star formation rate of the host to be $0.4\,M_\odot\,\mathrm{yr^{-1}}$ and a substantial host dispersion measure depth $\lesssim 324\,\mathrm{pc\,cm^{-3}}$. The net dispersion measure contribution of the host galaxy to FRB 121102 is likely to be lower than this value depending on geometrical factors. We show that the persistent radio source at FRB 121102's location reported by Marcote et al (2017) is offset from the galaxy's center of light by $\sim$200 mas and the host galaxy does not show optical signatures for AGN activity. If FRB 121102 is typical of the wider FRB population and if future interferometric localizations preferentially find them in dwarf galaxies with low metallicities and prominent emission lines, they would share such a preference with long gamma ray bursts and superluminous supernovae.Comment: 12 pages, 3 figures, Published in ApJ Letters. V2: Corrected mistake in author lis

N-1,2,3-triazole-isatin derivatives for cholinesterase and β-amyloid aggregation inhibition: A comprehensive bioassay study

Our goal was the evaluation of a series of N-1,2,3-triazole-isatin derivatives for multi-target activity which included cholinesterase (ChE) inhibition and β-amyloid (Aβ) peptide anti-aggregation. The compounds have shown considerable promise as butyrylcholinesterase (BuChE) inhibitors. Although the inhibition of eel acet- ylcholinesterase (eeAChE) was weak, the inhibitions against equine BuChE (eqBuChE) and human BuChE (hBuChE) were more significant with a best inhibition against eqBuChE of 0.46 μM. In some cases, these mo- lecules gave better inhibitions for hBuChE than eqBuChE. For greater insights into their mode of action, mole- cular docking studies were carried out, followed by STD-NMR validation. In addition, some of these compounds showed weak Aβ anti-aggregation activity. Hepatotoxicity studies showed that they were non-hepatoxic and neurotoxicity studies using neurite out- growth experiments led to the conclusion that these compounds are only weakly neurotoxic

Structurally optimised BODIPY derivatives for imaging of mitochondrial dysfunction in cancer and heart cells

The structural features required for mitochondrial uptake of BODIPY-based optical imaging agents have been explored. The first derivatives of this class of dyes shown to have mitochondrial membrane potential-dependent uptake in both cancer and heart cells have been developed

Telomere Length and the Risk of Cutaneous Malignant Melanoma in Melanoma-Prone Families with and without CDKN2A Mutations

Introduction: Recent evidence suggests a link between constitutional telomere length (TL) and cancer risk. Previous studies have suggested that longer telomeres were associated with an increased risk of melanoma and larger size and number of nevi. The goal of this study was to examine whether TL modified the risk of melanoma in melanoma-prone families with and without CDKN2A germline mutations. Materials and Methods We measured TL in blood DNA in 119 cutaneous malignant melanoma (CMM) cases and 208 unaffected individuals. We also genotyped 13 tagging SNPs in TERT. Results: We found that longer telomeres were associated with an increased risk of CMM (adjusted OR = 2.81, 95% CI = 1.02–7.72, P = 0.04). The association of longer TL with CMM risk was seen in CDKN2A- cases but not in CDKN2A+ cases. Among CMM cases, the presence of solar injury was associated with shorter telomeres (P = 0.002). One SNP in TERT, rs2735940, was significantly associated with TL (P = 0.002) after Bonferroni correction. Discussion Our findings suggest that TL regulation could be variable by CDKN2A mutation status, sun exposure, and pigmentation phenotype. Therefore, TL measurement alone may not be a good marker for predicting CMM risk

Co-Nanomet: Co-ordination of Nanometrology in Europe

Nanometrology is a subfield of metrology, concerned with the science of measurement at the nanoscale level. Today’s global economy depends on reliable measurements and tests, which are trusted and accepted internationally. It must provide the ability to measure in three dimensions with atomic resolution over large areas. For industrial application this must also be achieved at a suitable speed/throughput. Measurements in the nanometre range should be traceable back to internationally accepted units of measurement (e.g. of length, angle, quantity of matter, and force). This requires common, validated measurement methods, calibrated scientific instrumentation as well as qualified reference samples. In some areas, even a common vocabulary needs to be defined. A traceability chain for the required measurements in the nm range has been established in only a few special cases. A common strategy for European nanometrology has been defined, as captured herein, such that future nanometrology development in Europe may build out from our many current strengths. In this way, European nanotechnology will be supported to reach its full and most exciting potential. As a strategic guidance, this document contains a vision for European nanometrology 2020; future goals and research needs, building out from an evaluation of the status of science and technology in 2010. It incorporates concepts for the acceleration of European nanometrology, in support of the effective commercial exploitation of emerging nanotechnologies. The field of nanotechnology covers a breadth of disciplines, each of which has specific and varying metrological needs. To this end, a set of four core technology fields or priority themes (Engineered Nanoparticles, Nanobiotechnology, Thin Films and Structured Surfaces and Modelling & Simulation) are the focus of this review. Each represents an area within which rapid scientific development during the last decade has seen corresponding growth in or towards commercial exploitation routes. This document was compiled under the European Commission Framework Programme 7 project, Co-Nanomet. It has drawn together input from industry, research institutes, (national) metrology institutes, regulatory and standardisation bodies across Europe. Through the common work of the partners and all those interested parties who have contributed, it represents a significant collaborative European effort in this important field. In the next decade, nanotechnology can be expected to approach maturity, as a major enabling technological discipline with widespread application. This document provides a guide to the many bodies across Europe in their activities or responsibilities in the field of nanotechnology and related measurement requirements. It will support the commercial exploitation of nanotechnology, as it transitions through this next exciting decade