ACT: aggregation and correlation toolbox for analyses of genome tracks

We have implemented aggregation and correlation toolbox (ACT), an efficient, multifaceted toolbox for analyzing continuous signal and discrete region tracks from high-throughput genomic experiments, such as RNA-seq or ChIP-chip signal profiles from the ENCODE and modENCODE projects, or lists of single nucleotide polymorphisms from the 1000 genomes project. It is able to generate aggregate profiles of a given track around a set of specified anchor points, such as transcription start sites. It is also able to correlate related tracks and analyze them for saturation–i.e. how much of a certain feature is covered with each new succeeding experiment. The ACT site contains downloadable code in a variety of formats, interactive web servers (for use on small quantities of data), example datasets, documentation and a gallery of outputs. Here, we explain the components of the toolbox in more detail and apply them in various contexts

Trials and tribulations of recruiting 2,000 older women onto a clinical trial investigating falls and fractures : vital D study

Background Randomised, placebo-controlled trials are needed to provide evidence demonstrating safe, effective interventions that reduce falls and fractures in the elderly. The quality of a clinical trial is dependent on successful recruitment of the target participant group. This paper documents the successes and failures of recruiting over 2,000 women aged at least 70 years and at higher risk of falls or fractures onto a placebo-controlled trial of six years duration. The characteristics of study participants at baseline are also described for this study.Methods The Vital D Study recruited older women identified at high risk of fracture through the use of an eligibility algorithm, adapted from identified risk factors for hip fracture. Participants were randomised to orally receive either 500,000 IU vitamin D3 (cholecalciferol) or placebo every autumn for five consecutive years. A variety of recruitment strategies were employed to attract potential participants.Results Of the 2,317 participants randomised onto the study, 74% (n = 1716/2317) were consented onto the study in the last five months of recruiting. This was largely due to the success of a targeted mail-out. Prior to this only 541 women were consented in the 18 months of recruiting. A total of 70% of all participants were recruited as a result of targeted mail-out. The response rate from the letters increased from 2 to 7% following revision of the material by a public relations company. Participant demographic or risk factor profile did not differ between those recruited by targeted mail-outs compared with other methods.Conclusion The most successful recruitment strategy was the targeted mail-out and the response rate was no higher in the local region where the study had extensive exposure through other recruiting strategies. The strategies that were labour-intensive and did not result in successful recruitment include the activities directed towards the GP medical centres. Comprehensive recruitment programs employ overlapping strategies simultaneously with ongoing assessment of recruitment rates. In our experience, and others direct mail-outs work best although rights to privacy must be respected. <br /

Energy-efficient precoding in multicell networks with full-duplex base stations

© 2017, The Author(s). This paper considers multi-input multi-output (MIMO) multicell networks, where the base stations (BSs) are full-duplex transceivers, while uplink and downlink users are equipped with multiple antennas and operate in a half-duplex mode. The problem of interest is to design linear precoders for BSs and users to optimize the network’s energy efficiency. Given that the energy efficiency objective is not a ratio of concave and convex functions, the commonly used Dinkelbach-type algorithms are not applicable. We develop a low-complexity path-following algorithm that only invokes one simple convex quadratic program at each iteration, which converges at least to the local optimum. Numerical results demonstrate the performance advantage of our proposed algorithm in terms of energy efficiency

Risk of Recurrent Arterial Ischemic Stroke in Childhood: A Prospective International Study.

Background and purposePublished cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era.MethodsThe Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review.ResultsOf the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0-3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%-10%) at 1 month and 12% (8.5%-15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8-14). The 1-year recurrence rate was 32% (95% confidence interval, 18%-51%) for moyamoya, 25% (12%-48%) for transient cerebral arteriopathy, and 19% (8.5%-40%) for arterial dissection.ConclusionsChildren with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed

Catalytic Mechanism of Bacteriophage T4 Rad50 ATP Hydrolysis

Spontaneous double-strand breaks (DSBs) are one of the most deleterious forms of DNA damage, and their improper repair can lead to cellular dysfunction. The Mre11 and Rad50 proteins, a nuclease and an ATPase, respectively, form a well-conserved complex that is involved in the initial processing of DSBs. Here we examine the kinetic and catalytic mechanism of ATP hydrolysis by T4 Rad50 (gp46) in the presence and absence of Mre11 (gp47) and DNA. Single-turnover and pre-steady state kinetics on the wild-type protein indicate that the rate-limiting step for Rad50, the MR complex, and the MR-DNA complex is either chemistry or a conformational change prior to catalysis. Pre-steady state product release kinetics, coupled with viscosity steady state kinetics, also supports that the binding of DNA to the MR complex does not alter the rate-limiting step. The lack of a positive deuterium solvent isotope effect for the wild type and several active site mutants, combined with pH–rate profiles, implies that chemistry is rate-limiting and the ATPase mechanism proceeds via an asymmetric, dissociative-like transition state. Mutation of the Walker A/B and H-loop residues also affects the allosteric communication between Rad50 active sites, suggesting possible routes for cooperativity between the ATP active sites

Comparison of bacterial microbiota of the predatory mite Neoseiulus cucumeris (Acari: Phytoseiidae) and its factitious prey Tyrophagus putrescentiae (Acari: Acaridae)

Neoseiulus cucumeris is a predatory mite used for biological control of arthropod pests. Mass-reared predators are fed with factitious prey mites such as Tyrophagus putrescentiae. Although some information on certain endosymbionts of N. cucumeris and T. putrescentiae exists, it is unclear whether both species share bacterial communities. The bacterial communities in populations of predator and prey mites, as well as the occurence of potential acaropathogenic bacteria were analyzed. The comparisons were based on the following groups: (i) N. cucumeris mass-production; (ii) N. cucumeris laboratory population with disease symptoms; (iii) T. putrescentiae pure populations and; (iv) T. putrescentiae from rearing units of N. cucumeris. Only 15% of OTUs were present in all samples from predatory and prey mite populations (core OTUs): the intracellular symbionts Wolbachia, Cardinium, plus other Blattabacterium-like, Solitalea-like, and Bartonella-like symbionts. Environmental bacteria were more abundant in predatory mites, while symbiotic bacteria prevailed in prey mites. Relative numbers of certain bacterial taxa were significantly different between the microbiota of prey mites reared with and without N. cucumeris. No significant differences were found in the bacterial communities of healthy N. cucumeris compared to N. cucumeris showing disease symptoms. We did not identify any confirmed acaropathogenic bacteria among microbiota

Focus on Function – a randomized controlled trial comparing two rehabilitation interventions for young children with cerebral palsy

<p>Abstract</p> <p>Background</p> <p>Children with cerebral palsy receive a variety of long-term physical and occupational therapy interventions to facilitate development and to enhance functional independence in movement, self-care, play, school activities and leisure. Considerable human and financial resources are directed at the "intervention" of the problems of cerebral palsy, although the available evidence supporting current interventions is inconclusive. A considerable degree of uncertainty remains about the appropriate therapeutic approaches to manage the habilitation of children with cerebral palsy. The primary objective of this project is to conduct a multi-site randomized clinical trial to evaluate the efficacy of a task/context-focused approach compared to a child-focused remediation approach in improving performance of functional tasks and mobility, increasing participation in everyday activities, and improving quality of life in children 12 months to 5 years of age who have cerebral palsy.</p> <p>Method/Design</p> <p>A multi-centred randomized controlled trial research design will be used. Children will be recruited from a representative sample of children attending publicly-funded regional children's rehabilitation centers serving children with disabilities in Ontario and Alberta in Canada. Target sample size is 220 children with cerebral palsy aged 12 months to 5 years at recruitment date. Therapists are randomly assigned to deliver either a context-focused approach or a child-focused approach. Children follow their therapist into their treatment arm. Outcomes will be evaluated at baseline, after 6 months of treatment and at a 3-month follow-up period. Outcomes represent the components of the International Classification of Functioning, Disability and Health, including body function and structure (range of motion), activities (performance of functional tasks, motor function), participation (involvement in formal and informal activities), and environment (parent perceptions of care, parental empowerment).</p> <p>Discussion</p> <p>This paper presents the background information, design and protocol for a randomized controlled trial comparing a task/context-focused approach to a child-focused remediation approach in improving functional outcomes for young children with cerebral palsy.</p> <p>Trial registration</p> <p>[clinical trial registration #: NCT00469872]</p

The aged niche disrupts muscle stem cell quiescence

SUMMARY The niche is a conserved regulator of stem cell quiescence and function. During aging, stem cell function declines. To what extent and by which means age-related changes within the niche contribute to this phenomenon are unknown. We demonstrate that the aged muscle stem cell niche, the muscle fiber, expresses FGF2 under homeostatic conditions, driving a subset of satellite cells to break quiescence and lose self-renewing capacity. We show that relatively dormant aged satellite cells robustly express Sprouty1 (spry1), an inhibitor of FGF signalling. Increasing FGF signalling in aged satellite cells under homeostatic conditions by removing spry1, results in the loss of quiescence, satellite cell depletion and diminished regenerative capacity. Conversely, reducing niche-derived FGF activity through inhibition of FGFR1 signalling or overexpression of spry1 in satellite cells prevents their depletion. These experiments identify an age-dependent change in the stem cell niche that directly influences stem cell quiescence and function

Multifactorial Origins of Heart and Gut Defects in nipbl-Deficient Zebrafish, a Model of Cornelia de Lange Syndrome

nipbl-deficient zebrafish provide evidence that heart and gut defects in Cornelia de Lange Syndrome are caused by combined effects of multiple gene expression changes that occur during early embryonic development