Mining Biological Pathways Using WikiPathways Web Services

WikiPathways is a platform for creating, updating, and sharing biological pathways [1]. Pathways can be edited and downloaded using the wiki-style website. Here we present a SOAP web service that provides programmatic access to WikiPathways that is complementary to the website. We describe the functionality that this web service offers and discuss several use cases in detail. Exposing WikiPathways through a web service opens up new ways of utilizing pathway information and assisting the community curation process.     

A new predictor for the onset of atrial fibrillation?

In this issue of the Netherlands Heart Journal, the results of a substudy of the PREVEND trial are published.1 This prospective registry of presumably healthy citizens of Groningen aims to establish the association between microalbuminuria and the emergence of renal and cardiovascular diseases.2 This general population based long-term study extends the series of previous large-scale epidemiological trials conducted in the Netherlands. We recall among them the 1970 Vlagtwedde study for epidemiological cardiology and ischaemic heart disease, the 1982 Zutphen study of diet and cardiovascular diseases, the 1997 Maastricht study of circulatory arrest and sudden death, the 1998 Amsterdam study of out-of-hospital cardiac arrest and the 1999 Rotterdam study of prolonged QT interval and mortality.     

The Deep Atmospheric Boundary Layer and Its Significance to the Stratosphere and Troposphere Exchange over the Tibetan Plateau

In this study the depth of the atmospheric boundary layer (ABL) over the Tibetan Plateau was measured during a regional radiosonde observation campaign in 2008 and found to be deeper than indicated by previously measurements. Results indicate that during fair weather conditions on winter days, the top of the mixed layers can be up to 5 km above the ground (9.4 km above sea level). Measurements also show that the depth of the ABL is quite distinct for three different periods (winter, monsoon-onset, and monsoon seasons). Turbulence at the top of a deep mixing layer can rise up to the upper troposphere. As a consequence, as confirmed by trajectory analysis, interaction occurs between deep ABLs and the low tropopause during winter over the Tibetan Plateau.     

Observable Weight Distributions and Children's Individual Weight Assessment

Social networks theory suggests obesity is “contagious” within peer groups in that known friends highly influence weight. On the other hand, an alternative model suggests that observable weight distributions affect perception of one's own obesity level. We examine whether the BMI levels of the most obese classmates in the individual student's grade by gender is positively associated with “under‐assessment” of obesity and overweight (i.e., independently measured obesity or overweight, but subjective self‐assessment of normal weight). The data are the 2004–2005 School Physical Activity and Nutrition III (SPAN), a stratified, multistage probability sample of 4th, 8th, and 11th grade public school children in Texas. We used logistic regression to test whether the gender‐specific 85th percentile BMI level within the individual student's grade at their school is positively associated with “under‐assessment” of obesity and overweight. The results show that students are much more likely to under‐assess their own weight if the gender‐specific 85th percentile BMI level is higher in their grade at their school. These data suggest that observable weight distributions play a key role in the obesity epidemic.     

Time-Resolved and Tissue-Specific Systems Analysis of the Pathogenesis of Insulin Resistance

Background

The sequence of events leading to the development of insulin resistance (IR) as well as the underlying pathophysiological mechanisms are incompletely understood. As reductionist approaches have been largely unsuccessful in providing an understanding of the pathogenesis of IR, there is a need for an integrative, time-resolved approach to elucidate the development of the disease.

Methodology/Principal Findings

Male ApoE3Leiden transgenic mice exhibiting a humanized lipid metabolism were fed a high-fat diet (HFD) for 0, 1, 6, 9, or 12 weeks. Development of IR was monitored in individual mice over time by performing glucose tolerance tests and measuring specific biomarkers in plasma, and hyperinsulinemic-euglycemic clamp analysis to assess IR in a tissue-specific manner. To elucidate the dynamics and tissue-specificity of metabolic and inflammatory processes key to IR development, a time-resolved systems analysis of gene expression and metabolite levels in liver, white adipose tissue (WAT), and muscle was performed. During HFD feeding, the mice became increasingly obese and showed a gradual increase in glucose intolerance. IR became first manifest in liver (week 6) and then in WAT (week 12), while skeletal muscle remained insulin-sensitive. Microarray analysis showed rapid upregulation of carbohydrate (only liver) and lipid metabolism genes (liver, WAT). Metabolomics revealed significant changes in the ratio of saturated to polyunsaturated fatty acids (liver, WAT, plasma) and in the concentrations of glucose, gluconeogenesis and Krebs cycle metabolites, and branched amino acids (liver). HFD evoked an early hepatic inflammatory response which then gradually declined to near baseline. By contrast, inflammation in WAT increased over time, reaching highest values in week 12. In skeletal muscle, carbohydrate metabolism, lipid metabolism, and inflammation was gradually suppressed with HFD.

Conclusions/Significance

HFD-induced IR is a time- and tissue-dependent process that starts in liver and proceeds in WAT. IR development is paralleled by tissue-specific gene expression changes, metabolic adjustments, changes in lipid composition, and inflammatory responses in liver and WAT involving p65-NFkB and SOCS3. The alterations in skeletal muscle are largely opposite to those in liver and WAT.     

Development and preliminary validation of the cancer family impact scale for colorectal cancer

AIM: The aim of our study was to develop a measure of how a family history of colorectal cancer (CRC) affects families from the viewpoint of unaffected family members. METHOD: Using data from 1,285 participants (637 families) in the Johns Hopkins Colon Cancer Genetic Testing study, we developed and validated The Cancer Family Impact Scale (CFIS), an instrument for use in studies investigating relationships among family factors and CRC prevention behaviors when family history is a risk factor. RESULTS: Through exploratory factor analysis (EFA) using a 50% random sample of participants, we identified 5 latent constructs among 18 items: (1) NEGATIVE: negative effects of cancer on the family; (2) POSITIVE: positive effects of cancer on the family; (3) COMMUNICATE: how families communicate about cancer; (4) FLOW: how information about cancer is conveyed in families; and (5) NORM: how individuals react to family norms about cancer. Confirmatory factor analysis (CFA) on the same sample showed the CFIS to have a reasonably good fit (chi(2) = 389.97, degree of freedom (df ) = 122, root mean square error of approximation = 0.06 [0.05-0.07], comparative fit index = 0.90, Tucker-Lewis index = 0.88, goodness of fit index = 0.94), and findings were cross-validated on the remaining 50% of the participants. The reliability of the scale was alpha = 0.65. CONCLUSIONS: The CFIS could be used to clarify the role that family factors play in the association between CRC family history and CRC prevention behaviors, and also aid in the development and evaluation of family-based cancer prevention interventions.     

The sinus venosus myocardium contributes to the atrioventricular canal: potential role during atrioventricular node development?

The presence of distinct electrophysiological pathways within the atrioventricular node (AVN) is a prerequisite for atrioventricular nodal reentrant tachycardia to occur. In this study, the different cell contributions that may account for the anatomical and functional heterogeneity of the AVN were investigated. To study the temporal development of the AVN, the expression pattern of ISL1, expressed in cardiac progenitor cells, was studied in sequential stages performing co‐staining with myocardial markers (TNNI2 and NKX2‐5) and HCN4 (cardiac conduction system marker). An ISL1+/TNNI2+/HCN4+ continuity between the myocardium of the sinus venosus and atrioventricular canal was identified in the region of the putative AVN, which showed a pacemaker‐like phenotype based on single cell patch‐clamp experiments. Furthermore, qPCR analysis showed that even during early development, different cell populations can be identified in the region of the putative AVN. Fate mapping was performed by in ovo vital dye microinjection. Embryos were harvested and analysed 24 and 48 hrs post‐injection. These experiments showed incorporation of sinus venosus myocardium in the posterior region of the atrioventricular canal. The myocardium of the sinus venosus contributes to the atrioventricular canal. It is postulated that the myocardium of the sinus venosus contributes to nodal extensions or transitional cells of the AVN since these cells are located in the posterior region of the AVN. This finding may help to understand the origin of atrioventricular nodal reentrant tachycardia.     

PathVisio 3: An Extendable Pathway Analysis Toolbox

PathVisio is a commonly used pathway editor, visualization and analysis software. Biological pathways have been used by biologists for many years to describe the detailed steps in biological processes. Those powerful, visual representations help researchers to better understand, share and discuss knowledge. Since the first publication of PathVisio in 2008, the original paper was cited more than 170 times and PathVisio was used in many different biological studies. As an online editor PathVisio is also integrated in the community curated pathway database WikiPathways.Here we present the third version of PathVisio with the newest additions and improvements of the application. The core features of PathVisio are pathway drawing, advanced data visualization and pathway statistics. Additionally, PathVisio 3 introduces a new powerful extension systems that allows other developers to contribute additional functionality in form of plugins without changing the core application.PathVisio can be downloaded from http://www.pathvisio.org and in 2014 PathVisio 3 has been downloaded over 5,500 times. There are already more than 15 plugins available in the central plugin repository. PathVisio is a freely available, open-source tool published under the Apache 2.0 license (http://www.apache.org/licenses/LICENSE-2.0). It is implemented in Java and thus runs on all major operating systems. The code repository is available at http://svn.bigcat.unimaas.nl/pathvisio. The support mailing list for users is available on https://groups.google.com/forum/#!forum/wikipathways-discuss and for developers on https://groups.google.com/forum/#!forum/wikipathways-devel.

This is a PLOS Computational Biology software article.

     

Long-term bleeding events after mechanical aortic valve replacement in patients under the age of 60

BackgroundAlthough younger patients are supposed to be less susceptible to bleeding complications of mechanical aortic valve replacement (mAVR) than older patients, there is a relative paucity of data on this subject. Therefore, it remains uncertain whether younger patients are really at a lower risk of these complications than older patients.MethodsIncidence rates of bleeding events during 15 years of follow-up after mAVR were compared between 163 patients under 60 (group I), 122 patients between 60 and 65 (group II), and 145 patients over 65 (group III) years of age at operation. The target international normalised ratio (INR) was 3.0–4.0.ResultsDuring 15 years of follow-up, the annual incidence rate of major bleeding events (excluding haemorrhagic stroke) was lower in the youngest as compared with the oldest group (3.0 versus 4.7 %, respectively; p = 0.030). However, the annual incidence rate of haemorrhagic stroke was as high in the youngest as in the two older groups (0.6 versus 0.7 % and 0.7 %, respectively; p = 0.928).ConclusionsWith a target INR of 3.0–4.0, patients under 60 years of age are at equally high risk of haemorrhagic stroke after mAVR as older patients. This finding confirms the relevance of a lower target INR as used in international guidelines.