Protein-mediated RNA folding governs sequence-specific interactions between rotavirus genome segments

Segmented RNA viruses are ubiquitous pathogens, which include influenza viruses and rotaviruses. A major challenge in understanding their assembly is the combinatorial problem of a non-random selection of a full genomic set of distinct RNAs. This process involves complex protein/RNA interactions, which are often obscured by non-specific binding at concentrations approaching in vvo assembly conditions. Here, we present direct experimental evidence of sequence-specific inter-segment interactions in rotaviruses, taking place in a complex RNA- and protein- rich milieu. We show that binding of the rotaviral protein NSP2 to ssRNAs results in the remodeling of RNA, which is conducive to formation of inter-segment contacts. To identify the sites of these interactions, we have developed an RNA-RNA SELEX approach for mapping the sequences involved in inter-segment base-pairing. Our findings elucidate the molecular basis underlying inter-segment interactions in rotaviruses, paving the way for delineating RNA-RNA interactions that govern assembly of other segmented RNA viruse

Process evaluation of complex interventions tested in randomised controlled trials in musculoskeletal disorders: A systematic review protocol

Introduction The effectiveness of complex interventions for the management of musculoskeletal disorders has been estimated in many randomised clinical trials (RCTs). These trials inform which interventions are the most effective, however they do not always inform how an intervention achieved its clinical outcomes, nor how and what elements of an intervention were delivered to patients. Such information is useful for translating findings into clinical practice. A few process evaluation studies have been conducted alongside RCTs and a variety of methods have been used. To gain a better understanding of current practices of process evaluation in RCTs in musculoskeletal disorders, this systematic review is designed to answer the following research question: How are process evaluation of complex interventions tested in RCTs in musculoskeletal disorders being conducted? Methods and analysis We will systematically search seven electronic databases (MEDLINE, SCOPUS, CINAHL, PsycINFO, EMBASE, Web of Science and Cochrane database) from the date of inception to August 2018 for studies on process evaluation of RCTs on non-surgical and non-pharmacological management of musculoskeletal disorders. We will include qualitative and quantitative studies conducted alongside RCTs, reported with the RCTs or separate studies that assessed interventions for musculoskeletal disorders. Two reviewers will screen abstracts and apply prespecified inclusion criteria to identify relevant studies, extract the data and assess the risk of bias within included studies. We will follow recommendations from the Cochrane Qualitative and Implementation Methods Group Guidance Series' when assessing methodological strengths and limitations of included studies. We will use a narrative synthesis to describe findings. Ethics and dissemination Ethical approval is not required as this review will not collect original data. Findings from this systematic review will be presented at a scientific conference and published in a peer reviewed journal. PROSPERO registration number CRD4201810960

Mediators of the effects of exercise and manual therapy for people with knee and hip osteoarthritis: A secondary, exploratory analysis of the MOA trial

This is the final version. Available on open access from Elsevier via the DOI in this recordOBJECTIVE: To explore whether pain beliefs and functional strength mediate the treatment effect of manual therapy (MT) and exercise therapy (ET) on the Western Ontario and McMaster Osteoarthritis Index (WOMAC) composite scores and its subscales in individuals with hip and/or knee osteoarthritis in the MOA trial. DESIGN: Secondary analysis of a randomised controlled trial that compared the incremental effects of supervised MT and ET in addition to usual care in patients with osteoarthritis of the hip or knee. 206 participants enrolled in the MOA trial were analysed. The primary outcome measure was the WOMAC composite score after 1 year. RESULTS: Pain belief mediated the effect of MT (b: -10.7, 95 ​% CI: -22.3, -0.9), ET (b: -14.5 95%CI: -26.0, -4.4). Functional strength did not mediate the effect of MT, ET, or MT ​+ ​ET. Mediation sensitivity analyses suggest findings are likely to change if small confounding between those mediators and WOMAC composite score is present. CONCLUSIONS: We identified possible mediators of MT and ET. Future confirmatory studies could be designed to assess the mechanisms through which manual therapy and exercise cause improvements in pain and function scores in patients with hip or knee osteoarthritis.Health Research Council of New ZealandNational Institute for Health and Care Research (NIHR

Stability of local secondary structure determines selectivity of viral RNA chaperones

To maintain genome integrity, segmented double-stranded RNA viruses of the Reoviridae family must accurately select and package a complete set of up to a dozen distinct genomic RNAs. It is thought that the high fidelity segmented genome assembly involves multiple sequence-specific RNA–RNA interactions between single-stranded RNA segment precursors. These are mediated by virus-encoded non-structural proteins with RNA chaperone-like activities, such as rotavirus (RV) NSP2 and avian reovirus σNS. Here, we compared the abilities of NSP2 and σNS to mediate sequence-specific interactions between RV genomic segment precursors. Despite their similar activities, NSP2 successfully promotes inter-segment association, while σNS fails to do so. To understand the mechanisms underlying such selectivity in promoting inter-molecular duplex formation, we compared RNA-binding and helix-unwinding activities of both proteins. We demonstrate that octameric NSP2 binds structured RNAs with high affinity, resulting in efficient intramolecular RNA helix disruption. Hexameric σNS oligomerizes into an octamer that binds two RNAs, yet it exhibits only limited RNA-unwinding activity compared to NSP2. Thus, the formation of intersegment RNA–RNA interactions is governed by both helix-unwinding capacity of the chaperones and stability of RNA structure. We propose that this protein-mediated RNA selection mechanism may underpin the high fidelity assembly of multi-segmented RNA genomes in Reoviridae

Does Father Know Best? A Formal Model of the Paternal Influence on Childhood Social Anxiety

We explore paternal social anxiety as a specific risk factor for childhood social anxiety in a rational optimization model. In the course of human evolution, fathers specialized in external protection (e.g., confronting the external world) while mothers specialized in internal protection (e.g., providing comfort and food). Thus, children may instinctively be more influenced by the information signaled by paternal versus maternal behavior with respect to potential external threats. As a result, if fathers exhibit social anxiety, children interpret it as a strong negative signal about the external social world and rationally adjust their beliefs, thus becoming stressed. Under the assumption that paternal signals on social threats are more influential, a rational cognitive inference leads children of socially anxious fathers to develop social anxiety, unlike children of socially anxious mothers. We show in the model that mothers cannot easily compensate for anxious paternal behavior, but choose to increase maternal care to maintain the child’s wellbeing. We discuss research directions to test the proposed model as well as implications for the prevention and treatment of child social anxiety

New Mechanics of Traumatic Brain Injury

The prediction and prevention of traumatic brain injury is a very important aspect of preventive medical science. This paper proposes a new coupled loading-rate hypothesis for the traumatic brain injury (TBI), which states that the main cause of the TBI is an external Euclidean jolt, or SE(3)-jolt, an impulsive loading that strikes the head in several coupled degrees-of-freedom simultaneously. To show this, based on the previously defined covariant force law, we formulate the coupled Newton-Euler dynamics of brain's micro-motions within the cerebrospinal fluid and derive from it the coupled SE(3)-jolt dynamics. The SE(3)-jolt is a cause of the TBI in two forms of brain's rapid discontinuous deformations: translational dislocations and rotational disclinations. Brain's dislocations and disclinations, caused by the SE(3)-jolt, are described using the Cosserat multipolar viscoelastic continuum brain model. Keywords: Traumatic brain injuries, coupled loading-rate hypothesis, Euclidean jolt, coupled Newton-Euler dynamics, brain's dislocations and disclinationsComment: 18 pages, 1 figure, Late

Recommendations for a core outcome set for measuring standing balance in adult populations: a consensus-based approach

Standing balance is imperative for mobility and avoiding falls. Use of an excessive number of standing balance measures has limited the synthesis of balance intervention data and hampered consistent clinical practice.To develop recommendations for a core outcome set (COS) of standing balance measures for research and practice among adults.A combination of scoping reviews, literature appraisal, anonymous voting and face-to-face meetings with fourteen invited experts from a range of disciplines with international recognition in balance measurement and falls prevention. Consensus was sought over three rounds using pre-established criteria.The scoping review identified 56 existing standing balance measures validated in adult populations with evidence of use in the past five years, and these were considered for inclusion in the COS.Fifteen measures were excluded after the first round of scoring and a further 36 after round two. Five measures were considered in round three. Two measures reached consensus for recommendation, and the expert panel recommended that at a minimum, either the Berg Balance Scale or Mini Balance Evaluation Systems Test be used when measuring standing balance in adult populations.Inclusion of two measures in the COS may increase the feasibility of potential uptake, but poses challenges for data synthesis. Adoption of the standing balance COS does not constitute a comprehensive balance assessment for any population, and users should include additional validated measures as appropriate.The absence of a gold standard for measuring standing balance has contributed to the proliferation of outcome measures. These recommendations represent an important first step towards greater standardization in the assessment and measurement of this critical skill and will inform clinical research and practice internationally

The effect of bleach duration and age on the ERG photostress test

Background: The ERG photostress test assesses the recovery of the focal 41 Hz ERG following exposure to a bright light that bleaches a significant proportion of photopigment. The aims of this study were: 1) to compare the repeatability of the ERG photostress test recovery time constant following long and short duration light exposure, and 2) to determine the effect of age on the ERG photostress test recovery time constant. Methods: Focal 41 Hz ERGs were recorded from 23 participants (age range 20–71 years) at 20-second intervals for 5 minutes following either a short-duration (photoflash) or long-duration (equilibrium) light exposure. After a 5-minute wash-out period, the procedure was repeated using the second bleach modality. The time constant of cone recovery was determined by fitting an exponential model to the amplitude recovery data. The whole procedure was repeated on a second occasion. The co-efficient of repeatability (CoR) was calculated for each bleaching technique. The relationship between the time constant of recovery and age was investigated (Pearson’s correlation coefficient). Results: The time constant of recovery following an equilibrium bleach was more repeatable than recovery following a photoflash (CoR = 85s and 184s respectively). Eight trials (from seven participants) failed to show a reduction in amplitude following the photoflash, suggesting that a blink or fixation loss had occurred. All participants were reliably light-adapted by the equilibrium bleach. For the equilibrium bleach data, the time constant of recovery increased with age at a rate of 27 seconds per decade. Conclusions: The equilibrium bleach was more reliable and repeatable than the photoflash. Increasing participant age was shown to result in a lengthening of the recovery time constant, of a magnitude comparable to previously published psychophysical data

Genetic and Proteomic Approaches to Identify Cancer Drug Targets

While target-based small-molecule discovery has taken centre-stage in the pharmaceutical industry, there are many cancer-promoting proteins not easily addressed with a traditional target-based screening approach. In order to address this problem, as well as to identify modulators of biological states in the absence of knowing the protein target of the state switch, alternative phenotypic screening approaches, such as gene expression-based and high-content imaging, have been developed. With this renewed interest in phenotypic screening, however, comes the challenge of identifying the binding protein target(s) of small-molecule hits. Emerging technologies have the potential to improve the process of target identification. In this review, we discuss the application of genomic (gene expression-based), genetic (short hairpin RNA and open reading frame screening), and proteomic approaches to protein target identification

Support and Assessment for Fall Emergency Referrals (SAFER 1) trial protocol. Computerised on-scene decision support for emergency ambulance staff to assess and plan care for older people who have fallen: evaluation of costs and benefits using a pragmatic cluster randomised trial

Background: Many emergency ambulance calls are for older people who have fallen. As half of them are left at home, a community-based response may often be more appropriate than hospital attendance. The SAFER 1 trial will assess the costs and benefits of a new healthcare technology - hand-held computers with computerised clinical decision support (CCDS) software - to help paramedics decide who needs hospital attendance, and who can be safely left at home with referral to community falls services. Methods/Design: Pragmatic cluster randomised trial with a qualitative component. We shall allocate 72 paramedics ('clusters') at random between receiving the intervention and a control group delivering care as usual, of whom we expect 60 to complete the trial. Patients are eligible if they are aged 65 or older, live in the study area but not in residential care, and are attended by a study paramedic following an emergency call for a fall. Seven to 10 days after the index fall we shall offer patients the opportunity to opt out of further follow up. Continuing participants will receive questionnaires after one and 6 months, and we shall monitor their routine clinical data for 6 months. We shall interview 20 of these patients in depth. We shall conduct focus groups or semi-structured interviews with paramedics and other stakeholders. The primary outcome is the interval to the first subsequent reported fall (or death). We shall analyse this and other measures of outcome, process and cost by 'intention to treat'. We shall analyse qualitative data thematically. Discussion: Since the SAFER 1 trial received funding in August 2006, implementation has come to terms with ambulance service reorganisation and a new national electronic patient record in England. In response to these hurdles the research team has adapted the research design, including aspects of the intervention, to meet the needs of the ambulance services. In conclusion this complex emergency care trial will provide rigorous evidence on the clinical and cost effectiveness of CCDS for paramedics in the care of older people who have fallen