Experimental Pressure Distributions over Wing Tips at Mach Number 1.9 I : Wing Tip with Subsonic Leading Edge

An investigation was conducted at a Mach number of 1.91 to determine spanwise pressure distribution over a wing tip in a region influenced by a sharp subsonic leading edge swept back at 70 degrees. Except for pressure distribution on the top surface in the immediate vicinity of the subsonic leading edge, the maximum difference between linearized theory and experimental data was 2 1/2 percent (of free-stream dynamic pressure) for angles of attack up to 4 degrees and 7 percent for angles of attack up to 8 degrees. Pressures on the top surface nearest the subsonic edge indicated local expansions beyond values predicted by linearized theory

An antibody that prevents serpin polymerisation acts by inducing a novel allosteric behavior

Serpins are important regulators of proteolytic pathways with an antiprotease activity that involves a conformational transition from a metastable to a hyperstable state. Certain mutations permit the transition to occur in the absence of a protease; when associated with an intermolecular interaction, this yields linear polymers of hyperstable serpin molecules, which accumulate at the site of synthesis. This is the basis of many pathologies termed the serpinopathies. We have previously identified a monoclonal antibody (mAb4B12) that, in single-chain form, blocks α1-Antitrypsin (α1-AT) polymerisation in cells. Here, we describe the structural basis for this activity. The mAb4B12 epitope was found to encompass residues Glu32, Glu39 and His43 on helix A and Leu306 on helix I. This is not a region typically associated with the serpin mechanism of conformational change, and correspondingly the epitope was present in all tested structural forms of the protein. Antibody binding rendered β-sheet A - on the opposite face of the molecule - more liable to adopt an 'open' state, mediated by changes distal to the breach region and proximal to helix F. The allosteric propagation of induced changes through the molecule was evidenced by an increased rate of peptide incorporation and destabilisation of a preformed serpin-enzyme complex following mAb4B12 binding. These data suggest that prematurely shifting the β-sheet A equilibrium towards the 'open' state out of sequence with other changes suppresses polymer formation. This work identifies a region potentially exploitable for a rational design of ligands that is able to dynamically influence α1-AT polymerisation

The relationship between elevation roughness and tornado activity: A spatial statistical model fit to data from the central great plains

The statistical relationship between elevation roughness and tornado activity is quantified using a spatial model that controls for the effect of population on the availability of reports. Across a large portion of the central Great Plains the model shows that areas with uniform elevation tend to have more tornadoes on average than areas with variable elevation. The effect amounts to a 2.3% [(1.6%, 3.0%) = 95% credible interval] increase in the rate of a tornado occurrence per meter of decrease in elevation roughness, defined as the highest minus the lowest elevation locally. The effect remains unchanged if the model is fit to the data starting with the year 1995. The effect strengthens for the set of intense tornadoes and is stronger using an alternative definition of roughness. The elevation-roughness effect appears to be strongest over Kansas, but it is statistically significant over a broad domain that extends from Texas to South Dakota. The research is important for developing a local climatological description of tornado occurrence rates across the tornado-prone region of the Great Plains

Glycans modify mesenchymal stem cell differentiation to impact on the function of resulting osteoblasts

Glycans are inherently heterogeneous, yet glycosylation is essential in eukaryotes, and glycans show characteristic cell type-dependent distributions. By using an immortalized human mesenchymal stromal cell (MSC) line model, we show that both N- and O-glycan processing in the Golgi functionally modulates early steps of osteogenic differentiation. We found that inhibiting O-glycan processing in the Golgi prior to the start of osteogenesis inhibited the mineralization capacity of the formed osteoblasts 3 weeks later. In contrast, inhibition of N-glycan processing in MSCs altered differentiation to enhance the mineralization capacity of the osteoblasts. The effect of N-glycans on MSC differentiation was mediated by the phosphoinositide-3-kinase (PI3K)/Akt pathway owing to reduced Akt phosphorylation. Interestingly, by inhibiting PI3K during the first 2 days of osteogenesis, we were able to phenocopy the effect of inhibiting N-glycan processing. Thus, glycan processing provides another layer of regulation that can modulate the functional outcome of differentiation. Glycan processing can thereby offer a novel set of targets for many therapeutically attractive processes

Evolutionary insights of Bean common mosaic necrosis virus and Cowpea aphid-borne mosaic virus

Plant viral diseases are one of the major limitations in legume production within sub-Saharan Africa (SSA), as they account for up to 100% in production losses within smallholder farms. In this study, field surveys were conducted in the western highlands of Kenya with viral symptomatic leaf samples collected. Subsequently, next-generation sequencing was carried out to gain insights into the molecular evolution and evolutionary relationships of Bean common mosaic necrosis virus (BCMNV) and Cowpea aphid-borne mosaic virus (CABMV) present within symptomatic common bean and cowpea. Eleven near-complete genomes of BCMNV and two for CABMV were obtained from western Kenya. Bayesian phylogenomic analysis and tests for differential selection pressure within sites and across tree branches of the viral genomes were carried out. Three well–supported clades in BCMNV and one supported clade for CABMNV were resolved and in agreement with individual gene trees. Selection pressure analysis within sites and across phylogenetic branches suggested both viruses were evolving independently, but under strong purifying selection, with a slow evolutionary rate. These findings provide valuable insights on the evolution of BCMNV and CABMV genomes and their relationship to other viral genomes globally. The results will contribute greatly to the knowledge gap involving the phylogenomic relationship of these viruses, particularly for CABMV, for which there are few genome sequences available, and inform the current breeding efforts towards resistance for BCMNV and CABMV

Percutaneous injuries among dental professionals in Washington State

BACKGROUND: Percutaneous exposure incidents facilitate transmission of bloodborne pathogens such as human immunodeficiency virus (HIV), hepatitis C virus (HCV) and hepatitis B virus (HBV). This study was conducted to identify the circumstances and equipment related to percutaneous injuries among dental professionals. METHODS: We used workers' compensation claims submitted to the Department of Labor and Industries State Fund during a 7-year period (1995 through 2001) in Washington State for this study. We used the statement submitted by the injured worker on the workers' compensation claim form to determine the circumstances surrounding the injury including the type of activity and device involved. RESULTS: Of a total of 4,695 accepted State Fund percutaneous injury claims by health care workers (HCWs), 924 (20%) were submitted by dental professionals. Out of 924 percutaneous injuries reported by dental professionals 894 (97%) were among dental health care workers in non-hospital settings, including dentists (66, 7%), dental hygienists (61, 18%) and dental assistants (667, 75%). The majority of those reporting were females (638, 71%). Most (781, 87%) of the injuries involved syringes, dental instruments (77, 9%), and suture needles (23%). A large proportion (90%) of injuries occurred in offices and clinics of dentists, while remainder occurred in offices of clinics and of doctors of medicine (9%), and a few in specialty outpatient facilities (1%). Of the 894 dental health care workers with percutaneous injuries, there was evidence of HBV in 6 persons, HCV in 30 persons, HIV in 3 persons and both HBV and HVC (n = 2) exposure. CONCLUSION: Out of hospital percutaneous injuries are a substantial risk to dental health professionals in Washington State. Improved work practices and safer devices are needed to address this risk

The Newcastle 85+ study: biological, clinical and psychosocial factors associated with healthy ageing: study protocol

<p>Abstract</p> <p>Background</p> <p>The UK, like other developed countries, is experiencing a marked change in the age structure of its population characterised by increasing life expectancy and continuing growth in the older fraction of the population. There is remarkably little up-to-date information about the health of the <it>oldest old </it>(over 85 years), demographically the fastest growing section of the population. There is a need, from both a policy and scientific perspective, to describe in detail the health status of this population and the factors that influence individual health trajectories. For a very large proportion of medical conditions, age is the single largest risk factor. Gaining new knowledge about why aged cells and tissues are more vulnerable to pathology is likely to catalyse radical new insights and opportunities to intervene. The aims of the Newcastle 85+ Study are to expose the spectrum of health within an inception cohort of 800 85 year-olds; to examine health trajectories and outcomes as the cohort ages and their associations with underlying biological, medical and social factors; and to advance understanding of the biological nature of ageing.</p> <p>Methods</p> <p>A cohort of 800 85 year olds from Newcastle and North Tyneside will be recruited at baseline and followed until the last participant has died. Eligible individuals will be <it>all </it>those who turn 85 during the year 2006 (i.e. born in 1921) and who are registered with a Newcastle or North Tyneside general practice. Participants will be visited in their current residence (own home or institution) by a research nurse at baseline, 18 months and 36 months. The assessment protocol entails a detailed multi-dimensional health assessment together with review of general practice medical records. Participants will be flagged with the NHS Central Register to provide details of the date and cause of death.</p> <p>Discussion</p> <p>The Newcastle 85+ Study will address key questions about health and health-maintenance in the 85+ population, with a particular focus on quantitative assessment of factors underlying variability in health, and on the relationships between health, nutrition and biological markers of the fundamental processes of ageing.</p

Development of a small molecule that corrects misfolding and increases secretion of Z α1 -antitrypsin.

Severe α1 -antitrypsin deficiency results from the Z allele (Glu342Lys) that causes the accumulation of homopolymers of mutant α1 -antitrypsin within the endoplasmic reticulum of hepatocytes in association with liver disease. We have used a DNA-encoded chemical library to undertake a high-throughput screen to identify small molecules that bind to, and stabilise Z α1 -antitrypsin. The lead compound blocks Z α1 -antitrypsin polymerisation in vitro, reduces intracellular polymerisation and increases the secretion of Z α1 -antitrypsin threefold in an iPSC model of disease. Crystallographic and biophysical analyses demonstrate that GSK716 and related molecules bind to a cryptic binding pocket, negate the local effects of the Z mutation and stabilise the bound state against progression along the polymerisation pathway. Oral dosing of transgenic mice at 100 mg/kg three times a day for 20 days increased the secretion of Z α1 -antitrypsin into the plasma by sevenfold. There was no observable clearance of hepatic inclusions with respect to controls over the same time period. This study provides proof of principle that "mutation ameliorating" small molecules can block the aberrant polymerisation that underlies Z α1 -antitrypsin deficiency