Spatially Uniform ReliefF (SURF) for computationally-efficient filtering of gene-gene interactions

<p>Abstract</p> <p>Background</p> <p>Genome-wide association studies are becoming the de facto standard in the genetic analysis of common human diseases. Given the complexity and robustness of biological networks such diseases are unlikely to be the result of single points of failure but instead likely arise from the joint failure of two or more interacting components. The hope in genome-wide screens is that these points of failure can be linked to single nucleotide polymorphisms (SNPs) which confer disease susceptibility. Detecting interacting variants that lead to disease in the absence of single-gene effects is difficult however, and methods to exhaustively analyze sets of these variants for interactions are combinatorial in nature thus making them computationally infeasible. Efficient algorithms which can detect interacting SNPs are needed. ReliefF is one such promising algorithm, although it has low success rate for noisy datasets when the interaction effect is small. ReliefF has been paired with an iterative approach, Tuned ReliefF (TuRF), which improves the estimation of weights in noisy data but does not fundamentally change the underlying ReliefF algorithm. To improve the sensitivity of studies using these methods to detect small effects we introduce Spatially Uniform ReliefF (SURF).</p> <p>Results</p> <p>SURF's ability to detect interactions in this domain is significantly greater than that of ReliefF. Similarly SURF, in combination with the TuRF strategy significantly outperforms TuRF alone for SNP selection under an epistasis model. It is important to note that this success rate increase does not require an increase in algorithmic complexity and allows for increased success rate, even with the removal of a nuisance parameter from the algorithm.</p> <p>Conclusion</p> <p>Researchers performing genetic association studies and aiming to discover gene-gene interactions associated with increased disease susceptibility should use SURF in place of ReliefF. For instance, SURF should be used instead of ReliefF to filter a dataset before an exhaustive MDR analysis. This change increases the ability of a study to detect gene-gene interactions. The SURF algorithm is implemented in the open source Multifactor Dimensionality Reduction (MDR) software package available from <url>http://www.epistasis.org</url>.</p

Network analysis of the Viking Age in Ireland as portrayed in Cogadh Gaedhel re Gallaibh

Cogadh Gaedhel re Gallaibh (‘The War of the Gaedhil with the Gaill’) is a medieval Irish text, telling how an army under the leadership of Brian Boru challenged Viking invaders and their allies in Ireland, culminating with the Battle of Clontarf in 1014. Brian’s victory is widely remembered for breaking Viking power in Ireland, although much modern scholarship disputes traditional perceptions. Instead of an international conflict between Irish and Viking, interpretations based on revisionist scholarship consider it a domestic feud or civil war. Counterrevisionists challenge this view and a long-standing and lively debate continues. Here, we introduce quantitative measures to the discussions.We present statistical analyses of network data embedded in the text to position its sets of interactions on a spectrum from the domestic to the international. This delivers a picture that lies between antipodal traditional and revisionist extremes; hostilities recorded in the text are mostly between Irish and Viking—but internal conflict forms a significant proportion of the negative interactions too

Population genomics of domestic and wild yeasts

The natural genetics of an organism is determined by the distribution of sequences of its genome. Here we present one- to four-fold, with some deeper, coverage of the genome sequences of over seventy isolates of the domesticated baker&#x27;s yeast, _Saccharomyces cerevisiae_, and its closest relative, the wild _S. paradoxus_, which has never been associated with human activity. These were collected from numerous geographic locations and sources (including wild, clinical, baking, wine, laboratory and food spoilage). These sequences provide an unprecedented view of the population structure, natural (and artificial) selection and genome evolution in these species. Variation in gene content, SNPs, indels, copy numbers and transposable elements provide insights into the evolution of different lineages. Phenotypic variation broadly correlates with global genome-wide phylogenetic relationships however there is no correlation with source. _S. paradoxus_ populations are well delineated along geographic boundaries while the variation among worldwide _S. cerevisiae_ isolates show less differentiation and is comparable to a single _S. paradoxus_ population. Rather than one or two domestication events leading to the extant baker&#x27;s yeasts, the population structure of _S. cerevisiae_ shows a few well defined geographically isolated lineages and many different mosaics of these lineages, supporting the notion that human influence provided the opportunity for outbreeding and production of new combinations of pre-existing variation

A self-organized model for cell-differentiation based on variations of molecular decay rates

Systemic properties of living cells are the result of molecular dynamics governed by so-called genetic regulatory networks (GRN). These networks capture all possible features of cells and are responsible for the immense levels of adaptation characteristic to living systems. At any point in time only small subsets of these networks are active. Any active subset of the GRN leads to the expression of particular sets of molecules (expression modes). The subsets of active networks change over time, leading to the observed complex dynamics of expression patterns. Understanding of this dynamics becomes increasingly important in systems biology and medicine. While the importance of transcription rates and catalytic interactions has been widely recognized in modeling genetic regulatory systems, the understanding of the role of degradation of biochemical agents (mRNA, protein) in regulatory dynamics remains limited. Recent experimental data suggests that there exists a functional relation between mRNA and protein decay rates and expression modes. In this paper we propose a model for the dynamics of successions of sequences of active subnetworks of the GRN. The model is able to reproduce key characteristics of molecular dynamics, including homeostasis, multi-stability, periodic dynamics, alternating activity, differentiability, and self-organized critical dynamics. Moreover the model allows to naturally understand the mechanism behind the relation between decay rates and expression modes. The model explains recent experimental observations that decay-rates (or turnovers) vary between differentiated tissue-classes at a general systemic level and highlights the role of intracellular decay rate control mechanisms in cell differentiation.Comment: 16 pages, 5 figure

Uncovering treatment burden as a key concept for stroke care: a systematic review of qualitative research

&lt;b&gt;Background&lt;/b&gt; Patients with chronic disease may experience complicated management plans requiring significant personal investment. This has been termed ‘treatment burden’ and has been associated with unfavourable outcomes. The aim of this systematic review is to examine the qualitative literature on treatment burden in stroke from the patient perspective.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Methods and findings&lt;/b&gt; The search strategy centred on: stroke, treatment burden, patient experience, and qualitative methods. We searched: Scopus, CINAHL, Embase, Medline, and PsycINFO. We tracked references, footnotes, and citations. Restrictions included: English language, date of publication January 2000 until February 2013. Two reviewers independently carried out the following: paper screening, data extraction, and data analysis. Data were analysed using framework synthesis, as informed by Normalization Process Theory. Sixty-nine papers were included. Treatment burden includes: (1) making sense of stroke management and planning care, (2) interacting with others, (3) enacting management strategies, and (4) reflecting on management. Health care is fragmented, with poor communication between patient and health care providers. Patients report inadequate information provision. Inpatient care is unsatisfactory, with a perceived lack of empathy from professionals and a shortage of stimulating activities on the ward. Discharge services are poorly coordinated, and accessing health and social care in the community is difficult. The study has potential limitations because it was restricted to studies published in English only and data from low-income countries were scarce.&lt;p&gt;&lt;/p&gt; &lt;b&gt;Conclusions&lt;/b&gt; Stroke management is extremely demanding for patients, and treatment burden is influenced by micro and macro organisation of health services. Knowledge deficits mean patients are ill equipped to organise their care and develop coping strategies, making adherence less likely. There is a need to transform the approach to care provision so that services are configured to prioritise patient needs rather than those of health care systems

Primary peritoneal and ovarian cancers: an epidemiological comparative analysis

We performed case–control analyses using data from the North Carolina Ovarian Cancer Study to determine risk factors that distinguish primary peritoneal cancer (PPC) from epithelial ovarian cancer (EOC). Our risk factor analyses were restricted to invasive serous cancers including 495 EOC cases, 62 PPC cases and 1,086 control women. Logistic regression analyses were used to calculate adjusted odds ratios and 95% confidence intervals for risk factor associations. Although many case–control associations for the invasive serous PPC cases were similar to those of the invasive serous EOC cases, some differences were observed including a twofold increase in risk of invasive serous PPC in women who were ≥35 years at last pregnancy, whereas a decreased risk was observed for invasive serous EOC risk. We could not confirm a previous report of an association between tubal ligation and PPC, a factor consistently associated with a decreased risk of EOC. The difference in the risk factor associations between invasive serous PPC and EOC cancers suggests divergent molecular development of peritoneal and ovarian cancers. A larger study to determine risk factors for invasive serous PPC is warranted

Effect of 28 days of creatine ingestion on muscle metabolism and performance of a simulated cycling road race

<p>Abstract</p> <p>Purpose</p> <p>The effects of creatine supplementation on muscle metabolism and exercise performance during a simulated endurance road race was investigated.</p> <p>Methods</p> <p>Twelve adult male (27.3 ± 1.0 yr, 178.6 ± 1.4 cm, 78.0 ± 2.5 kg, 8.9 ± 1.1 %fat) endurance-trained (53.3 ± 2.0 ml* kg^-1* min^-1, cycling ~160 km/wk) cyclists completed a simulated road race on a cycle ergometer (Lode), consisting of a two-hour cycling bout at 60% of peak aerobic capacity (VO_2peak) with three 10-second sprints performed at 110% VO_{2 peak}every 15 minutes. Cyclists completed the 2-hr cycling bout before and after dietary creatine monohydrate or placebo supplementation (3 g/day for 28 days). Muscle biopsies were taken at rest and five minutes before the end of the two-hour ride.</p> <p>Results</p> <p>There was a 24.5 ± 10.0% increase in resting muscle total creatine and 38.4 ± 23.9% increase in muscle creatine phosphate in the creatine group (<it>P </it>< 0.05). Plasma glucose, blood lactate, and respiratory exchange ratio during the 2-hour ride, as well as VO_{2 peak}, were not affected by creatine supplementation. Submaximal oxygen consumption near the end of the two-hour ride was decreased by approximately 10% by creatine supplementation (P < 0.05). Changes in plasma volume from pre- to post-supplementation were significantly greater in the creatine group (⁺14.0 ± 6.3%) than the placebo group (^-10.4 ± 4.4%; <it>P </it>< 0.05) at 90 minutes of exercise. The time of the final sprint to exhaustion at the end of the 2-hour cycling bout was not affected by creatine supplementation (creatine pre, 64.4 ± 13.5s; creatine post, 88.8 ± 24.6s; placebo pre, 69.0 ± 24.8s; placebo post 92.8 ± 31.2s: creatine vs. placebo not significant). Power output for the final sprint was increased by ~33% in both groups (creatine vs. placebo not significant).</p> <p>Conclusions</p> <p>It can be concluded that although creatine supplementation may increase resting muscle total creatine, muscle creatine phosphate, and plasma volume, and may lead to a reduction in oxygen consumption during submaximal exercise, creatine supplementation does not improve sprint performance at the end of endurance cycling exercise.</p

Nebulization of the acidified sodium nitrite formulation attenuates acute hypoxic pulmonary vasoconstriction

<p>Abstract</p> <p>Background</p> <p>Generalized hypoxic pulmonary vasoconstriction (HPV) occurring during exposure to hypoxia is a detrimental process resulting in an increase in lung vascular resistance. Nebulization of sodium nitrite has been shown to inhibit HPV. The aim of this project was to investigate and compare the effects of nebulization of nitrite and different formulations of acidified sodium nitrite on acute HPV.</p> <p>Methods</p> <p><it>Ex vivo </it>isolated rabbit lungs perfused with erythrocytes in Krebs-Henseleit buffer (adjusted to 10% hematocrit) and <it>in vivo </it>anesthetized catheterized rabbits were challenged with periods of hypoxic ventilation alternating with periods of normoxic ventilation. After baseline hypoxic challenges, vehicle, sodium nitrite or acidified sodium nitrite was delivered via nebulization. In the <it>ex vivo </it>model, pulmonary arterial pressure and nitric oxide concentrations in exhaled gas were monitored. Nitrite and nitrite/nitrate were measured in samples of perfusion buffer. Pulmonary arterial pressure, systemic arterial pressure, cardiac output and blood gases were monitored in the <it>in vivo </it>model.</p> <p>Results</p> <p>In the <it>ex vivo </it>model, nitrite nebulization attenuated HPV and increased nitric oxide concentrations in exhaled gas and nitrite concentrations in the perfusate. The acidified forms of sodium nitrite induced higher levels of nitric oxide in exhaled gas and had longer vasodilating effects compared to nitrite alone. All nitrite formulations increased concentrations of circulating nitrite to the same degree. In the <it>in vivo </it>model, inhaled nitrite inhibited HPV, while pulmonary arterial pressure, cardiac output and blood gases were not affected. All nitrite formulations had similar potency to inhibit HPV. The tested concentration of appeared tolerable.</p> <p>Conclusion</p> <p>Nitrite alone and in acidified forms effectively and similarly attenuates HPV. However, acidified nitrite formulations induce a more pronounced increase in nitric oxide exhalation.</p