Transcription factor co-localization patterns affect human cell type-specific gene expression.

BACKGROUND: Cellular development requires the precise control of gene expression states. Transcription factors are involved in this regulatory process through their combinatorial binding with DNA. Information about transcription factor binding sites can help determine which combinations of factors work together to regulate a gene, but it is unclear how far the binding data from one cell type can inform about regulation in other cell types. RESULTS: By integrating data on co-localized transcription factor binding sites in the K562 cell line with expression data across 38 distinct hematopoietic cell types, we developed regression models to describe the relationship between the expression of target genes and the transcription factors that co-localize nearby. With K562 binding sites identifying the predictors, the proportion of expression explained by the models is statistically significant only for monocytic cells (p-value< 0.001), which are closely related to K562. That is, cell type specific binding patterns are crucial for choosing the correct transcription factors for the model. Comparison of predictors obtained from binding sites in the GM12878 cell line with those from K562 shows that the amount of difference between binding patterns is directly related to the quality of the prediction. By identifying individual genes whose expression is predicted accurately by the binding sites, we are able to link transcription factors FOS, TAF1 and YY1 to a sparsely studied gene LRIG2. We also find that the activity of a transcription factor may be different depending on the cell type and the identity of other co-localized factors. CONCLUSION: Our approach shows that gene expression can be explained by a modest number of co-localized transcription factors, however, information on cell-type specific binding is crucial for understanding combinatorial gene regulation.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Comparison of methods for competitive tests of pathway analysis.

It has been suggested that pathway analysis can complement single-SNP analysis in exploring genomewide association data. Pathway analysis incorporates the available biological knowledge of genes and SNPs and is expected to improve the chances of revealing the underlying genetic architecture of complex traits. Methods for pathway analysis can be classified as competitive (enrichment) or self-contained (association) according to the hypothesis tested. Although association tests are statistically more powerful than enrichment tests they can be difficult to calibrate because biases in analysis accumulate across multiple SNPs or genes. Furthermore, enrichment tests can be more scientifically relevant than association tests, as they detect pathways with relatively more evidence for association than the remaining genes. Here we show how some well known association tests can be simply adapted to test for enrichment, and compare their performance to some established enrichment tests. We propose versions of the Adaptive Rank Truncated Product (ARTP), Tail Strength Measure and Fisher's combination of p-values for testing the enrichment null hypothesis. We compare the behaviour of these proposed methods with the established Hypergeometric Test and Gene-Set Enrichment Analysis (GSEA). The results of the simulation study show that the modified version of the ARTP method has generally the best performance across the situations considered. The methods were also applied for finding enriched pathways for body mass index (BMI) and platelet function phenotypes. The pathway analysis of BMI identified the Vasoactive Intestinal Peptide pathway as significantly associated with BMI. This pathway has been previously reported as associated with BMI and the risk of obesity. The ARTP method was the method that identified the largest number of enriched pathways across all tested pathway databases and phenotypes. The simulation and data application results are in agreement with previous work on association tests and suggests that the ARTP should be preferred for both enrichment and association testing

Proyecto estratégico integral para el proceso de salud ocupacional con énfasis en gestión del conocimiento empresa Totto, sucursal Florencia

El presente proyecto elaborado por los estudiantes matriculados al Diplomado de Profundización en gerencia del talento humano, conformados para la construcción del trabajo final en un grupo colaborativo de 5 integrantes. Él cual fue predeterminado desde el inicio del curso, por la dirección del curso asignado, en cumplimiento de las indicaciones presentadas en la guía integrada de actividades para esta fase, se consolida el siguiente proyecto de investigación teniendo como base la empresa del contexto seleccionada por el grupo y con la que se que vienen trabajando desde la Fase 2, de la cual los integrantes de grupo colaborativo mediante estrategias investigativas se logró obtener acceso a la información que nos permitió el desarrollo y posterior consolidación donde se aplicó parte de la temática vista en el curso, permitiendo identificar la línea de investigación: Gestión de las Organizaciones, sobre la cual se articula el presente trabajo final y con base a esta se llevó a cabo la investigación. Es vital que en las empresas ofrezcan un ambiente de trabajo que resguarde al personal de accidentes de trabajo y enfermedades laborales, y por eso es oportuno presentar herramientas para mejorar la calidad laboral.Integral strategic project for the occupational health process with emphasis in knowledge management company totto, branch florenc

Factores perceptuales del uso del marketing digital en pequeñas y medianas empresas

Today, the impact of the COVID-19 coronavirus pandemic on small and medium-sized businesses is enormous,therefore, digital marketing emerges as a strategy to attract new customers and reach consumers using digital media. The objective of this study is to identify the factors that influence the use of digital marketing by small and mediumsized companies in the city of Medellín. The fundamental theory, a qualitative approach and an exploratory-descriptive scope were used, applying 9 semi-structured interviews to people in positions related to the area of marketing and digital marketing in small and medium-sized companies in the service and manufacturing sector. It was obtained that thesecompanies have been using the Internet as the main communication tool that will show advantages for the consumer when accessing products and making purchases. It was concluded that the most outstanding factors in the use of digital marketing by these companies are Factors of use, motivation, strategies and means; and advantages of using these tools.Hoy en día, el impacto de la pandemia por el coronavirus COVID-19 en las pequeñas y medianas empresas esenorme, por tanto, el marketing digital surge como una estrategia para captar nuevos clientes y llegar a los consumidoresutilizando medios digitales. El objetivo de este estudio es identificar los factores que influyen en la utilización del marketing digital por parte de las pequeñas y medianas empresas de la ciudad de Medellín. Se empleó la teoría fundamentada, un enfoque cualitativo y alcance exploratorio-descriptivo, aplicando nueve entrevistas semiestructuradas a personas de cargos relacionados con el área de mercadeo y marketing digital en las pequeñas y medianas empresas del sector de servicios y manufactura. Los hallazgos señalan que estas empresas han venido utilizando Internet como principal herramienta de comunicación, generando ventajas para el consumidor al momento de acceder a los productos y realizar compras. Se concluyó que los factores más influyentes en la utilización del marketing digital por parte de estas empresas son: factores de uso, motivación, estrategias y medios; y ventajas del uso de esas herramientas

Gray platelet syndrome: proinflammatory megakaryocytes and α-granule loss cause myelofibrosis and confer metastasis resistance in mice.

NBEAL2 encodes a multidomain scaffolding protein with a putative role in granule ontogeny in human platelets. Mutations in NBEAL2 underlie gray platelet syndrome (GPS), a rare inherited bleeding disorder characterized by a lack of α-granules within blood platelets and progressive bone marrow fibrosis. We present here a novel Nbeal2(-/-) murine model of GPS and demonstrate that the lack of α-granules is due to their loss from platelets/mature megakaryocytes (MKs), and not by initial impaired formation. We show that the lack of Nbeal2 confers a proinflammatory phenotype to the bone marrow MKs, which in combination with the loss of proteins from α-granules drives the development of bone marrow fibrosis. In addition, we demonstrate that α-granule deficiency impairs platelet function beyond their purely hemostatic role and that Nbeal2 deficiency has a protective effect against cancer metastasis.This work was funded by the British Heart Foundation to CG (FS09/039) and WHO and AR (RG/09/12/28096); NHSBT to CB and HM; Wellcome Trust (WT098051) to ZM, ELC, JE, HWJ and AOS.This is the accepted manuscript. The final published version is available from Blood at http://www.bloodjournal.org/content/early/2014/09/25/blood-2014-04-566760

HGVA: the Human Genome Variation Archive.

High-profile genomic variation projects like the 1000 Genomes project or the Exome Aggregation Consortium, are generating a wealth of human genomic variation knowledge which can be used as an essential reference for identifying disease-causing genotypes. However, accessing these data, contrasting the various studies and integrating those data in downstream analyses remains cumbersome. The Human Genome Variation Archive (HGVA) tackles these challenges and facilitates access to genomic data for key reference projects in a clean, fast and integrated fashion. HGVA provides an efficient and intuitive web-interface for easy data mining, a comprehensive RESTful API and client libraries in Python, Java and JavaScript for fast programmatic access to its knowledge base. HGVA calculates population frequencies for these projects and enriches their data with variant annotation provided by CellBase, a rich and fast annotation solution. HGVA serves as a proof-of-concept of the genome analysis developments being carried out by the University of Cambridge together with UK's 100 000 genomes project and the National Institute for Health Research BioResource Rare-Diseases, in particular, deploying open-source for Computational Biology (OpenCB) software platform for storing and analyzing massive genomic datasets

Catálogo de terremotos de América del Sur homogéneo en Mw para el periodo pre-1964

On the frame of The South America Risk Assessment (SARA) project, an earthquake catalogue was compiled for South America, in terms of the moment magnitude (Mw), with data from the Centro Regional de Sismología para América del Sur (CERESIS), recent national and international studies, and from the analysis conducted during the project. In particular, it is included the latest versions of catalogue CERESIS-91 prepared by CERESIS and published by the National Council of Science and Technology CONCYTEC of Peru, the determination of parameters by recent studies, including those proposed by the ISC-GEM catalogue, and where available, the national catalogues that meet the criteria of transparency required by the project. The results presented in this work correspond to the pre-1964 time window. The first phase of the study is the development of a critical inventory of all public studies related to earthquakes in South America. Studies for the same event have been associated with each other from the comparison of the time, of the epicentre coordinates and the size of the earthquake (magnitude or maximum seismic intensity). For each event, a set of parameters considered reliable has been preliminarily selected. The main problem of the catalogue is the need to express the values of magnitude in terms of moment magnitude (Mw). Currently, few studies on historical earthquakes provide this value for the study region. For many events, values in terms of Ms and mb are available; although for most cases, because of the time of occurrence of these events, the magnitude values were calculated from macroseismic data. For these earthquakes we have used empirical conversion relationships published in literature for Ms and mb to Mw. There are also events for which only a value of maximum intensity (Imax or Io) is available. For these events, regional relationships Imax to Mw have been determined, using the most reliable and recent data of Mw and Imax values. In a second phase, for some events that have a sufficient number of macroseismic data, the source parameters have (including location, Mw and uncertainties) been determined using the method of Bakun and Wentworth (1997), regionally calibrated, based on what already has been obtained for Ecuador, Venezuela in literature and Colombia in the present project. In this way, the magnitude Mw was evaluated for 2564 earthquakes in South America. The lower threshold is defined in Mw = 5 for the Andean region. For Brazil, a lower threshold was not applied.Published6T. Studi di pericolosità sismica e da maremotoN/A or not JC

Whole genome sequencing for the diagnosis of neurological repeat expansion disorders in the UK: a retrospective diagnostic accuracy and prospective clinical validation study

BACKGROUND: Repeat expansion disorders affect about 1 in 3000 individuals and are clinically heterogeneous diseases caused by expansions of short tandem DNA repeats. Genetic testing is often locus-specific, resulting in underdiagnosis of people who have atypical clinical presentations, especially in paediatric patients without a previous positive family history. Whole genome sequencing is increasingly used as a first-line test for other rare genetic disorders, and we aimed to assess its performance in the diagnosis of patients with neurological repeat expansion disorders. METHODS: We retrospectively assessed the diagnostic accuracy of whole genome sequencing to detect the most common repeat expansion loci associated with neurological outcomes (AR, ATN1, ATXN1, ATXN2, ATXN3, ATXN7, C9orf72, CACNA1A, DMPK, FMR1, FXN, HTT, and TBP) using samples obtained within the National Health Service in England from patients who were suspected of having neurological disorders; previous PCR test results were used as the reference standard. The clinical accuracy of whole genome sequencing to detect repeat expansions was prospectively examined in previously genetically tested and undiagnosed patients recruited in 2013-17 to the 100 000 Genomes Project in the UK, who were suspected of having a genetic neurological disorder (familial or early-onset forms of ataxia, neuropathy, spastic paraplegia, dementia, motor neuron disease, parkinsonian movement disorders, intellectual disability, or neuromuscular disorders). If a repeat expansion call was made using whole genome sequencing, PCR was used to confirm the result. FINDINGS: The diagnostic accuracy of whole genome sequencing to detect repeat expansions was evaluated against 793 PCR tests previously performed within the NHS from 404 patients. Whole genome sequencing correctly classified 215 of 221 expanded alleles and 1316 of 1321 non-expanded alleles, showing 97·3% sensitivity (95% CI 94·2-99·0) and 99·6% specificity (99·1-99·9) across the 13 disease-associated loci when compared with PCR test results. In samples from 11 631 patients in the 100 000 Genomes Project, whole genome sequencing identified 81 repeat expansions, which were also tested by PCR: 68 were confirmed as repeat expansions in the full pathogenic range, 11 were non-pathogenic intermediate expansions or premutations, and two were non-expanded repeats (16% false discovery rate). INTERPRETATION: In our study, whole genome sequencing for the detection of repeat expansions showed high sensitivity and specificity, and it led to identification of neurological repeat expansion disorders in previously undiagnosed patients. These findings support implementation of whole genome sequencing in clinical laboratories for diagnosis of patients who have a neurological presentation consistent with a repeat expansion disorder. FUNDING: Medical Research Council, Department of Health and Social Care, National Health Service England, National Institute for Health Research, and Illumina

Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis

Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant (