Maximal information component analysis: a novel non-linear network analysis method.

BackgroundNetwork construction and analysis algorithms provide scientists with the ability to sift through high-throughput biological outputs, such as transcription microarrays, for small groups of genes (modules) that are relevant for further research. Most of these algorithms ignore the important role of non-linear interactions in the data, and the ability for genes to operate in multiple functional groups at once, despite clear evidence for both of these phenomena in observed biological systems.ResultsWe have created a novel co-expression network analysis algorithm that incorporates both of these principles by combining the information-theoretic association measure of the maximal information coefficient (MIC) with an Interaction Component Model. We evaluate the performance of this approach on two datasets collected from a large panel of mice, one from macrophages and the other from liver by comparing the two measures based on a measure of module entropy, Gene Ontology (GO) enrichment, and scale-free topology (SFT) fit. Our algorithm outperforms a widely used co-expression analysis method, weighted gene co-expression network analysis (WGCNA), in the macrophage data, while returning comparable results in the liver dataset when using these criteria. We demonstrate that the macrophage data has more non-linear interactions than the liver dataset, which may explain the increased performance of our method, termed Maximal Information Component Analysis (MICA) in that case.ConclusionsIn making our network algorithm more accurately reflect known biological principles, we are able to generate modules with improved relevance, particularly in networks with confounding factors such as gene by environment interactions

Diseño de un instrumento para medir estigma hacia la tuberculosis

RESUMENIntroducción: La tuberculosis continúa siendo un problema en salud pública con alta carga de la enfermedad. El efecto del estigma en el control de la TBC es desconocido porque se han realizado pocos estudios formales sobre el tema. Objetivo: Desarrollar un instrumento para medir el estigma hacia la TBC. Materiales y métodos: Estudio de evaluación de tecnología diagnóstica, con diseño del instrumento bajo las recomendaciones de Wolfe y Smith, basados en el modelo de análisis Rasch. Resultados: Se diseñó un instrumento con 35 ítems, que presentaron una adecuada comprensión por parte de las personas evaluadas. Conclusiones: El instrumento diseñado contribuirá en la medición de este constructo y en la comprensión de sus efectos en el control de la TBC.Palabras Claves: Estigma, tuberculosis, medición, instrumento. Design of an instrument for the measurement of tuberculosis stigmaABSTRACTIntroduction: Tuberculosis remains a public health problem with high burden of disease. The effect of stigma in TB control is unknown because there have been too few formal studies on the subject. Objective: To design an instrument to measure the tuberculosis stigma. Methodology: Study of diagnostic technologies evaluation, aiming at the elaboration of an instrument based on the Rasch- Analysis in accordance with the recommendations of Wolfe and Smith. Results: An instrument has been designed featuring 35 items that had been adequately understood by the persons assessed. Conclusions: The tool designed will contribute to measuring stigma and to understanding its impact on TB control.Keywords: Stigma, tuberculosis, measurement, instrument. Forma de citar: Upegui LD. Orozco LC. Diseño de un instrumento para medir estigma hacia la tuberculosis. rev.univ.ind.santander.salud 2014; 46 (1): 23-3

Defining human-machine micro-task workflows for constitution making

This paper presents a novel task-oriented approach to crowdsource the drafting of a constitution. By considering micro-tasking as a particular form of crowdsourcing, it defines a workflow-based approach based on Onto2Flow, an ontology that models the basic concepts and roles to represent workflow-definitions. The approach is then applied to a prototype platform for constitution-making where human workers are requested to contribute to a set of tasks. The paper concludes by discussing previous approaches to participatory constitution-making and identifying areas for future work.This work is part-funded by FEDER Funds, by the ERDF (European Regional Development Fund) through the COMPETE Programme (Operational Programme for Competitiveness) and by National Funds through the FCT (Portuguese Foundation for Science and Technology) within the project FCOMP-01-0124-FEDER-028980 (PTDC/EEI-SII/1386/2012). The work of Nuno Luz is supported by the doctoral grant SFRH/BD/70302/2010. The work of Marta Poblet draws from previous research within the framework of the project “Crowdsourcing: instrumentos semánticos para el desarrollo de la participación y la mediación online” (DER 2012-39492-C02-01) by the Spanish Ministry of Economy and Competitiveness.info:eu-repo/semantics/publishedVersio

Mergeomics : multidimensional data integration to identify pathogenic perturbations to biological systems

Background: Complex diseases are characterized by multiple subtle perturbations to biological processes. New omics platforms can detect these perturbations, but translating the diverse molecular and statistical information into testable mechanistic hypotheses is challenging. Therefore, we set out to create a public tool that integrates these data across multiple datasets, platforms, study designs and species in order to detect the most promising targets for further mechanistic studies. Results: We developed Mergeomics, a computational pipeline consisting of independent modules that 1) leverage multi-omics association data to identify biological processes that are perturbed in disease, and 2) overlay the disease-associated processes onto molecular interaction networks to pinpoint hubs as potential key regulators. Unlike existing tools that are mostly dedicated to specific data type or settings, the Mergeomics pipeline accepts and integrates datasets across platforms, data types and species. We optimized and evaluated the performance of Mergeomics using simulation and multiple independent datasets, and benchmarked the results against alternative methods. We also demonstrate the versatility of Mergeomics in two case studies that include genome-wide, epigenome-wide and transcriptome-wide datasets from human and mouse studies of total cholesterol and fasting glucose. In both cases, the Mergeomics pipeline provided statistical and contextual evidence to prioritize further investigations in the wet lab. The software implementation of Mergeomics is freely available as a Bioconductor R package. Conclusion: Mergeomics is a flexible and robust computational pipeline for multidimensional data integration. It outperforms existing tools, and is easily applicable to datasets from different studies, species and omics data types for the study of complex traits.Peer reviewe

A novel thymidylate synthase from the Vibrionales, Alteromonadales, Aeromonadales, and Pasteurellales (VAAP) clade with altered nucleotide and folate binding sites

Thymidylate synthase (TS, E.C. 2.1.1.45) is a crucial enzyme for de novo deoxythymidine monophosphate (dTMP) biosynthesis. The gene for this enzyme is thyA, which encodes the folate-dependent TS that converts deoxyuridine monophosphate group (dUMP) into (dTMP) using the cofactor 5,10-methylenetetrahydrofolate (mTHF) as a carbon donor. We identified the thyA gene in the genome of the Vibrio parahaemolyticus strain FIM-S1708+ that is innocuous to humans but pathogenic to crustaceans. Surprisingly, we found changes in the residues that bind the substrate dUMP and mTHF, previously postulated as invariant among all TSs known (Finer-Moore, Santi & Stroud, 2003). Interestingly, those amino acid changes were also found in a clade of microorganisms that contains Vibrionales, Alteromonadales, Aeromonadales, and Pasteurellales (VAAP) from the Gammaproteobacteria class. In this work, we studied the biochemical properties of recombinant TS from V. parahemolyticus FIM-S1708+ (VpTS) to address the natural changes in the TS amino acid sequence of the VAAP clade. Interestingly, the Km for dUMP was 27.3 ± 4.3 µM, about one-fold larger compared to other TSs. The Km for mTHF was 96.3 ± 18 µM, about three- to five-fold larger compared to other species, suggesting also loss of affinity. Thus, the catalytic efficiency was between one or two orders of magnitude smaller for both substrates. We used trimethoprim, a common antibiotic that targets both TS and DHFR for inhibition studies. The IC50 values obtained were high compared to other results in the literature. Nonetheless, this molecule could be a lead for the design antibiotics towards pathogens from the VAAP clade. Overall, the experimental results also suggest that in the VAAP clade the nucleotide salvage pathway is important and should be investigated, since the de novo dTMP synthesis appears to be compromised by a less efficient thymidylate synthase

Mouse Genome-Wide Association and Systems Genetics Identify Asxl2 As a Regulator of Bone Mineral Density and Osteoclastogenesis

Significant advances have been made in the discovery of genes affecting bone mineral density (BMD); however, our understanding of its genetic basis remains incomplete. In the current study, genome-wide association (GWA) and co-expression network analysis were used in the recently described Hybrid Mouse Diversity Panel (HMDP) to identify and functionally characterize novel BMD genes. In the HMDP, a GWA of total body, spinal, and femoral BMD revealed four significant associations (−log10P>5.39) affecting at least one BMD trait on chromosomes (Chrs.) 7, 11, 12, and 17. The associations implicated a total of 163 genes with each association harboring between 14 and 112 genes. This list was reduced to 26 functional candidates by identifying those genes that were regulated by local eQTL in bone or harbored potentially functional non-synonymous (NS) SNPs. This analysis revealed that the most significant BMD SNP on Chr. 12 was a NS SNP in the additional sex combs like-2 (Asxl2) gene that was predicted to be functional. The involvement of Asxl2 in the regulation of bone mass was confirmed by the observation that Asxl2 knockout mice had reduced BMD. To begin to unravel the mechanism through which Asxl2 influenced BMD, a gene co-expression network was created using cortical bone gene expression microarray data from the HMDP strains. Asxl2 was identified as a member of a co-expression module enriched for genes involved in the differentiation of myeloid cells. In bone, osteoclasts are bone-resorbing cells of myeloid origin, suggesting that Asxl2 may play a role in osteoclast differentiation. In agreement, the knockdown of Asxl2 in bone marrow macrophages impaired their ability to form osteoclasts. This study identifies a new regulator of BMD and osteoclastogenesis and highlights the power of GWA and systems genetics in the mouse for dissecting complex genetic traits

Systolic blood pressure and the risk of kidney replacement therapy and mortality in patients with chronic kidney disease stage 4-5

Introduction In patients with chronic kidney disease stage 4 and 5 (CKD stages 4-5) without dialysis and arterial hypertension, it is unknown if the values of systolic blood pressure (SBP) considered in control <120 mmHg are associated with kidney replacement therapy (KRT) and mortality. Methods In this retrospective cohort study, hypertensive CKD stages 4-5 patients attending the Renal Health Clinic at the Hospital Civil de Guadalajara were enrolled. We divided them into those that achieved SBP 120 mmHg), the uncontrolled group. Our primary objective was to analyze the association between the controlled group and KRT; the secondary objective was the mortality risk, and if there were subgroups of patients that achieved more benefit. Data were analyzed using Stata software, version. 15.1. Results During 2017 to 2022 a total 275 hypertensive CKD stages 4-5 patients met the inclusion criteria for the analysis, 62 in the controlled group and 213 in the uncontrolled group; mean age 61 years, 49.82% were male, SBP was significantly lower in the controlled group (111 mmHg) compared to the uncontrolled group (140 mmHg), eGFR was similar between groups (20.41 ml/min/1.73m2). There was a tendency to increase the mortality risk in the uncontrolled group (HR 6.47 [0.78-53.27]; p= 0.082) and an association by the Kaplan-Meir analysis (Log-rank p= 0.043). The subgroup analysis for risk of KRT in the controlled group revealed that patients ≥ 61 years had a lower risk of KRT (HR 0.87 [95% CI, 0-76-0.99]; p=0.03, p of interaction = 0.005), but no differences were found in the subgroup analysis for mortality. In a follow-up of 1.34 years, no association was found in the risk of KRT according to the controlled or uncontrolled groups in a multivariate Cox analysis. Conclusion In a retrospective cohort of patients with CKD stages 4-5 and hypertension, SBP >120 mmHg was not associated with risk of KRT but could be associated with the risk of death. Clinical trials are required in this group of patients to demonstrate the impact of reaching the SBP goals recommended by the KDIGO guidelines

Prevalence, associated factors and outcomes of pressure injuries in adult intensive care unit patients: the DecubICUs study

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347Funder: Flemish Society for Critical Care NursesAbstract: Purpose: Intensive care unit (ICU) patients are particularly susceptible to developing pressure injuries. Epidemiologic data is however unavailable. We aimed to provide an international picture of the extent of pressure injuries and factors associated with ICU-acquired pressure injuries in adult ICU patients. Methods: International 1-day point-prevalence study; follow-up for outcome assessment until hospital discharge (maximum 12 weeks). Factors associated with ICU-acquired pressure injury and hospital mortality were assessed by generalised linear mixed-effects regression analysis. Results: Data from 13,254 patients in 1117 ICUs (90 countries) revealed 6747 pressure injuries; 3997 (59.2%) were ICU-acquired. Overall prevalence was 26.6% (95% confidence interval [CI] 25.9–27.3). ICU-acquired prevalence was 16.2% (95% CI 15.6–16.8). Sacrum (37%) and heels (19.5%) were most affected. Factors independently associated with ICU-acquired pressure injuries were older age, male sex, being underweight, emergency surgery, higher Simplified Acute Physiology Score II, Braden score 3 days, comorbidities (chronic obstructive pulmonary disease, immunodeficiency), organ support (renal replacement, mechanical ventilation on ICU admission), and being in a low or lower-middle income-economy. Gradually increasing associations with mortality were identified for increasing severity of pressure injury: stage I (odds ratio [OR] 1.5; 95% CI 1.2–1.8), stage II (OR 1.6; 95% CI 1.4–1.9), and stage III or worse (OR 2.8; 95% CI 2.3–3.3). Conclusion: Pressure injuries are common in adult ICU patients. ICU-acquired pressure injuries are associated with mainly intrinsic factors and mortality. Optimal care standards, increased awareness, appropriate resource allocation, and further research into optimal prevention are pivotal to tackle this important patient safety threat