Biophysical Features of Bacillithiol, the Glutathione Surrogate of Bacillus subtilis and other Firmicutes

Bacillithiol (BSH) is the major low-molecular-weight (LMW) thiol in many low-G+C Gram-positive bacteria (Firmicutes). Evidence now emerging suggests that BSH functions as an important LMW thiol in redox regulation and xenobiotic detoxification, analogous to what is already known for glutathione and mycothiol in other microorganisms. The biophysical properties and cellular concentrations of such LMW thiols are important determinants of their biochemical efficiency both as biochemical nucleophiles and as redox buffers. Here, BSH has been characterised and compared with other LMW thiols in terms of its thiol pKa, redox potential and thiol–disulfide exchange reactivity. Both the thiol pKa and the standard thiol redox potential of BSH are shown to be significantly lower than those of glutathione whereas the reactivities of the two compounds in thiol–disulfide reactions are comparable. The cellular concentration of BSH in Bacillus subtilis varied over different growth phases and reached up to 5 mM, which is significantly greater than previously observed from single measurements taken during mid-exponential growth. These results demonstrate that the biophysical characteristics of BSH are distinctively different from those of GSH and that its cellular concentrations can reach levels much higher than previously reported

Discovery of a missense mutation (Q222K) of the APOE gene from the Australian imaging, biomarker and lifestyle study

After age, polymorphisms of the Apolipoprotein E (APOE) gene are the biggest risk factor for the development of Alzheimer\u27s disease (AD). During our investigation to discovery biomarkers in plasma, using 2D gel electrophoresis, we found an individual with and unusual apoE isoelectric point compared to APOE ϵ2, ϵ3, and ϵ4 carriers. Whole exome sequencing of APOE from the donor confirmed a single nucleotide polymorphism (SNP) in exon 4, translating to a rare Q222K missense mutation. The apoE ϵ4 (Q222K) mutation did not form dimers or complexes observed for apoE ϵ2 ϵ3 proteins

Cryotomography of budding influenza a virus reveals filaments with diverse morphologies that mostly do not bear a genome at their distal end

Influenza viruses exhibit striking variations in particle morphology between strains. Clinical isolates of influenza A virus have been shown to produce long filamentous particles while laboratory-adapted strains are predominantly spherical. However, the role of the filamentous phenotype in the influenza virus infectious cycle remains undetermined. We used cryo-electron tomography to conduct the first three-dimensional study of filamentous virus ultrastructure in particles budding from infected cells. Filaments were often longer than 10 microns and sometimes had bulbous heads at their leading ends, some of which contained tubules we attribute to M1 while none had recognisable ribonucleoprotein (RNP) and hence genome segments. Long filaments that did not have bulbs were infrequently seen to bear an ordered complement of RNPs at their distal ends. Imaging of purified virus also revealed diverse filament morphologies; short rods (bacilliform virions) and longer filaments. Bacilliform virions contained an ordered complement of RNPs while longer filamentous particles were narrower and mostly appeared to lack this feature, but often contained fibrillar material along their entire length. The important ultrastructural differences between these diverse classes of particles raise the possibility of distinct morphogenetic pathways and functions during the infectious process

Northeastern Atlantic cold-water coral reefs and climate

U-series age patterns obtained on reef framework-forming cold-water corals collected over a nearly 6,000 km long continental margin sector, extending from off Mauritania to the south-western Barents Sea reveal strong climate influences on the geographical distribution and sustained development of these ecosystems. During glacial times densely populated cold-water coral reefs flourished in the temperate east Atlantic, where at present only scarce live coral occurrences exist. In contrast, climate warming induces a rapid northward colonization of cold-water coral reefs with the biogeographic limit advancing from ~45°N to ~70°N. Thus, we invoke here that north-south oscillations of the polar front during the past glacial-interglacial cycles and the consequent displacement of cold nutrient-rich intermediate waters and productivity drives the decline and expansion of cold-water coral ecosystems and its biogeographic limits in the northeast Atlantic

Saturable elimination of piperacillin in critically ill patients:implications for continuous infusion

The study aimed to evaluate saturation of piperacillin elimination in critically ill adult patients. Seventeen critically ill adult patients received continuous and intermittent infusion of piperacillin/tazobactam. Piperacillin plasma concentrations (n = 217) were analysed using population pharmacokinetic (PopPK) modelling. Post-hoc simulations were performed to evaluate the type I error rate associated with the study. Unseen data were used to validate the final model. The mean error (ME) and root mean square error (RMSE) were calculated as a measure of bias and imprecision, respectively. A PopPK model with parallel linear and non-linear elimination best fitted the data. The median and 95% confidence interval (CI) for the model parameters drug clearance (CL), volume of central compartment (V), volume of peripheral compartment (V-p) and intercompartmental clearance (Q) were 9 (7.69-11) L/h, 6.18 (4.93-11.2) L, 11.17 (7.26-12) L and 15.61 (12.66-23.8) L/h, respectively. The Michaelis-Menten constant (K-m) and the maximum elimination rate for Michaelis-Menten elimination (V-max) were estimated without population variability in the model to avoid overfitting and inflation of the type I error rate. The population estimates for K-m and V-max were 37.09 mg/L and 353.57 mg/h, respectively. The bias (ME) was -20.8 (95% CI -26.2 to -15.4) mg/L, whilst imprecision (RMSE) was 49.2 (95% CI 41.2-56) mg/L. In conclusion, piperacillin elimination is (partially) saturable. Moreover, the population estimate for K-m lies within the therapeutic window and therefore saturation of elimination should be accounted for when defining optimum dosing regimens for piperacillin in critically ill patients. (C) 2019 Elsevier B.V. and International Society of Chemotherapy. All rights reserved

Physical model of near-Earth asteroid (1917) Cuyo from ground-based optical and thermal-IR observations

Context: The near-Earth asteroid (1917) Cuyo was subject to radar and lightcurve observations during a close approach in 1989, and observed up until 2008. It was selected as one of our ESO Large Programme targets, aimed at observational detections of the YORP effect through long-term lightcurve monitoring and physical modelling of near-Earth asteroids. Aims: We aimed to constrain physical properties of Cuyo: shape, spin-state, and spectroscopic & thermophysical properties of the surface. Methods: We acquired photometric lightcurves of Cuyo spanning the period between 2010 and 2013, which we combined with published lightcurves from 1989-2008. Our thermal-infrared observations were obtained in 2011. Rotationally-resolved optical spectroscopy data were acquired in 2011 and combined with all available published spectra to investigate any surface material variegation. Results: We developed a convex lightcurve-inversion shape of Cuyo that suggests the presence of an equatorial ridge, typical for an evolved system close to shedding mass due to fast rotation. We determine limits of YORP strength through lightcurve-based spin-state modelling, including both negative and positive acceleration values, between -0.7x10-8 rad day-2 and 1.7x10-8 rad day-2. Thermo-physical modelling with the ATPM provides constraints on the geometric albedo, PV = 0.24 ± 0.07, the effective diameter Deff = 3.15 ± 0.08 km, the thermal inertia, 44 ±- 9 J m-2s-1/2K-1, and a roughness fraction of 0.52 ± 0.26. This enabled a YORP strength prediction of (-6.39 ± 0.96)x10-10 rad day-2. We also see evidence of surface compositional variation. Conclusions: The low value of YORP predicted by means of thermophysical analysis, consistent with the results of the lightcurve study, might be due to the self-limiting properties of rotational YORP, possibly involving movement of sub-surface and surface material. This may also be consistent with the surface compositional variation that we see. The physical model of Cuyo can be used to investigate cohesive forces as a way to explain why some targets survive rotation rates faster than the fission limit

Rubidium and potassium levels are altered in Alzheimer's disease brain and blood but not in cerebrospinal fluid

Loss of intracellular compartmentalization of potassium is a biochemical feature of Alzheimer's disease indicating a loss of membrane integrity and mitochondrial dysfunction. We examined potassium and rubidium (a biological proxy for potassium) in brain tissue, blood fractions and cerebrospinal fluid from Alzheimer's disease and healthy control subjects to investigate the diagnostic potential of these two metal ions. We found that both potassium and rubidium levels were significantly decreased across all intracellular compartments in the Alzheimer's disease brain. Serum from over 1000 participants in the Australian Imaging, Biomarkers and Lifestyle Flagship Study of Ageing (AIBL), showed minor changes according to disease state. Potassium and rubidium levels in erythrocytes and cerebrospinal fluid were not significantly different according to disease state, and rubidium was slightly decreased in Alzheimer's disease patients compared to healthy controls. Our data provides evidence that contrasts the hypothesized disruption of the blood-brain barrier in Alzheimer's disease, with the systemic decrease in cortical potassium and rubidium levels suggesting influx of ions from the blood is minimal and that the observed changes are more likely indicative of an internal energy crisis within the brain. These findings may be the basis for potential diagnostic imaging studies using radioactive potassium and rubidium tracers

Exploring the dynamics of compliance with community penalties

In this paper, we examine how compliance with community penalties has been theorized hitherto and seek to develop a new dynamic model of compliance with community penalties. This new model is developed by exploring some of the interfaces between existing criminological and socio-legal work on compliance. The first part of the paper examines the possible definitions and dimensions of compliance with community supervision. Secondly, we examine existing work on explanations of compliance with community penalties, supplementing this by drawing on recent socio-legal scholarship on private individuals’ compliance with tax regimes. In the third part of the paper, we propose a dynamic model of compliance, based on the integration of these two related analyses. Finally, we consider some of the implications of our model for policy and practice concerning community penalties, suggesting the need to move beyond approaches which, we argue, suffer from compliance myopia; that is, a short-sighted and narrowly focused view of the issues

Mutations in FRMD7, a newly identified member of the FERM family, cause X-linked idiopathic congenital nystagmus.

Idiopathic congenital nystagmus is characterized by involuntary, periodic, predominantly horizontal oscillations of both eyes. We identified 22 mutations in FRMD7 in 26 families with X-linked idiopathic congenital nystagmus. Screening of 42 singleton cases of idiopathic congenital nystagmus (28 male, 14 females) yielded three mutations (7%). We found restricted expression of FRMD7 in human embryonic brain and developing neural retina, suggesting a specific role in the control of eye movement and gaze stability