Analysis of the hydration water around bovine serum albumin using terahertz coherent synchrotron radiation.

Terahertz spectroscopy was used to study the absorption of bovine serum albumin (BSA) in water. The Diamond Light Source operating in a low alpha mode generated coherent synchrotron radiation that covered a useable spectral bandwidth of 0.3-3.3 THz (10-110 cm(-1)). As the BSA concentration was raised, there was a nonlinear change in absorption inconsistent with Beer's law. At low BSA concentrations (0-1 mM), the absorption remained constant or rose slightly. Above a concentration of 1 mM BSA, a steady decrease in absorption was observed, which was followed by a plateau that started at 2.5 mM. Using a overlapping hydration layer model, the hydration layer was estimated to extend 15 Å from the protein. Calculation of the corrected absorption coefficient (αcorr) for the water around BSA by subtracting the excluded volume of the protein provides an alternative approach to studying the hydration layer that provides evidence for complexity in the population of water around BSA.This is the accepted version of an article first published in The Journal of Physical Chemistry A. The version of record is available from ACS Publications at http://pubs.acs.org/doi/abs/10.1021/jp407410

Three Stages of Lysozyme Thermal Stabilization by High and Medium Charge Density Anions

Addition of high and medium charge density anions (phosphate, sulfate, and chloride) to lysozyme in pure water demonstrates three stages for stabilization of the protein structure. The first two stages have a minor impact on lysozyme stability and are probably associated with direct interaction of the ions with charged and partial charges on the protein’s surface. There is a clear transition between the second and third stages; in the case of sodium chloride, disodium sulfate and disodium hydrogen phosphate this is at 550, 210, and 120 mM, respectively. Stabilization of lysozyme can be explained by the free energy required to hydrate the protein as it unfolds. At low ion concentrations, the protein’s hydration layer is at equilibrium with the bulk water. After the transition, bulk water is depleted and the protein is competing for water with the ions. With competition for water between the protein and the ions at higher salt concentrations, the free energy required to hydrate the interior of the protein rises and it is this that stabilizes the protein structure

STEP: Satellite Test of the Equivalence Principle. Report on the phase A study

During Phase A, the STEP Study Team identified three types of experiments that can be accommodated on the STEP satellite within the mission constraints and whose performance is orders of magnitude better than any present or planned future experiment of the same kind on the ground. The scientific objectives of the STEP mission are to: test the Equivalence Principle to one part in 10(exp 17), six orders of magnitude better than has been achieved on the ground; search for a new interaction between quantum-mechanical spin and ordinary matter with a sensitivity of the mass-spin coupling constant g(sub p)g(sub s) = 6 x 10(exp -34) at a range of 1 mm, which represents a seven order-of-magnitude improvement over comparable ground-based measurements; and determine the constant of gravity G with a precision of one part in 10(exp 6) and to test the validity of the inverse square law with the same precision, both two orders of magnitude better than has been achieved on the ground

Dynamical scaling and isotope effect in temporal evolution of mesoscopic structure during hydration of cement

The evolution of mesoscopic structure for cement-water mixtures turning into colloidal gels remains far from being understood. Recent neutron scattering investigations (Phys. Rev. Lett. 93, 255704 (2004); Phys. Rev. B. 72, 224208 (2005); Phys. Rev. B. 82, 064203 (2010)),, reveal the role of hydrogen bond in temporal evolution of the mesoscopic structure during hydration of cement which is the most consumed synthetic material. The present neutron scattering investigation on hydration of cement with a mixture of light and heavy water points to incomprehensibility of the temporal evolution of the mesoscopic structure in terms of earlier observations on hydration with pure light or heavy water. Unlike in the case of hydration with light water, disagreement has been observed with the hypothesis of dynamical scaling for hydration of cement with a mixture of the two types of water. The dynamics of evolution of the mesoscopic structure has been observed to be nonlinear in regard to the composition of hydration medium.Comment: 16 Pages, 5 Figure

Leading Disability Research and Workforce Development: A Western Sydney Collaboration

In this White Paper we draw attention to the potential of excellence in research and workforce development as a means, in part, to foster greater inclusion and participation for people with disability. We present a critique of the current limitations in research and workforce development and highlight the urgency to address such shortcomings to realise inclusion within our communities. We demonstrate that Western Sydney University is well positioned as a leading institution to address many of these concerns. This White paper showcases the innovative work of our team, and calls for seven key actions, to advance inclusion and participation for people and communities in Greater Western Sydney, Australia, and beyond

Football fans in training: the development and optimization of an intervention delivered through professional sports clubs to help men lose weight, become more active and adopt healthier eating habits

<p>Background: The prevalence of obesity in men is rising, but they are less likely than women to engage in existing weight management programmes. The potential of professional sports club settings to engage men in health promotion activities is being increasingly recognised. This paper describes the development and optimization of the Football Fans in Training (FFIT) programme, which aims to help overweight men (many of them football supporters) lose weight through becoming more active and adopting healthier eating habits.</p> <p>Methods: The MRC Framework for the design and evaluation of complex interventions was used to guide programme development in two phases. In Phase 1, a multidisciplinary working group developed the pilot programme (p-FFIT) and used a scoping review to summarize previous research and identify the target population. Phase 2 involved a process evaluation of p-FFIT in 11 Scottish Premier League (SPL) clubs. Participant and coach feedback, focus group discussions and interviews explored the utility/acceptability of programme components and suggestions for changes. Programme session observations identified examples of good practice and problems/issues with delivery. Together, these findings informed redevelopment of the optimized programme (FFIT), whose components were mapped onto specific behaviour change techniques using an evidence-based taxonomy.</p> <p>Results: p-FFIT comprised 12, weekly, gender-sensitised, group-based weight management classroom and ‘pitch-side’ physical activity sessions. These in-stadia sessions were complemented by an incremental, pedometer-based walking programme. p-FFIT was targeted at men aged 35-65 years with body mass index ≥ 27 kg/m2. Phase 2 demonstrated that participants in p-FFIT were enthusiastic about both the classroom and physical activity components, and valued the camaraderie and peer-support offered by the programme. Coaches appreciated the simplicity of the key healthy eating and physical activity messages. Suggestions for improvements that were incorporated into the optimized FFIT programme included: more varied in-stadia physical activity with football-related components; post-programme weight management support (emails and a reunion session); and additional training for coaches in SMART goal setting and the pedometer-based walking programme.</p> <p>Conclusions: The Football Fans in Training programme is highly acceptable to participants and SPL coaches, and is appropriate for evaluation in a randomised controlled trial.</p&gt

Integrating exome sequencing into a diagnostic pathway for epileptic encephalopathy: Evidence of clinical utility and cost effectiveness

© 2017 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. Background: Epileptic encephalopathies are a devastating group of neurological conditions in which etiological diagnosis can alter management and clinical outcome. Exome sequencing and gene panel testing can improve diagnostic yield but there is no cost-effectiveness analysis of their use or consensus on how to best integrate these tests into clinical diagnostic pathways. Methods: We conducted a retrospective cost-effectiveness study comparing trio exome sequencing with a standard diagnostic approach, for a well-phenotyped cohort of 32 patients with epileptic encephalopathy, who remained undiagnosed after “first-tier” testing. Sensitivity analysis was included with a range of commercial exome and multigene panels. Results: The diagnostic yield was higher for the exome sequencing (16/32; 50%) than the standard arm (2/32; 6.2%). The trio exome sequencing pathway was cost-effective compared to the standard diagnostic pathway with a cost saving of AU$5,236 (95$2,482; $9,784) per additional diagnosis; the standard pathway cost approximately 10 times more per diagnosis. Sensitivity analysis demonstrated that the majority of commercial exome sequencing and multigene panels studied were also cost-effective. The clinical utility of all diagnoses was reported. Conclusion: Our study supports the integration of exome sequencing and gene panel testing into the diagnostic pathway for epileptic encephalopathy, both in terms of cost effectiveness and clinical utility. We propose a diagnostic pathway that integrates initial rapid screening for treatable causes and comprehensive genomic screening. This study has important implications for health policy and public funding for epileptic encephalopathy and other neurological conditions

Static and Dynamic Lung Volumes in Swimmers and Their Ventilatory Response to Maximal Exercise

Purpose While the static and dynamic lung volumes of active swimmers is often greater than the predicted volume of similarly active non-swimmers, little is known if their ventilatory response to exercise is also different. Methods Three groups of anthropometrically matched male adults were recruited, daily active swimmers (n = 15), daily active in fields sport (Rugby and Football) (n = 15), and recreationally active (n = 15). Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), and maximal voluntary ventilation (MVV) was measured before and after exercise to volitional exhaustion. Results Swimmers had significantly larger FVC (6.2 ± 0.6 l, 109 ± 9% pred) than the other groups (5.6 ± 0.5 l, 106 ± 13% pred, 5.5 ± 0.8, 99% pred, the sportsmen and recreational groups, respectively). FEV1 and MVV were not different. While at peak exercise, all groups reached their ventilatory reserve (around 20%), the swimmers had a greater minute ventilation rate than the recreational group (146 ± 19 vs 120 ± 87 l/min), delivering this volume by breathing deeper and slower. Conclusions The swimmers utilised their larger static volumes (FVC) differently during exercise by meeting their ventilation volume through long and deep breaths

Functional characterisation of the amyotrophic lateral sclerosis risk locus GPX3/TNIP1

Background: Amyotrophic lateral sclerosis (ALS) is a complex, late-onset, neurodegenerative disease with a genetic contribution to disease liability. Genome-wide association studies (GWAS) have identified ten risk loci to date, including the TNIP1/GPX3 locus on chromosome five. Given association analysis data alone cannot determine the most plausible risk gene for this locus, we undertook a comprehensive suite of in silico, in vivo and in vitro studies to address this. // Methods: The Functional Mapping and Annotation (FUMA) pipeline and five tools (conditional and joint analysis (GCTA-COJO), Stratified Linkage Disequilibrium Score Regression (S-LDSC), Polygenic Priority Scoring (PoPS), Summary-based Mendelian Randomisation (SMR-HEIDI) and transcriptome-wide association study (TWAS) analyses) were used to perform bioinformatic integration of GWAS data (Ncases = 20,806, Ncontrols = 59,804) with ‘omics reference datasets including the blood (eQTLgen consortium N = 31,684) and brain (N = 2581). This was followed up by specific expression studies in ALS case-control cohorts (microarray Ntotal = 942, protein Ntotal = 300) and gene knockdown (KD) studies of human neuronal iPSC cells and zebrafish-morpholinos (MO). // Results: SMR analyses implicated both TNIP1 and GPX3 (p < 1.15 × 10−6), but there was no simple SNP/expression relationship. Integrating multiple datasets using PoPS supported GPX3 but not TNIP1. In vivo expression analyses from blood in ALS cases identified that lower GPX3 expression correlated with a more progressed disease (ALS functional rating score, p = 5.5 × 10−3, adjusted R2 = 0.042, Beffect = 27.4 ± 13.3 ng/ml/ALSFRS unit) with microarray and protein data suggesting lower expression with risk allele (recessive model p = 0.06, p = 0.02 respectively). Validation in vivo indicated gpx3 KD caused significant motor deficits in zebrafish-MO (mean difference vs. control ± 95% CI, vs. control, swim distance = 112 ± 28 mm, time = 1.29 ± 0.59 s, speed = 32.0 ± 2.53 mm/s, respectively, p for all < 0.0001), which were rescued with gpx3 expression, with no phenotype identified with tnip1 KD or gpx3 overexpression. // Conclusions: These results support GPX3 as a lead ALS risk gene in this locus, with more data needed to confirm/reject a role for TNIP1. This has implications for understanding disease mechanisms (GPX3 acts in the same pathway as SOD1, a well-established ALS-associated gene) and identifying new therapeutic approaches. Few previous examples of in-depth investigations of risk loci in ALS exist and a similar approach could be applied to investigate future expected GWAS findings