A cancer cell-line titration series for evaluating somatic classification.

BackgroundAccurate detection of somatic single nucleotide variants and small insertions and deletions from DNA sequencing experiments of tumour-normal pairs is a challenging task. Tumour samples are often contaminated with normal cells confounding the available evidence for the somatic variants. Furthermore, tumours are heterogeneous so sub-clonal variants are observed at reduced allele frequencies. We present here a cell-line titration series dataset that can be used to evaluate somatic variant calling pipelines with the goal of reliably calling true somatic mutations at low allele frequencies.ResultsCell-line DNA was mixed with matched normal DNA at 8 different ratios to generate samples with known tumour cellularities, and exome sequenced on Illumina HiSeq to depths of >300×. The data was processed with several different variant calling pipelines and verification experiments were performed to assay >1500 somatic variant candidates using Ion Torrent PGM as an orthogonal technology. By examining the variants called at varying cellularities and depths of coverage, we show that the best performing pipelines are able to maintain a high level of precision at any cellularity. In addition, we estimate the number of true somatic variants undetected as cellularity and coverage decrease.ConclusionsOur cell-line titration series dataset, along with the associated verification results, was effective for this evaluation and will serve as a valuable dataset for future somatic calling algorithm development. The data is available for further analysis at the European Genome-phenome Archive under accession number EGAS00001001016. Data access requires registration through the International Cancer Genome Consortium's Data Access Compliance Office (ICGC DACO)

Nuclear Scaling Is Coordinated among Individual Nuclei in Multinucleated Muscle Fibers

Optimal cell performance depends on cell size and the appropriate relative size, i.e., scaling, of the nucleus. How nuclear scaling is regulated and contributes to cell function is poorly understood, especially in skeletal muscle fibers, which are among the largest cells, containing hundreds of nuclei. Here, we present a Drosophila in vivo system to analyze nuclear scaling in whole multinucleated muscle fibers, genetically manipulate individual components, and assess muscle function. Despite precise global coordination, we find that individual nuclei within a myofiber establish different local scaling relationships by adjusting their size and synthetic activity in correlation with positional or spatial cues. While myonuclei exhibit compensatory potential, even minor changes in global nuclear size scaling correlate with reduced muscle function. Our study provides the first comprehensive approach to unraveling the intrinsic regulation of size in multinucleated muscle fibers. These insights to muscle cell biology will accelerate the development of interventions for muscle diseases

Revealed cardinal preference

I prove that as long as we allow the marginal utility for money (lambda) to vary between purchases (similarly to the budget) then the quasi-linear and the ordinal budget-constrained models rationalize the same data. However, we know that lambda is approximately constant. I provide a simple constructive proof for the necessary and sufficient condition for the constant lambda rationalization, which I argue should replace the Generalized Axiom of Revealed Preference in empirical studies of consumer behavior. 'Go Cardinals!' It is the minimal requirement of any scientifi c theory that it is consistent with the data it is trying to explain. In the case of (Hicksian) consumer theory it was revealed preference -introduced by Samuelson (1938,1948) - that provided an empirical test to satisfy this need. At that time most of economic reasoning was done in terms of a competitive general equilibrium, a concept abstract enough so that it can be built on the ordinal preferences over baskets of goods - even if the extremely specialized ones of Arrow and Debreu. However, starting in the sixties, economics has moved beyond the 'invisible hand' explanation of how -even competitive- markets operate. A seemingly unavoidable step of this 'revolution' was that ever since, most economic research has been carried out in a partial equilibrium context. Now, the partial equilibrium approach does not mean that the rest of the markets are ignored, rather that they are held constant. In other words, there is a special commodity -call it money - that reflects the trade-offs of moving purchasing power across markets. As a result, the basic building block of consumer behavior in partial equilibrium is no longer the consumer's preferences over goods, rather her valuation of them, in terms of money. This new paradigm necessitates a new theory of revealed preference

Engagement of the motor system in position monitoring: reduced distractor suppression and effects of internal representation quality on motor kinematics

The position monitoring task is a measure of divided spatial attention in which participants track the changing positions of one or more objects, attempting to represent positions with as much precision as possible. Typically precision of representations declines with each target object added to participants' attention load. Since the motor system requires precise representations of changing target positions, we investigated whether position monitoring would be facilitated by increasing engagement of the motor system. Using motion capture, we recorded the positions of participants’ index finger during pointing responses. Participants attempted to monitor the changing positions of between one and four target discs as they moved randomly around a large projected display. After a period of disc motion, all discs disappeared and participants were prompted to report the final position of one of the targets, either by mouse click or by pointing to the final perceived position on the screen. For mouse click responses, precision declined with attentional load. For pointing responses, precision declined only up to three targets and remained at the same level for four targets, suggesting obligatory attention to all four objects for loads above two targets. Kinematic profiles for pointing responses for highest and lowest loads showed greater motor adjustments during the point, demonstrating that, like external environmental task demands, the quality of internal representations affects motor kinematics. Specifically, these adjustments reflect the difficulty of both pointing to very precisely represented locations as well as keeping representations distinct from one another

Why alternative teenagers self-harm: exploring the link between non-suicidal self-injury, attempted suicide and adolescent identity

Background: The term ‘self-harm’ encompasses both attempted suicide and non-suicidal self-injury (NSSI). Specific adolescent subpopulations such as ethnic or sexual minorities, and more controversially, those who identify as ‘Alternative’ (Goth, Emo) have been proposed as being more likely to self-harm, while other groups such as ‘Jocks’ are linked with protective coping behaviours (for example exercise). NSSI has autonomic (it reduces negative emotions) and social (it communicates distress or facilitates group ‘bonding’) functions. This study explores the links between such aspects of self-harm, primarily NSSI, and youth subculture.<p></p> Methods: An anonymous survey was carried out of 452 15 year old German school students. Measures included: identification with different youth cultures, i.e. Alternative (Goth, Emo, Punk), Nerd (academic) or Jock (athletic); social background, e.g. socioeconomic status; and experience of victimisation. Self-harm (suicide and NSSI) was assessed using Self-harm Behavior Questionnaire and the Functional Assessment of Self-Mutilation (FASM).<p></p> Results: An “Alternative” identity was directly (r ≈ 0.3) and a “Jock” identity inversely (r ≈ -0.1) correlated with self-harm. “Alternative” teenagers self-injured more frequently (NSSI 45.5% vs. 18.8%), repeatedly self-injured, and were 4–8 times more likely to attempt suicide (even after adjusting for social background) than their non-Alternative peers. They were also more likely to self-injure for autonomic, communicative and social reasons than other adolescents.<p></p> Conclusions: About half of ‘Alternative’ adolescents’ self-injure, primarily to regulate emotions and communicate distress. However, a minority self-injure to reinforce their group identity, i.e. ‘To feel more a part of a group’

Sample size calculations for cluster randomised controlled trials with a fixed number of clusters

Background\ud Cluster randomised controlled trials (CRCTs) are frequently used in health service evaluation. Assuming an average cluster size, required sample sizes are readily computed for both binary and continuous outcomes, by estimating a design effect or inflation factor. However, where the number of clusters are fixed in advance, but where it is possible to increase the number of individuals within each cluster, as is frequently the case in health service evaluation, sample size formulae have been less well studied. \ud \ud Methods\ud We systematically outline sample size formulae (including required number of randomisation units, detectable difference and power) for CRCTs with a fixed number of clusters, to provide a concise summary for both binary and continuous outcomes. Extensions to the case of unequal cluster sizes are provided. \ud \ud Results\ud For trials with a fixed number of equal sized clusters (k), the trial will be feasible provided the number of clusters is greater than the product of the number of individuals required under individual randomisation ($n_i$) and the estimated intra-cluster correlation ($\rho$). So, a simple rule is that the number of clusters ($\kappa$) will be sufficient provided: \ud \ud $\kappa$ > $n_i$ x $\rho$\ud \ud Where this is not the case, investigators can determine the maximum available power to detect the pre-specified difference, or the minimum detectable difference under the pre-specified value for power. \ud \ud Conclusions\ud Designing a CRCT with a fixed number of clusters might mean that the study will not be feasible, leading to the notion of a minimum detectable difference (or a maximum achievable power), irrespective of how many individuals are included within each cluster. \ud \u

RAD51L3 (RAD51-like 3 (S. cerevisiae))

Review on RAD51L3 (RAD51-like 3 (S. cerevisiae)), with data on DNA, on the protein encoded, and where the gene is implicated

Erosion of Trust in the Medical Profession in India : Time for Doctors to Act

In India, over the last decade, a series of stewardship failures in the health system, particularly in the medical profession, have led to a massive erosion of trust in these institutions. In many low- and middle-income countries (LMICs), the situation is similar and has reached crisis proportions; this crisis requires urgent attention. This paper draws on the insights from the recent developments in India, to argue that a purely control-based regulatory response to this crisis in the medical profession, as is being currently envisaged by the Parliament and the Supreme Court of India, runs the risk of undermining the trusting interpersonal relations between doctors and their patients. A more balanced approach which takes into account the differences between system and interpersonal forms of trust and distrust is warranted. Such an approach should on one hand strongly regulate the institutions mandated with the stewardship and qualities of care functions, and simultaneously on the other hand, initiate measures to nurture the trusting interpersonal relations between doctors and patients. The paper concludes by calling for doctors, and those mandated with the stewardship of the profession, to individually and collectively, critically self-reflect upon the state of their profession, its priorities and its future direction

Twenty years and counting: epidemiology of an outbreak of isoniazid-resistant tuberculosis in England and Wales, 1995 to 2014

An outbreak of isoniazid-resistant tuberculosis first identified in London has now been ongoing for 20 years, making it the largest drug-resistant outbreak of tuberculosis documented to date worldwide. We identified culture-confirmed cases with indistinguishable molecular strain types and extracted demographic, clinical, microbiological and social risk factor data from surveillance systems. We summarised changes over time and used kernel-density estimation and k-function analysis to assess geographic clustering. From 1995 to 2014, 508 cases were reported, with a declining trend in recent years. Overall, 70% were male (n = 360), 60% born in the United Kingdom (n = 306), 39% white (n = 199), and 26% black Caribbean (n = 134). Median age increased from 25 years in the first 5 years to 42 in the last 5. Approximately two thirds of cases reported social risk factors: 45% drug use (n = 227), 37% prison link (n = 189), 25% homelessness (n = 125) and 13% alcohol dependence (n = 64). Treatment was completed at 12 months by 52% of cases (n = 206), and was significantly lower for those with social risk factors (p < 0.05), but increased over time for all patients (p < 0.05). The outbreak remained focused in north London throughout. Control of this outbreak requires continued efforts to prevent and treat further active cases through targeted screening and enhanced case management