GeTallele: A Method for Analysis of DNA and RNA Allele Frequency Distributions

This is the final version. Available on open access from Frontiers Media via the DOI in this recordData Availability Statement: The data analyzed in this study is subject to the following licenses/restrictions: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Requests to access these datasets should be directed to [email protected] allele frequencies (VAF) are an important measure of genetic variation that can be estimated at single-nucleotide variant (SNV) sites. RNA and DNA VAFs are used as indicators of a wide-range of biological traits, including tumor purity and ploidy changes, allele-specific expression and gene-dosage transcriptional response. Here we present a novel methodology to assess gene and chromosomal allele asymmetries and to aid in identifying genomic alterations in RNA and DNA datasets. Our approach is based on analysis of the VAF distributions in chromosomal segments (continuous multi-SNV genomic regions). In each segment we estimate variant probability, a parameter of a random process that can generate synthetic VAF samples that closely resemble the observed data. We show that variant probability is a biologically interpretable quantitative descriptor of the VAF distribution in chromosomal segments which is consistent with other approaches. To this end, we apply the proposed methodology on data from 72 samples obtained from patients with breast invasive carcinoma (BRCA) from The Cancer Genome Atlas (TCGA). We compare DNA and RNA VAF distributions from matched RNA and whole exome sequencing (WES) datasets and find that both genomic signals give very similar segmentation and estimated variant probability profiles. We also find a correlation between variant probability with copy number alterations (CNA). Finally, to demonstrate a practical application of variant probabilities, we use them to estimate tumor purity. Tumor purity estimates based on variant probabilities demonstrate good concordance with other approaches (Pearson's correlation between 0.44 and 0.76). Our evaluation suggests that variant probabilities can serve as a dependable descriptor of VAF distribution, further enabling the statistical comparison of matched DNA and RNA datasets. Finally, they provide conceptual and mechanistic insights into relations between structure of VAF distributions and genetic events. The methodology is implemented in a Matlab toolbox that provides a suite of functions for analysis, statistical assessment and visualization of Genome and Transcriptome allele frequencies distributions. GeTallele is available at: https://github.com/SlowinskiPiotr/GeTalleleMcCormick Genomic and Proteomic Center (MGPC)George Washington UniversityWellcome TrustEngineering and Physical Sciences Research Council (EPSRC

The developmental dynamics of terrorist organizations

We identify robust statistical patterns in the frequency and severity of violent attacks by terrorist organizations as they grow and age. Using group-level static and dynamic analyses of terrorist events worldwide from 1968-2008 and a simulation model of organizational dynamics, we show that the production of violent events tends to accelerate with increasing size and experience. This coupling of frequency, experience and size arises from a fundamental positive feedback loop in which attacks lead to growth which leads to increased production of new attacks. In contrast, event severity is independent of both size and experience. Thus larger, more experienced organizations are more deadly because they attack more frequently, not because their attacks are more deadly, and large events are equally likely to come from large and small organizations. These results hold across political ideologies and time, suggesting that the frequency and severity of terrorism may be constrained by fundamental processes.Comment: 28 pages, 8 figures, 4 tables, supplementary materia

Removing exogenous information using pedigree data

Management of certain populations requires the preservation of its pure genetic background. When, for different reasons, undesired alleles are introduced, the original genetic conformation must be recovered. The present study tested, through computer simulations, the power of recovery (the ability for removing the foreign information) from genealogical data. Simulated scenarios comprised different numbers of exogenous individuals taking partofthe founder population anddifferent numbers of unmanaged generations before the removal program started. Strategies were based on variables arising from classical pedigree analyses such as founders? contribution and partial coancestry. The ef?ciency of the different strategies was measured as the proportion of native genetic information remaining in the population. Consequences on the inbreeding and coancestry levels of the population were also evaluated. Minimisation of the exogenous founders? contributions was the most powerful method, removing the largest amount of genetic information in just one generation.However, as a side effect, it led to the highest values of inbreeding. Scenarios with a large amount of initial exogenous alleles (i.e. high percentage of non native founders), or many generations of mixing became very dif?cult to recover, pointing out the importance of being careful about introgression events in populatio

Clinician acquisition and retention of Motivational Interviewing skills: a two-and-a-half-year exploratory study

<p>Abstract</p> <p>Background</p> <p>Motivational interviewing (MI) is a collaborative, client-centred counselling style aimed at eliciting and strengthening clients' intrinsic motivation to change. There is strong research evidence supporting the efficacy of MI, notably in its application among alcohol and drug abuse populations. MI interventions in smoking cessation may yield modest but significant increases in quitting. The present study sought to assess the acquisition and retention of MI skills in counsellors at the Swedish National Tobacco Quitline.</p> <p>Methods</p> <p>Three audio-recorded sessions from each of three counsellors were assessed using the Motivational Interviewing Treatment Integrity (MITI) Code Version 3.0 over 11 assessment periods at fixed intervals in a two-and-a-half year period during which counsellors received ongoing supervision.</p> <p>Results</p> <p>The mean skill for all counsellors improved throughout the study period in most MITI variables. However, great variations in MI skill between counsellors were observed, as well as fluctuations in performance in counsellors over time.</p> <p>Conclusion</p> <p>The present exploratory study covers a longer time period than most evaluations of MI training, and has several advantages with regard to study design. It may provide a basis for (larger sample) replication to test MI skill (as measured by the MITI) in relation to behaviour change in clients, to evaluate MI training, and to assess the acquisition and retention of MI skill over time. Difficulties in acquiring and retaining MI skill may raise the issue of a selection policy for MI training. Moreover, fluctuations in MI skill over time emphasise the greater importance of continuous feedback and supervision over initial MI training, and the need for the use of validated treatment integrity assessment instruments in ordinary clinical implementations of MI.</p

Intrinsic activity in the fly brain gates visual information during behavioral choices

The small insect brain is often described as an input/output system that executes reflex-like behaviors. It can also initiate neural activity and behaviors intrinsically, seen as spontaneous behaviors, different arousal states and sleep. However, less is known about how intrinsic activity in neural circuits affects sensory information processing in the insect brain and variability in behavior. Here, by simultaneously monitoring Drosophila's behavioral choices and brain activity in a flight simulator system, we identify intrinsic activity that is associated with the act of selecting between visual stimuli. We recorded neural output (multiunit action potentials and local field potentials) in the left and right optic lobes of a tethered flying Drosophila, while its attempts to follow visual motion (yaw torque) were measured by a torque meter. We show that when facing competing motion stimuli on its left and right, Drosophila typically generate large torque responses that flip from side to side. The delayed onset (0.1-1 s) and spontaneous switch-like dynamics of these responses, and the fact that the flies sometimes oppose the stimuli by flying straight, make this behavior different from the classic steering reflexes. Drosophila, thus, seem to choose one stimulus at a time and attempt to rotate toward its direction. With this behavior, the neural output of the optic lobes alternates; being augmented on the side chosen for body rotation and suppressed on the opposite side, even though the visual input to the fly eyes stays the same. Thus, the flow of information from the fly eyes is gated intrinsically. Such modulation can be noise-induced or intentional; with one possibility being that the fly brain highlights chosen information while ignoring the irrelevant, similar to what we know to occur in higher animals

Development of an invasively monitored porcine model of acetaminophen-induced acute liver failure

Background: The development of effective therapies for acute liver failure (ALF) is limited by our knowledge of the pathophysiology of this condition, and the lack of suitable large animal models of acetaminophen toxicity. Our aim was to develop a reproducible invasively-monitored porcine model of acetaminophen-induced ALF. Method: 35kg pigs were maintained under general anaesthesia and invasively monitored. Control pigs received a saline infusion, whereas ALF pigs received acetaminophen intravenously for 12 hours to maintain blood concentrations between 200-300 mg/l. Animals surviving 28 hours were euthanased. Results: Cytochrome p450 levels in phenobarbital pre-treated animals were significantly higher than non pre-treated animals (300 vs 100 pmol/mg protein). Control pigs (n=4) survived 28-hour anaesthesia without incident. Of nine pigs that received acetaminophen, four survived 20 hours and two survived 28 hours. Injured animals developed hypotension (mean arterial pressure; 40.8+/-5.9 vs 59+/-2.0 mmHg), increased cardiac output (7.26+/-1.86 vs 3.30+/-0.40 l/min) and decreased systemic vascular resistance (8.48+/-2.75 vs 16.2+/-1.76 mPa/s/m3). Dyspnoea developed as liver injury progressed and the increased pulmonary vascular resistance (636+/-95 vs 301+/-26.9 mPa/s/m3) observed may reflect the development of respiratory distress syndrome. Liver damage was confirmed by deterioration in pH (7.23+/-0.05 vs 7.45+/-0.02) and prothrombin time (36+/-2 vs 8.9+/-0.3 seconds) compared with controls. Factor V and VII levels were reduced to 9.3 and 15.5% of starting values in injured animals. A marked increase in serum AST (471.5+/-210 vs 42+/-8.14) coincided with a marked reduction in serum albumin (11.5+/-1.71 vs 25+/-1 g/dL) in injured animals. Animals displayed evidence of renal impairment; mean creatinine levels 280.2+/-36.5 vs 131.6+/-9.33 mumol/l. Liver histology revealed evidence of severe centrilobular necrosis with coagulative necrosis. Marked renal tubular necrosis was also seen. Methaemoglobin levels did not rise >5%. Intracranial hypertension was not seen (ICP monitoring), but there was biochemical evidence of encephalopathy by the reduction of Fischer's ratio from 5.6 +/- 1.1 to 0.45 +/- 0.06. Conclusion: We have developed a reproducible large animal model of acetaminophen-induced liver failure, which allows in-depth investigation of the pathophysiological basis of this condition. Furthermore, this represents an important large animal model for testing artificial liver support systems

A Systematic Review of Mosquito Coils and Passive Emanators: Defining Recommendations for Spatial Repellency Testing Methodologies.

Mosquito coils, vaporizer mats and emanators confer protection against mosquito bites through the spatial action of emanated vapor or airborne pyrethroid particles. These products dominate the pest control market; therefore, it is vital to characterize mosquito responses elicited by the chemical actives and their potential for disease prevention. The aim of this review was to determine effects of mosquito coils and emanators on mosquito responses that reduce human-vector contact and to propose scientific consensus on terminologies and methodologies used for evaluation of product formats that could contain spatial chemical actives, including indoor residual spraying (IRS), long lasting insecticide treated nets (LLINs) and insecticide treated materials (ITMs). PubMed, (National Centre for Biotechnology Information (NCBI), U.S. National Library of Medicine, NIH), MEDLINE, LILAC, Cochrane library, IBECS and Armed Forces Pest Management Board Literature Retrieval System search engines were used to identify studies of pyrethroid based coils and emanators with key-words "Mosquito coils" "Mosquito emanators" and "Spatial repellents". It was concluded that there is need to improve statistical reporting of studies, and reach consensus in the methodologies and terminologies used through standardized testing guidelines. Despite differing evaluation methodologies, data showed that coils and emanators induce mortality, deterrence, repellency as well as reduce the ability of mosquitoes to feed on humans. Available data on efficacy outdoors, dose-response relationships and effective distance of coils and emanators is inadequate for developing a target product profile (TPP), which will be required for such chemicals before optimized implementation can occur for maximum benefits in disease control

Enzymatic degradation of starch thermoplastic blends using samples of different thickness

The material studied was a thermoplastic blend of corn starch with a poly(ethylene-vinyl alcohol) copolymer, SEVA-C. The influence of both the material’s exposed surface and enzyme concentration on degradation kinetics was studied. As α-amylase is present in the blood plasma, experiments were performed, varying the material thickness and the α-amylase between 50 and 100 units/l, at 37°C, lasting up to 90 days. Four different batches using SEVA-C and starch samples of different thickness were performed. The positive correlation between degradation rate and the exposed material surface was confirmed, since thin films with larger exposed surfaces were degraded faster than thick square plates having the same total mass. The degradation extent depends on the total amount of amorphous starch present in the formulation rather than on the amount of enzyme used and the minimum thickness to ensure maximum degradation was estimated to be close to 0.25 mm

Pedestrian, Crowd, and Evacuation Dynamics

This contribution describes efforts to model the behavior of individual pedestrians and their interactions in crowds, which generate certain kinds of self-organized patterns of motion. Moreover, this article focusses on the dynamics of crowds in panic or evacuation situations, methods to optimize building designs for egress, and factors potentially causing the breakdown of orderly motion.Comment: This is a review paper. For related work see http://www.soms.ethz.c