Prediction of Type III Secretion Signals in Genomes of Gram-Negative Bacteria

Background: Pathogenic bacteria infecting both animals as well as plants use various mechanisms to transport virulence factors across their cell membranes and channel these proteins into the infected host cell. The type III secretion system represents such a mechanism. Proteins transported via this pathway (‘‘effector proteins’’) have to be distinguished from all other proteins that are not exported from the bacterial cell. Although a special targeting signal at the N-terminal end of effector proteins has been proposed in literature its exact characteristics remain unknown. Methodology/Principal Findings: In this study, we demonstrate that the signals encoded in the sequences of type III secretion system effectors can be consistently recognized and predicted by machine learning techniques. Known protein effectors were compiled from the literature and sequence databases, and served as training data for artificial neural networks and support vector machine classifiers. Common sequence features were most pronounced in the first 30 amino acids of the effector sequences. Classification accuracy yielded a cross-validated Matthews correlation of 0.63 and allowed for genome-wide prediction of potential type III secretion system effectors in 705 proteobacterial genomes (12% predicted candidates protein), their chromosomes (11%) and plasmids (13%), as well as 213 Firmicute genomes (7%). Conclusions/Significance: We present a signal prediction method together with comprehensive survey of potential type III secretion system effectors extracted from 918 published bacterial genomes. Our study demonstrates that the analyzed signal features are common across a wide range of species, and provides a substantial basis for the identification of exported pathogenic proteins as targets for future therapeutic intervention. The prediction software is publicly accessible from our web server ( www.modlab.org )

An Examination of the Benefits, Preferred Training Delivery Modes, and Preferred Topics of 4-H Youth Development Volunteers

Training is a critical component of any successful volunteer management system. The evaluation reported here examined the benefits of the 4-H Youth Development Volunteer training as well as ranks preferred training methods and topics. Participants in leader training reported that training yielded motivational and educational benefits. As part of the evaluation, volunteers identified the preferred training delivery modes as group trainings and electronic communication. Volunteers were most interested in learning about 4-H opportunities and leadership development

Development and characterization of positively selected brain-adapted SIV

HIV is found in the brains of most infected individuals but only 30% develop neurological disease. Both viral and host factors are thought to contribute to the motor and cognitive disorders resulting from HIV infection. Here, using the SIV/rhesus monkey system, we characterize the salient characteristics of the virus from the brain of animals with neuropathological disorders. Nine unique molecular clones of SIV were derived from virus released by microglia cultured from the brains of two macaques with SIV encephalitis. Sequence analysis revealed a remarkably high level of similarity between their env and nef genes as well as their 3' LTR. As this genotype was found in the brains of two separate animals, and it encoded a set of distinct amino acid changes from the infecting virus, it demonstrates the convergent evolution of the virus to a unique brain-adapted genotype. This genotype was distinct from other macrophage-tropic and neurovirulent strains of SIV. Functional characterization of virus derived from representative clones showed a robust in vitro infection of 174xCEM cells, primary macrophages and primary microglia. The infectious phenotype of this virus is distinct from that shown by other strains of SIV, potentially reflecting the method by which the virus successfully infiltrates and infects the CNS. Positive in vivo selection of a brain-adapted strain of SIV resulted in a near-homogeneous strain of virus with distinct properties that may give clues to the viral basis of neuroAIDS

Getting out and about in older adults: the nature of daily trips and their association with objectively assessed physical activity

<p>Abstract</p> <p>Background</p> <p>A key public health objective is increasing health-enhancing physical activity (PA) for older adults (OAs). Daily trip frequency is independently associated with objectively assessed PA volumes (OAs). Little is known about correlates and these trips' transport mode, and how these elements relate to PA. Purpose: to describe the frequency, purpose, and travel mode of daily trips in OAs, and their association with participant characteristics and objectively-assessed PA.</p> <p>Methods</p> <p>Participants (n = 214, aged 78.1 SD 5.7 years), completed a seven-day trips log recording daily-trip frequency, purpose and transport mode. Concurrently participants wore an accelerometer which provided mean daily steps (steps·d^-1), and minutes of moderate to vigorous PA (MVPA·d^-1). Participants' physical function (PF) was estimated and demographic, height and weight data obtained.</p> <p>Results</p> <p>Trip frequency was associated with gender, age, physical function, walking-aid use, educational attainment, number of amenities within walking distance and cars in the household. Participants reported 9.6 (SD 4.2) trips per week (trips·wk^-1). Most trips (61%) were by car (driver 44%, passenger 17%), 30% walking or cycling (active) and 9% public transport/other. Driving trips·wk^-1were more common in participants who were males (5.3 SD 3.6), well-educated (5.0 SD 4.3), high functioning (5.1 SD 4.6), younger (5.6 SD 4.9), affluent area residents (5.1 SD 4.2) and accessing > one car (7.2 SD 4.7). Active trips·wk^-1were more frequent in participants who were males (3.4 SD 3.6), normal weight (3.2 SD 3.4), not requiring walking aids (3.5 SD 3.3), well-educated (3.7 SD 0.7), from less deprived neighbourhoods (3.9 SD 3.9) and with ≥ 8 amenities nearby (4.4 SD 3.8).</p> <p>Public transport, and active trip frequency, were significantly associated with steps·d^-1(p < 0.001), even after adjustment for other trip modes and potential confounders. Public transport, active, or car driving trips were independently associated with minutes MVPA·d^-1(p < 0.01).</p> <p>Conclusions</p> <p>Daily trips are associated with objectively-measured PA as indicated by daily MVPA and steps. Public transport and active trips are associated with greater PA than those by car, especially as a car passenger. Strategies encouraging increased trips, particularly active or public transport trips, in OAs can potentially increase their PA and benefit public health.</p

Ultrasound evidence of altered lumbar connective tissue structure in human subjects with chronic low back pain

<p>Abstract</p> <p>Background</p> <p>Although the connective tissues forming the fascial planes of the back have been hypothesized to play a role in the pathogenesis of chronic low back pain (LBP), there have been no previous studies quantitatively evaluating connective tissue structure in this condition. The goal of this study was to perform an ultrasound-based comparison of perimuscular connective tissue structure in the lumbar region in a group of human subjects with chronic or recurrent LBP for more than 12 months, compared with a group of subjects without LBP.</p> <p>Methods</p> <p>In each of 107 human subjects (60 with LBP and 47 without LBP), parasagittal ultrasound images were acquired bilaterally centered on a point 2 cm lateral to the midpoint of the L2-3 interspinous ligament. The outcome measures based on these images were subcutaneous and perimuscular connective tissue thickness and echogenicity measured by ultrasound.</p> <p>Results</p> <p>There were no significant differences in age, sex, body mass index (BMI) or activity levels between LBP and No-LBP groups. Perimuscular thickness and echogenicity were not correlated with age but were positively correlated with BMI. The LBP group had ~25% greater perimuscular thickness and echogenicity compared with the No-LBP group (ANCOVA adjusted for BMI, p < 0.01 and p < 0.001 respectively).</p> <p>Conclusion</p> <p>This is the first report of abnormal connective tissue structure in the lumbar region in a group of subjects with chronic or recurrent LBP. This finding was not attributable to differences in age, sex, BMI or activity level between groups. Possible causes include genetic factors, abnormal movement patterns and chronic inflammation.</p

Mental Well-Being in UK Higher Education During Covid-19: Do Students Trust Universities and the Government?

This paper draws upon the concept of recreancy to examine the mental well-being of university students during the Covid-19 pandemic. Briefly, recreancy is loss of societal trust that results when institutional actors can no longer be counted on to perform their responsibilities. Our study of mental well-being and recreancy focuses on the role of universities and government regulators within the education sector. We surveyed 600 UK students attending 161 different public higher education providers in October 2020 during a time when many UK students were isolated in their residences and engaged in online learning. We assessed student well-being using the Short Warwick-Edinburgh Mental Well-being Scale (scored 7–35) and found the mean score to be 19.9 [95% confidence interval (CI) 19.6, 20.2]. This level of well-being indicates that a significant proportion of UK students face low levels of mental well-being. Structural equation modeling (SEM) analysis indicates that high recreancy—measured as a low trust in universities and the government—is associated with low levels of mental well-being across the student sample. While these findings are suggestive, they are also important and we suggest that government and university leaders should not only work to increase food and housing security during the Covid-19 pandemic, but also consider how to combat various sector trends that might intensify recreancy

Probing Evolutionary Repeatability: Neutral and Double Changes and the Predictability of Evolutionary Adaptation

The question of how organisms adapt is among the most fundamental in evolutionary biology. Two recent studies investigated the evolution of Escherichia coli in response to challenge with the antibiotic cefotaxime. Studying five mutations in the beta-lactamase gene that together confer significant antibiotic resistance, the authors showed a complex fitness landscape that greatly constrained the identity and order of intermediates leading from the initial wildtype genotype to the final resistant genotype. Out of 18 billion possible orders of single mutations leading from non-resistant to fully-resistant form, they found that only 27 (1.5x10(-7)%) pathways were characterized by consistently increasing resistance, thus only a tiny fraction of possible paths are accessible by positive selection. I further explore these data in several ways.Allowing neutral changes (those that do not affect resistance) increases the number of accessible pathways considerably, from 27 to 629. Allowing multiple simultaneous mutations also greatly increases the number of accessible pathways. Allowing a single case of double mutation to occur along a pathway increases the number of pathways from 27 to 259, and allowing arbitrarily many pairs of simultaneous changes increases the number of possible pathways by more than 100 fold, to 4800. I introduce the metric 'repeatability,' the probability that two random trials will proceed via the exact same pathway. In general, I find that while the total number of accessible pathways is dramatically affected by allowing neutral or double mutations, the overall evolutionary repeatability is generally much less affected.These results probe the conceivable pathways available to evolution. Even when many of the assumptions of the analysis of Weinreich et al. (2006) are relaxed, I find that evolution to more highly cefotaxime resistant beta-lactamase proteins is still highly repeatable

The relationship between shame, perfectionism and Anorexia Nervosa: a grounded theory study

Objectives The aim of this study was to explore the potential relationship between shame, perfectionism and Anorexia Nervosa (AN) and their impact on recovery from AN. Method Semi-structured interviews were conducted with 11 people currently accessing services for AN. Interviews were transcribed and analysed using constructivist-grounded theory methodology. Results A model was developed which found a vicious cycle between shame and perfectionism. Participants tried to alleviate their feelings of shame by striving for perfectionism, however failing caused them more shame. Participants who disclosed childhood trauma believed their shame preceded their perfectionism. Participants who did not disclose trauma either believed their perfectionism preceded shame or they were unsure of which occurred first. Participants' responses suggested the following pathways from perfectionism to AN: needing goals; the need for a perfect life including a perfect body and AN being something they could be perfect at. The pathways identified between shame and AN entailed mechanisms via which AN could be used to escape shame, either by seeking pride through AN, seeking to numb shame through AN, seeking to escape body shame and punishing the self. AN was found to feed back into shame in two ways: when people had AN they felt ashamed when they broke their dietary rules, and also simultaneously people felt ashamed of their AN as they were not able to recover. Shame and perfectionism influenced one another in a cyclical pattern, in which shame drove perfectionism and not attaining high standards led to shame. Shame and perfectionism also impacted on recovery in several ways. AN functioned to numb participants' emotions, becoming part of their identity over time. AN also brought respite from a constant striving towards perfectionism. The need for a perfect recovery also influenced their motivation to engage in treatment, and fear of a return of strong emotions was another deterrent to recovery. Conclusion The findings of this paper show perfectionism and shame to both be important in the aetiology and maintenance of AN and to have an impact on recovery from AN

Dementia priority setting partnership with the James Lind Alliance: using patient and public involvement and the evidence base to inform the research agenda.

BACKGROUND: The James Lind Alliance (JLA) created an approach to elicit the views of those under-represented in research priority exercises. Building on this, the JLA Dementia Priority Setting Partnership was set up as an independent and evidence-based project to identify and prioritise unanswered questions ('uncertainties') about prevention, diagnosis, treatment and care relating to dementia. METHODS: A survey was widely disseminated to stakeholders with an interest in the needs of the older population. Thematic analysis was used to identify themes from the large amount of questions collected from which research questions were developed using PICO framework (Population, Intervention, Comparator, Outcome). Each question was checked against an extensive evidence base of high-quality systematic reviews to verify whether they were true uncertainties. FINDINGS: One thousand five hundred and sixty-three questionnaires were received, from people with dementia, carers/relatives, and health and care professionals; 85 uncertainties were identified from other sources. Questions were refined and formatted iteratively into 146 unique uncertainties. An interim prioritisation process involving diverse organisations identified the top 25 ranked questions. At a final face-to-face prioritisation workshop, 18 people representing the above constituencies arrived by consensus at the top 10 priority questions. The impact of patient and public involvement on the priorities is discussed. INTERPRETATION: The long (146 questions) and top 10 lists of dementia research priorities provide a focus for researchers, funders and commissioners. They highlight a need for more research into care for people with dementia and carers, and a need for high-quality effectiveness trials in all aspects of dementia research.This work was funded by the Alzheimer’s Society, UK (grant number RG66301) and supported by the National Institute for Health Research Collaborations for Leadership in Applied Health Research and Care (CLAHRC) for Cambridgeshire and Peterborough. No funding source had a role in the preparation of this paper, or the decision to submit it for publication.This is the final published version of the article. It was originally published in Age and Ageing (Age and Ageing 2015; 44: 985–993 doi: 10.1093/ageing/afv143). The final version is available at http://dx.doi.org/10.1093/ageing/afv14