Quantitative genomics of starvation stress resistance in Drosophila

BACKGROUND: A major challenge of modern biology is to understand the networks of interacting genes regulating complex traits, and the subset of these genes that affect naturally occurring quantitative genetic variation. Previously, we used P-element mutagenesis and quantitative trait locus (QTL) mapping in Drosophila to identify candidate genes affecting resistance to starvation stress, and variation in resistance to starvation stress between the Oregon-R (Ore) and 2b strains. Here, we tested the efficacy of whole-genome transcriptional profiling for identifying genes affecting starvation stress resistance. RESULTS: We evaluated whole-genome transcript abundance for males and females of Ore, 2b, and four recombinant inbred lines derived from them, under control and starved conditions. There were significant differences in transcript abundance between the sexes for nearly 50% of the genome, while the transcriptional response to starvation stress involved approximately 25% of the genome. Nearly 50% of P-element insertions in 160 genes with altered transcript abundance during starvation stress had mutational effects on starvation tolerance. Approximately 5% of the genome exhibited genetic variation in transcript abundance, which was largely attributable to regulation by unlinked genes. Genes exhibiting variation in transcript abundance among lines did not cluster within starvation resistance QTLs, and none of the candidate genes affecting variation in starvation resistance between Ore and 2b exhibited significant differences in transcript abundance between lines. CONCLUSIONS: Expression profiling is a powerful method for identifying networks of pleiotropic genes regulating complex traits, but the relationship between variation in transcript abundance among lines used to map QTLs and genes affecting variation in quantitative traits is complicated

"Boring formal methods" or "Sherlock Holmes deduction methods"?

This paper provides an overview of common challenges in teaching of logic and formal methods to Computer Science and IT students. We discuss our experiences from the course IN3050: Applied Logic in Engineering, introduced as a "logic for everybody" elective course at at TU Munich, Germany, to engage pupils studying Computer Science, IT and engineering subjects on Bachelor and Master levels. Our goal was to overcome the bias that logic and formal methods are not only very complicated but also very boring to study and to apply. In this paper, we present the core structure of the course, provide examples of exercises and evaluate the course based on the students' surveys.Comment: Preprint. Accepted to the Software Technologies: Applications and Foundations (STAF 2016). Final version published by Springer International Publishing AG. arXiv admin note: substantial text overlap with arXiv:1602.0517

Bilateral pedicle stress fracture in the lumbar spine of a sedentary office worker

A case of bilateral pedicle fracture in the lumbar spine of a sedentary office worker is being presented. No such case has been reported in the literature previously. Bilateral pedicle fracture is a rare entity. Few cases have been reported in literature. All the reported cases had some underlying causative factors like degenerative spine disease, previous spinal surgery or stress-related activities, e.g. athletes. Our case is a 36-year-old sedentary office worker with none of the factors mentioned. We present a case of a 36-year-old sedentary worker with long-standing low backache. There were no root tension signs. Plain radiographs were inconclusive. The patient had a CT scan. The CT scan revealed long-standing defects in the pedicles of L2 vertebra with pseudoarthrosis. Infiltration with anaesthetic relieved the symptoms. Our patient was managed conservatively with spine rehabilitation physiotherapy program. Pedicle fracture can develop due to abnormal stresses in the pedicle either because of previous spinal surgery or spondylitic changes in the spine. Bilateral pedicle fracture in the absence of these conditions is extremely rare

The Rewiring of Ubiquitination Targets in a Pathogenic Yeast Promotes Metabolic Flexibility, Host Colonization and Virulence

Funding: This work was funded by the European Research Council [http://erc.europa.eu/], AJPB (STRIFE Advanced Grant; C-2009-AdG-249793). The work was also supported by: the Wellcome Trust [www.wellcome.ac.uk], AJPB (080088, 097377); the UK Biotechnology and Biological Research Council [www.bbsrc.ac.uk], AJPB (BB/F00513X/1, BB/K017365/1); the CNPq-Brazil [http://cnpq.br], GMA (Science without Borders fellowship 202976/2014-9); and the National Centre for the Replacement, Refinement and Reduction of Animals in Research [www.nc3rs.org.uk], DMM (NC/K000306/1). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank Dr. Elizabeth Johnson (Mycology Reference Laboratory, Bristol) for providing strains, and the Aberdeen Proteomics facility for the biotyping of S. cerevisiae clinical isolates, and to Euroscarf for providing S. cerevisiae strains and plasmids. We are grateful to our Microscopy Facility in the Institute of Medical Sciences for their expert help with the electron microscopy, and to our friends in the Aberdeen Fungal Group for insightful discussions.Peer reviewedPublisher PD

Comparison of tonic spinal cord stimulation, high-frequency and burst stimulation in patients with complex regional pain syndrome: a double-blind, randomised placebo controlled trial

BACKGROUND: Complex Regional Pain Syndrome (CRPS) is a disabling disease that is sometimes difficult to treat. Although spinal cord stimulation (SCS) can reduce pain in most patients with CRPS, some do not achieve the desired reduction in pain. Moreover, the pain reduction can diminish over time even after an initially successful period of SCS. Pain reduction can be regained by increasing the SCS frequency, but this has not been investigated in a prospective trial. This study compares pain reduction using five SCS frequencies (standard 40 Hz, 500 Hz, 1200 Hz, burst and placebo stimulation) in patients with CRPS to determine which of the modalities is most effective. DESIGN: All patients with a confirmed CRPS diagnosis that have unsuccessfully tried all other therapies and are eligible for SCS, can enroll in this trial (primary implantation group). CRPS patients that already receive SCS therapy, or those previously treated with SCS but with loss of therapeutic effect over time, can also participate (re-implantation group). Once all inclusion criteria are met and written informed consent obtained, patients will undergo a baseline assessment (T0). A 2-week trial with SCS is performed and, if successful, a rechargeable internal pulse generator (IPG) is implanted. For the following 3 months the patient will have standard 40 Hz stimulation therapy before a follow-up assessment (T1) is performed. Those who have completed the T1 assessment will enroll in a 10-week crossover period in which the five SCS frequencies are tested in five periods, each frequency lasting for 2 weeks. At the end of the crossover period, the patient will choose which frequency is to be used for stimulation for an additional 3 months, until the T2 assessment. DISCUSSION: Currently no trials are available that systematically investigate the importance of variation in frequency during SCS in patients with CRPS. Data from this trial will provide better insight as to whether SCS with a higher frequency, or with burst stimulation, results in more effective pain relief. TRIAL REGISTRATION: Current Controlled Trials ISRCTN3665525

Genetic analyses of maternal and teacher ratings on attention problems in 7-year-old Dutch twins

The goal of the present study is to examine genetic and environmental influences on maternal and teacher ratings of Attention Problems (AP) in 7-year-old children. Teachers completed the Teacher Report Form (N=2259 pairs), and mothers the Child Behavior Checklist (N=2057 pairs). Higher correlations were found in twins rated by the same teacher than in twins rated by different teachers. This can be explained by rater bias or by a greater environmental sharing in twins, who are in the same classroom. We further found that 41% of the variation in maternal and teacher ratings is explained by a common factor. The heritability of this common factor is 78%. The heritabilities of the rater specific factors of mothers and teachers are 76% and 39%, respectively. Because Attention Problems that are persistent over situations may indicate more serious behavior problems than context dependent Attention Problems, we believe that gene finding strategies should focus on this common phenotype

Investigating the Role of Islet Cytoarchitecture in Its Oscillation Using a New β-Cell Cluster Model

The oscillatory insulin release is fundamental to normal glycemic control. The basis of the oscillation is the intercellular coupling and bursting synchronization of β cells in each islet. The functional role of islet β cell mass organization with respect to its oscillatory bursting is not well understood. This is of special interest in view of the recent finding of islet cytoarchitectural differences between human and animal models. In this study we developed a new hexagonal closest packing (HCP) cell cluster model. The model captures more accurately the real islet cell organization than the simple cubic packing (SCP) cluster that is conventionally used. Using our new model we investigated the functional characteristics of β-cell clusters, including the fraction of cells able to burst fb, the synchronization index λ of the bursting β cells, the bursting period Tb, the plateau fraction pf, and the amplitude of intracellular calcium oscillation [Ca]. We determined their dependence on cluster architectural parameters including number of cells nβ, number of inter-β cell couplings of each β cell nc, and the coupling strength gc. We found that at low values of nβ, nc and gc, the oscillation regularity improves with their increasing values. This functional gain plateaus around their physiological values in real islets, at nβ∼100, nc∼6 and gc∼200 pS. In addition, normal β-cell clusters are robust against significant perturbation to their architecture, including the presence of non-β cells or dead β cells. In clusters with nβ>∼100, coordinated β-cell bursting can be maintained at up to 70% of β-cell loss, which is consistent with laboratory and clinical findings of islets. Our results suggest that the bursting characteristics of a β-cell cluster depend quantitatively on its architecture in a non-linear fashion. These findings are important to understand the islet bursting phenomenon and the regulation of insulin secretion, under both physiological and pathological conditions

Considering methodological options for reviews of theory: illustrated by a review of theories linking income and health

Background: Review of theory is an area of growing methodological advancement. Theoretical reviews are particularly useful where the literature is complex, multi-discipline, or contested. It has been suggested that adopting methods from systematic reviews may help address these challenges. However, the methodological approaches to reviews of theory, including the degree to which systematic review methods can be incorporated, have received little discussion in the literature. We recently employed systematic review methods in a review of theories about the causal relationship between income and health. Methods: This article discusses some of the methodological issues we considered in developing the review and offers lessons learnt from our experiences. It examines the stages of a systematic review in relation to how they could be adapted for a review of theory. The issues arising and the approaches taken in the review of theories in income and health are considered, drawing on the approaches of other reviews of theory. Results: Different approaches to searching were required, including electronic and manual searches, and electronic citation tracking to follow the development of theories. Determining inclusion criteria was an iterative process to ensure that inclusion criteria were specific enough to make the review practical and focused, but not so narrow that key literature was excluded. Involving subject specialists was valuable in the literature searches to ensure principal papers were identified and during the inductive approaches used in synthesis of theories to provide detailed understanding of how theories related to another. Reviews of theory are likely to involve iterations and inductive processes throughout, and some of the concepts and techniques that have been developed for qualitative evidence synthesis can be usefully translated to theoretical reviews of this kind. Conclusions: It may be useful at the outset of a review of theory to consider whether the key aim of the review is to scope out theories relating to a particular issue; to conduct in-depth analysis of key theoretical works with the aim of developing new, overarching theories and interpretations; or to combine both these processes in the review. This can help decide the most appropriate methodological approach to take at particular stages of the review

Amyloid-Mediated Sequestration of Essential Proteins Contributes to Mutant Huntingtin Toxicity in Yeast

BACKGROUND: Polyglutamine expansion is responsible for several neurodegenerative disorders, among which Huntington disease is the most well-known. Studies in the yeast model demonstrated that both aggregation and toxicity of a huntingtin (htt) protein with an expanded polyglutamine region strictly depend on the presence of the prion form of Rnq1 protein ([PIN+]), which has a glutamine/asparagine-rich domain. PRINCIPAL FINDINGS: Here, we showed that aggregation and toxicity of mutant htt depended on [PIN+] only quantitatively: the presence of [PIN+] elevated the toxicity and the levels of htt detergent-insoluble polymers. In cells lacking [PIN+], toxicity of mutant htt was due to the polymerization and inactivation of the essential glutamine/asparagine-rich Sup35 protein and related inactivation of another essential protein, Sup45, most probably via its sequestration into Sup35 aggregates. However, inhibition of growth of [PIN+] cells depended on Sup35/Sup45 depletion only partially, suggesting that there are other sources of mutant htt toxicity in yeast. CONCLUSIONS: The obtained data suggest that induced polymerization of essential glutamine/asparagine-rich proteins and related sequestration of other proteins which interact with these polymers represent an essential source of htt toxicity

Communication, social capital and workplace health management as determinants of the innovative climate in German banks

The present study aims to measure the determinants of the innovative climate in German banks with a focus on workplace health management (WHM). We analyze the determinants of innovative climate with multiple regressions using a dataset based on standardized telephone interviews conducted with health promotion experts from 198 randomly selected German banks. The regression analysis provided a good explanation of the variance in the dependent variable (RA(2)A = 55%). Communication climate (beta = 0.55; p < 0.001), social capital (beta = 0.21; p < 0.01), the establishment of a WHM program (beta = 0.13; p < 0.05) as well as company size (beta = 0.15; p < 0.01) were found to have a significant impact on an organization's innovative climate. In order to foster an innovation-friendly climate, organizations should establish shared values. An active step in this direction involves strengthening the organizations' social capital and communication climate through trustworthy management decisions such as the implementation of a WHM program