Morphological development and cytochrome c oxidase activity in Streptomyces lividans are dependent on the action of a copper bound Sco protein

Copper has an important role in the life cycle of many streptomycetes, stimulating the developmental switch between vegetative mycelium and aerial hyphae concomitant with the production of antibiotics. In streptomycetes, a gene encoding for a putative Sco-like protein has been identified and is part of an operon that contains two other genes predicted to handle cellular copper. We report on the Sco-like protein from Streptomyces lividans (Sco Sl ) and present a series of experiments that firmly establish a role for Sco Sl as a copper metallochaperone as opposed to a role as a thiol-disulphide reductase that has been assigned to other bacterial Sco proteins. Under low copper concentrations, a Δ sco mutant in S. lividans displays two phenotypes; the development switch between vegetative mycelium and aerial hyphae stalls and cytochrome c oxidase (CcO) activity is significantly decreased. At elevated copper levels, the development and CcO activity in the Δ sco mutant are restored to wild-type levels and are thus independent of Sco Sl . A CcO knockout reveals that morphological development is independent of CcO activity leading us to suggest that Sco Sl has at least two targets in S. lividans . We establish that one Sco Sl target is the dinuclear Cu A domain of CcO and it is the cupric form of Sco Sl that is functionally active. The mechanism of cupric ion capture by Sco Sl has been investigated, and an important role for a conserved His residue is identified. </jats:p

Multi-Stage 20-m Shuttle Run Fitness Test, Maximal Oxygen Uptake and Velocity at Maximal Oxygen Uptake.

The multi-stage 20-m shuttle run fitness test (20mMSFT) is a popular field test which is widely used to measure aerobic fitness by predicting maximum oxygen uptake (VO2max) and performance. However, the velocity at which VO2max occurs (vVO2max) is a better indicator of performance than VO2max, and can be used to explain inter-individual differences in performance that VO2max cannot. It has been reported as a better predictor for running performance and it can be used to monitor athletes' training for predicting optimal training intensity. This study investigated the validity and suitability of predicting VO2max and vVO2max of adult subjects on the basis of the performance of the 20mMST. Forty eight (25 male and 23 female) physical education students performed, in random order, a laboratory based continuous horizontal treadmill test to determine VO2max, vVO2max and a 20mMST, with an interval of 3 days between each test. The results revealed significant correlations between the number of shuttles in the 20mMSFT and directly determined VO2max (r = 0.87, p<0.05) and vVO2max (r = 0.93, p<0.05). The equation for prediction of VO2max was y = 0.0276x + 27.504, whereas for vVO2max it was y = 0.0937x + 6.890. It can be concluded that the 20mMSFT can accurately predict VO2max and vVO2max and this field test can provide useful information regarding aerobic fitness of adults. The predicted vVO2max can be used in monitoring athletes, especially in determining optimal training intensity

Solving the Boltzmann equation on GPU’s

This paper was presented at the 2nd Micro and Nano Flows Conference (MNF2009), which was held at Brunel University, West London, UK. The conference was organised by Brunel University and supported by the Institution of Mechanical Engineers, IPEM, the Italian Union of Thermofluid dynamics, the Process Intensification Network, HEXAG - the Heat Exchange Action Group and the Institute of Mathematics and its Applications.We present algorithms specifically tailored for solving kinetic equations onto graphics processing units. Unlike particle methods, the proposed methods of solution are ideally suited for solving the unsteady low speed flows which typically occur inMEMS containing oscillating components. The efficiency of the algorithms is demonstrated by solving the two-dimensional low Mach number driven cavity flow of a monatomic gas. Computational results show that it is possible to cut down the computing time of the sequential codes up to two order of magnitudes. The algorithms can easily be extended to three-dimensional flows and to non-equilibrium flows of mixtures

Porometry, porosimetry, image analysis and void network modelling in the study of the pore-level properties of filters

We present fundamental and quantitative comparisons between the techniques of porometry (or flow permporometry), porosimetry, image analysis and void network modelling for seven types of filter, chosen to encompass the range of simple to complex void structure. They were metal, cellulose and glass fibre macro- and meso-porous filters of various types. The comparisons allow a general re-appraisal of the limitations of each technique for measuring void structures. Porometry is shown to give unrealistically narrow void size distributions, but the correct filtration characteristic when calibrated. Shielded mercury porosimetry can give the quaternary (sample-level anisotropic) characteristics of the void structure. The first derivative of a mercury porosimetry intrusion curve is shown to underestimate the large number of voids, but this error can be largely corrected by the use of a void network model. The model was also used to simulate the full filtration characteristic of each sample, which agreed with the manufacturer's filtration ratings. The model was validated through its correct a priori simulation of absolute gas permeabilities for track etch, cellulose nitrate and sintered powder filters. © 2011 Elsevier Ltd

Use and effectiveness of dapagliflozin in routine clinical practice. An Italian multicenter retrospective study

In randomized controlled trials (RCTs), sodium-glucose co-transporter-2 (SGLT2) inhibitors have been shown to confer glycaemic and extra-glycaemic benefits. The DARWIN-T2D (DApagliflozin Real World evIdeNce in Type 2 Diabetes) study was a multicentre retrospective study designed to evaluate the baseline characteristics of patients receiving dapagliflozin vs those receiving selected comparators (dipeptidyl peptidase-4 inhibitors, gliclazide, or glucagon-like peptide-1 receptor agonists), and drug effectiveness in routine clinical practice. From a population of 281 217, the analysis included 17 285 patients initiating dapagliflozin or comparator glucose-lowering medications (GLMs), 6751 of whom had a follow-up examination. At baseline, participants starting dapagliflozin were younger, had a longer disease duration, higher glycated haemoglobin (HbA1c) concentration, and a more complex history of previous GLM use, but the clinical profile of patients receiving dapagliflozin changed during the study period. Dapagliflozin reduced HbA1c by 0.7%, body weight by 2.7 kg, and systolic blood pressure by 3.0 mm Hg. Effects of comparator GLMs were also within the expected range, based on RCTs. This real-world study shows an initial channelling of dapagliflozin to difficult-to-treat patients. Nonetheless, dapagliflozin provided significant benefits with regard to glucose control, body weight and blood pressure that were in line with findings from RCTs

Immune compromise in HIV-1/HTLV-1 coinfection with paradoxical resolution of CD4 lymphocytosis during antiretroviral therapy: a case report

Human immunodeficiency virus type-1 (HIV-1) and human T lymphotropic virus type-1 (HTLV-1) infections have complex effects on adaptive immunity, with specific tropism for, but contrasting effects on, CD4 T lymphocytes: depletion with HIV-1, proliferation with HTLV-1. Impaired T lymphocyte function occurs early in HIV-1 infection but opportunistic infections (OIs) rarely occur in the absence of CD4 lymphopenia. In the unusual case where a HIV-1 infected individual with a high CD4 count presents with recurrent OIs, a clinician is faced with the possibility of a second underlying comorbidity. We present a case of pseudo-adult T cell leukemia/lymphoma (ATLL) in HIV-1/HTLV-1 coinfection where the individual fulfilled Shimoyama criteria for chronic ATLL and had pulmonary Mycobacterium kansasii, despite a high CD4 lymphocyte count. However, there was no evidence of clonal T-cell proliferation by T-cell receptor gene rearrangement studies nor of monoclonal HTLV-1 integration by high-throughput sequencing. Mutually beneficial interplay between HIV-1 and HTLV-1, maintaining high level HIV-1 and HTLV-1 viremia and proliferation of poorly functional CD4 cells despite chronicity of infection is a postulated mechanism. Despite good microbiological response to antimycobacterial therapy, the patient remained systemically unwell with refractory anemia. Subsequent initiation of combined antiretroviral therapy led to paradoxical resolution of CD4 T lymphocytosis as well as HIV-1 viral suppression and decreased HTLV-1 proviral load. This is proposed to be the result of attenuation of immune activation post-HIV virological control. This case illustrates the importance of screening for HTLV-1 in HIV-1 patients with appropriate clinical presentation and epidemiological risk factors and explores mechanisms for the complex interactions on HIV-1/HTLV-1 adaptive immunity

SIRT1 Activity Is Linked to Its Brain Region-Specific Phosphorylation and Is Impaired in Huntington’s Disease Mice

Huntingtons disease (HD) is a neurodegenerative disorder for which there are no disease-modifying treatments. SIRT1 is a NAD+-dependent protein deacetylase that is implicated in maintaining neuronal health during development, differentiation and ageing. Previous studies suggested that the modulation of SIRT1 activity is neuroprotective in HD mouse models, however, the mechanisms controlling SIRT1 activity are unknown. We have identified a striatum-specific phosphorylation-dependent regulatory mechanism of SIRT1 induction under normal physiological conditions, which is impaired in HD. We demonstrate that SIRT1 activity is down-regulated in the brains of two complementary HD mouse models, which correlated with altered SIRT1 phosphorylation levels. This SIRT1 impairment could not be rescued by the ablation of DBC1, a negative regulator of SIRT1, but was linked to changes in the sub-cellular distribution of AMPK-α1, a positive regulator of SIRT1 function. This work provides insights into the regulation of SIRT1 activity with the potential for the development of novel therapeutic strategies

Entropies, volumes, and Einstein metrics

We survey the definitions and some important properties of several asymptotic invariants of smooth manifolds, and discuss some open questions related to them. We prove that the (non-)vanishing of the minimal volume is a differentiable property, which is not invariant under homeomorphisms. We also formulate an obstruction to the existence of Einstein metrics on four-manifolds involving the volume entropy. This generalizes both the Gromov--Hitchin--Thorpe inequality and Sambusetti's obstruction.Comment: This is a substantial revision and expansion of the 2004 preprint, which I prepared in spring of 2010 and which has since been published. The version here is essentially the published one, minus the problems introduced by Springer productio

Shoulder posture and median nerve sliding

Background: Patients with upper limb pain often have a slumped sitting position and poorshoulder posture. Pain could be due to poor posture causing mechanical changes (stretch; localpressure) that in turn affect the function of major limb nerves (e.g. median nerve). This studyexamines (1) whether the individual components of slumped sitting (forward head position, trunkflexion and shoulder protraction) cause median nerve stretch and (2) whether shoulderprotraction restricts normal nerve movements.Methods: Longitudinal nerve movement was measured using frame-by-frame cross-correlationanalysis from high frequency ultrasound images during individual components of slumped sitting.The effects of protraction on nerve movement through the shoulder region were investigated byexamining nerve movement in the arm in response to contralateral neck side flexion.Results: Neither moving the head forward or trunk flexion caused significant movement of themedian nerve. In contrast, 4.3 mm of movement, adding 0.7% strain, occurred in the forearm duringshoulder protraction. A delay in movement at the start of protraction and straightening of thenerve trunk provided evidence of unloading with the shoulder flexed and elbow extended and thescapulothoracic joint in neutral. There was a 60% reduction in nerve movement in the arm duringcontralateral neck side flexion when the shoulder was protracted compared to scapulothoracicneutral.Conclusion: Slumped sitting is unlikely to increase nerve strain sufficient to cause changes tonerve function. However, shoulder protraction may place the median nerve at risk of injury, sincenerve movement is reduced through the shoulder region when the shoulder is protracted andother joints are moved. Both altered nerve dynamics in response to moving other joints and localchanges to blood supply may adversely affect nerve function and increase the risk of developingupper quadrant pain