Inter-domain dynamics in the chaperone SurA and multi-site binding to its outer membrane protein clients

The periplasmic chaperone SurA plays a key role in outer membrane protein (OMP) biogenesis. E. coli SurA comprises a core domain and two peptidylprolyl isomerase domains (P1 and P2), but its mechanisms of client binding and chaperone function have remained unclear. Here, we use chemical cross-linking, hydrogen-deuterium exchange mass spectrometry, single-molecule FRET and molecular dynamics simulations to map the client binding site(s) on SurA and interrogate the role of conformational dynamics in OMP recognition. We demonstrate that SurA samples an array of conformations in solution in which P2 primarily lies closer to the core/P1 domains than suggested in the SurA crystal structure. OMP binding sites are located primarily in the core domain, and OMP binding results in conformational changes between the core/P1 domains. Together, the results suggest that unfolded OMP substrates bind in a cradle formed between the SurA domains, with structural flexibility between domains assisting OMP recognition, binding and release

High Burden of Impetigo and Scabies in a Tropical Country

Scabies and impetigo are often thought of as nuisance diseases, but have the potential to cause a great deal of morbidity and even mortality if infection becomes complicated. Accurate assessments of these diseases are lacking, particularly in tropical developing countries. We performed a series of studies in infants and primary school children in Fiji, a tropical developing country in the South Pacific. Impetigo was very common: more than a quarter of school-aged children and 12% of infants had active impetigo. Scabies was also very common affecting 18% of school children and 14% of infants. The group A streptococcus was the most common infective organism followed by Staphylococcus aureus. The size of the problem has been underestimated, particularly in the Pacific. It is time for more concerted public health efforts in controlling impetigo and scabies

Cognitive behaviour therapy versus counselling intervention for anxiety in young people with high-functioning autism spectrum disorders: a pilot randomised controlled trial

The use of cognitive-behavioural therapy (CBT) as a treatment for children and adolescents with autism spectrum disorder (ASD) has been explored in a number of trials. Whilst CBT appears superior to no treatment or treatment as usual, few studies have assessed CBT against a control group receiving an alternative therapy. Our randomised controlled trial compared use of CBT against person-centred counselling for anxiety in 36 young people with ASD, ages 12–18. Outcome measures included parent- teacher- and self-reports of anxiety and social disability. Whilst each therapy produced improvements inparticipants, neither therapy was superior to the other to a significant degree on any measure. This is consistent with findings for adults

Modeling Slope Instability as Shear Rupture Propagation in a Saturated Porous Medium

When a region of intense shear in a slope is much thinner than other relevant geometric lengths, this shear failure may be approximated as localized slip, as in faulting, with strength determined by frictional properties of the sediment and effective stress normal to the failure surface. Peak and residual frictional strengths of submarine sediments indicate critical slope angles well above those of most submarine slopes—in contradiction to abundant failures. Because deformation of sediments is governed by effective stress, processes affecting pore pressures are a means of strength reduction. However, common methods of exami ning slope stability neglect dynamically variable pore pressure during failure. We examine elastic-plastic models of the capped Drucker-Prager type and derive approximate equations governing pore pressure about a slip surface when the adjacent material may deform plastically. In the process we identify an elastic-plastic hydraulic diffusivity with an evolving permeability and plastic storage term analogous to the elastic term of traditional poroelasticity. We also examine their application to a dynamically propagating subsurface rupture and find indications of downslope directivity.Earth and Planetary SciencesEngineering and Applied Science

Concurrent acute illness and comorbid conditions poorly predict antibiotic use in upper respiratory tract infections: a cross-sectional analysis

<p>Abstract</p> <p>Background</p> <p>Inappropriate antibiotic use promotes resistance. Antibiotics are generally not indicated for upper respiratory infections (URIs). Our objectives were to describe patterns of URI treatment and to identify patient and provider factors associated with antibiotic use for URIs.</p> <p>Methods</p> <p>This study was a cross-sectional analysis of medical and pharmacy claims data from the Pennsylvania Medicaid fee-for-service program database. We identified Pennsylvania Medicaid recipients with a URI office visit over a one-year period. Our outcome variable was antibiotic use within seven days after the URI visit. Study variables included URI type and presence of concurrent acute illnesses and chronic conditions. We considered the associations of each study variable with antibiotic use in a logistic regression model, stratifying by age group and adjusting for confounders.</p> <p>Results</p> <p>Among 69,936 recipients with URI, 35,786 (51.2%) received an antibiotic. In all age groups, acute sinusitis, chronic sinusitis, otitis, URI type and season were associated with antibiotic use. Except for the oldest group, physician specialty and streptococcal pharyngitis were associated with antibiotic use. History of chronic conditions was not associated with antibiotic use in any age group. In all age groups, concurrent acute illnesses and history of chronic conditions had only had fair to poor ability to distinguish patients who received an antibiotic from patients who did not.</p> <p>Conclusion</p> <p>Antibiotic prevalence for URIs was high, indicating that potentially inappropriate antibiotic utilization is occurring. Our data suggest that demographic and clinical factors are associated with antibiotic use, but additional reasons remain unexplained. Insight regarding reasons for antibiotic prescribing is needed to develop interventions to address the growing problem of antibiotic resistance.</p

CloVR: A virtual machine for automated and portable sequence analysis from the desktop using cloud computing

Next-generation sequencing technologies have decentralized sequence acquisition, increasing the demand for new bioinformatics tools that are easy to use, portable across multiple platforms, and scalable for high-throughput applications. Cloud computing platforms provide on-demand access to computing infrastructure over the Internet and can be used in combination with custom built virtual machines to distribute pre-packaged with pre-configured software. We describe the Cloud Virtual Resource, CloVR, a new desktop application for push-button automated sequence analysis that can utilize cloud computing resources. CloVR is implemented as a single portable virtual machine (VM) that provides several automated analysis pipelines for microbial genomics, including 16S, whole genome and metagenome sequence analysis. The CloVR VM runs on a personal computer, utilizes local computer resources and requires minimal installation, addressing key challenges in deploying bioinformatics workflows. In addition CloVR supports use of remote cloud computing resources to improve performance for large-scale sequence processing. In a case study, we demonstrate the use of CloVR to automatically process next-generation sequencing data on multiple cloud computing platforms. The CloVR VM and associated architecture lowers the barrier of entry for utilizing complex analysis protocols on both local single- and multi-core computers and cloud systems for high throughput data processing.https://doi.org/10.1186/1471-2105-12-35

Does smoking among friends explain apparent genetic effects on current smoking in adolescence and young adulthood?

We used data from a prospective cohort study of twins to investigate the influence of unmeasured genetic and measured and unmeasured environmental factors on the smoking behaviour of adolescents and young adults. Twins were surveyed in 1988 (aged 11–18 years), 1991, 1996 and 2004 with data from 1409, 1121, 732 and 758 pairs analysed from each survey wave, respectively. Questionnaires assessed the smoking behaviour of twins and the perceived smoking behaviour of friends and parents. Using a novel logistic regression analysis, we simultaneously modelled individual risk and excess concordance for current smoking as a function of zygosity, survey wave, parental smoking and peer smoking. Being concordant for having peers who smoked was a predictor of concordance for current smoking (P<0.001). After adjusting for peer smoking, monozygotic (MZ) pairs were no more alike than dizygotic pairs for current smoking at waves 2, 3 and 4. Genetic explanations are not needed to explain the greater concordance for current smoking among adult MZ pairs. However, if they are invoked, the role of genes may be due to indirect effects acting through the social environment. Smoking prevention efforts may benefit more by targeting social factors than attempting to identify genetic factors associated with smoking