reComBat: batch-effect removal in large-scale multi-source gene-expression data integration

With the steadily increasing abundance of omics data produced all over the world under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch-effect removal for entire databases lies in the large number of batches and biological variation, which can result in design matrix singularity. This problem can currently not be solved satisfactorily by any common batch-correction algorithm.; We present; reComBat; , a regularized version of the empirical Bayes method to overcome this limitation and benchmark it against popular approaches for the harmonization of public gene-expression data (both microarray and bulkRNAsq) of the human opportunistic pathogen; Pseudomonas aeruginosa; . Batch-effects are successfully mitigated while biologically meaningful gene-expression variation is retained.; reComBat; fills the gap in batch-correction approaches applicable to large-scale, public omics databases and opens up new avenues for data-driven analysis of complex biological processes beyond the scope of a single study.; The code is available at https://github.com/BorgwardtLab/reComBat, all data and evaluation code can be found at https://github.com/BorgwardtLab/batchCorrectionPublicData.; Supplementary data are available at; Bioinformatics Advances; online

reComBat: Batch effect removal in large-scale, multi-source omics data integration

With the steadily increasing abundance of omics data produced all over the world, some-times decades apart and under vastly different experimental conditions residing in public databases, a crucial step in many data-driven bioinformatics applications is that of data integration. The challenge of batch effect removal for entire databases lies in the large number and coincide of both batches and desired, biological variation resulting in design matrix singularity. This problem currently cannot be solved by any common batch correction algorithm. In this study, we present reComBat , a regularised version of the empirical Bayes method to overcome this limitation. We demonstrate our approach for the harmonisation of public gene expression data of the human opportunistic pathogen Pseudomonas aeruginosa and study a several metrics to empirically demonstrate that batch effects are successfully mitigated while biologically meaningful gene expression variation is retained. reComBat fills the gap in batch correction approaches applicable to large scale, public omics databases and opens up new avenues for data driven analysis of complex biological processes beyond the scope of a single study

X-chromosome tiling path array detection of copy number variants in patients with chromosome X-linked mental retardation

Contiene 3 ficheros adicionales con información suplementaria.-- et al.[Background] Aproximately 5–10% of cases of mental retardation in males are due to copy number variations (CNV) on the X chromosome. Novel technologies, such as array comparative genomic hybridization (aCGH), may help to uncover cryptic rearrangements in X-linked mental retardation (XLMR) patients. We have constructed an X-chromosome tiling path array using bacterial artificial chromosomes (BACs) and validated it using samples with cytogenetically defined copy number changes. We have studied 54 patients with idiopathic mental retardation and 20 controls subjects.[Results] Known genomic aberrations were reliably detected on the array and eight novel submicroscopic imbalances, likely causative for the mental retardation (MR) phenotype, were detected. Putatively pathogenic rearrangements included three deletions and five duplications (ranging between 82 kb to one Mb), all but two affecting genes previously known to be responsible for XLMR. Additionally, we describe different CNV regions with significant different frequencies in XLMR and control subjects (44% vs. 20%).[Conclusion] This tiling path array of the human X chromosome has proven successful for the detection and characterization of known rearrangements and novel CNVs in XLMR patients.The authors thank the "Genoma España" and Genome Canada joint R+D+I projects in human health, plants and aquiculture; the former "Departament d'Universitats i Societat de la Informació" (DURSI) and the "Departament de Salut", from the Catalan Autonomous Government (2005SGR00008 - Generalitat de Catalunya); the Instituto de Salud Carlos III (PI041126, CIBER-ESP), the EU's Sixth Framework Programme [FP6-2005-LIFESCIHEALTH-7; ANEUPLOIDY No. 037627] and Fundación Areces (U-2006-FARECES-O).Peer reviewe

Revisión y propuesta de mejora del programa de Prácticum del Grado de Educación Social

Este documento se corresponde con la memoria justificativa de trabajo llevada a cabo en el Proyecto de Innova-Gestión nº 73 cuya finalidad principal ha sido acometer la revisión del programa de Prácticum en el Grado de Educación Social para establecer una serie de mejoras con las que se ha pretendido dar solución a algunos de los inconvenientes que los distintos colectivos implicados en el programa han podido constatar durante los cursos transcurridos desde la implantación del Grado, desde el curso 2009-2010 hasta la actualidad

Incidence, clinical characteristics and management of inflammatory bowel disease in Spain: large-scale epidemiological study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD—Crohn’s disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)—during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100, 000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31–56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery. © 2021 by the authors. Licensee MDPI, Basel, Switzerland

Correction : Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. J. Clin. Med. 2021, 10, 2885

The authors wish to make the following corrections to this paper [...]

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain : Large-Scale Epidemiological Study

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year. (3) Results: We identified 3611 incident cases of IBD diagnosed during 2017 in 108 hospitals covering over 22 million inhabitants. The overall incidence (cases/100,000 person-years) was 16 for IBD, 7.5 for CD, 8 for UC, and 0.5 for IBD-U; 53% of patients were male and median age was 43 years (interquartile range = 31-56 years). During a median 12-month follow-up, 34% of patients were treated with systemic steroids, 25% with immunomodulators, 15% with biologics and 5.6% underwent surgery. The percentage of patients under these treatments was significantly higher in CD than UC and IBD-U. Use of systemic steroids and biologics was significantly higher in hospitals with high resources. In total, 28% of patients were hospitalized (35% CD and 22% UC patients, p < 0.01). (4) Conclusion: The incidence of IBD in Spain is rather high and similar to that reported in Northern Europe. IBD patients require substantial therapeutic resources, which are greater in CD and in hospitals with high resources, and much higher than previously reported. One third of patients are hospitalized in the first year after diagnosis and a relevant proportion undergo surgery

Comparación de distintas estrategias para la predicción de muerte a corto plazo en el paciente anciano infectado

Objective. The aim of this study was to determine the utility of a post hoc lactate added to SIRS and qSOFA score to predict 30-day mortality in older non-severely dependent patients attended for infection in the Emergency Department (ED). Methods. We performed an analytical, observational, prospective cohort study including patients of 75 years of age or older, without severe functional dependence, attended for an infectious disease in 69 Spanish ED for 2-day three seasonal periods. Demographic, clinical and analytical data were collected. The primary outcome was 30-day mortality after the index event. Results. We included 739 patients with a mean age of 84.9 (SD 6.0) years; 375 (50.7%) were women. Ninety-one (12.3%) died within 30 days. The AUC was 0.637 (IC 95% 0.587-0.688; p= 2 and 0.698 (IC 95% 0.635- 0.761; p= 2. Comparing receiver operating characteristic (ROC) there was a better accuracy of qSOFA vs SIRS (p=0.041). Both scales improve the prognosis accuracy with lactate inclusion. The AUC was 0.705 (IC95% 0.652-0.758; p<0.001) for SIRS plus lactate and 0.755 (IC95% 0.696-0.814; p<0.001) for qSOFA plus lactate, showing a trend to statistical significance for the second strategy (p=0.0727). Charlson index not added prognosis accuracy to SIRS (p=0.2269) or qSOFA (p=0.2573). Conclusions. Lactate added to SIRS and qSOFA score improve the accuracy of SIRS and qSOFA to predict short-term mortality in older non-severely dependent patients attended for infection. There is not effect in adding Charlson index

Régulation post-transcriptionnelle par le dégradosome à ARN chez le pathogène gastrique Helicobacter pylori

Helicobacter pylori est une bactérie pathogène qui colonise l'estomac de la moitié de la population humaine mondiale. Cette infection est responsable de gastrites, d'ulcères et d'adénocarcinomes qui entrainent 800.000 morts chaque année. Au laboratoire, nous étudions les mécanismes qui permettent à H. pylori de coloniser l'estomac de manière persistante. La régulation post-transcriptionnelle est un niveau majeur du contrôle de l'expression génique. Cette régulation dépend en grande partie de complexes multi-protéiques comportant des ribonucléases. Ces complexes sont nommés dégradosomes à ARN chez les bactéries, et qui jouent un rôle central dans la dégradation et la maturation des ARN. Notre laboratoire a mis en évidence l'existence, chez H. pylori, d'un dégradosome à ARN minimaliste composé de RNase J, une endoexoribonucléase 5'-3' et d'une hélicase à ARN de type DEAD-box, RhpA. Ce complexe joue un rôle majeur dans la dégradation des ARNm chez H. pylori. Au cours de ma thèse, je me suis intéressé au fonctionnement et à la régulation de cette machine moléculaire chez H. pylori. Tout d'abord, l'analyse de la localisation subcellulaire de RNase J et de RhpA chez H. pylori a révélé que ces protéines sont associées à la membrane interne. La protéine RNase J-GFP forme des clusters que nous avons caractérisés par microscopie à super-résolution et qui sont régulés par la concentration cellulaire d'ARN libre. Nous postulons que, chez H. pylori, ces clusters membranaires correspondraient à la forme active du dégradosome à ARN. Ensuite, plusieurs sites d'acétylation de RNase J ont été mis en évidence chez H. pylori, suggérant que le dégradosome à ARN est également régulé au niveau post-traductionnel. Nous avons montré que l'acétylation de la lysine 649 influence l'oligomérisation et l'activité de RNase J in vitro. De plus, la substitution de différents résidus acétylés par des alanines produit, chez H. pylori, des défauts d’activité de RNase J qui se traduisent par une morphologie aberrante de H. pylori. Finalement, par des tests de double hybride, nous avons identifié un nouvel interactant de RhpA, l'exoribonucléase 3'-5' RNase R. Cette interaction a été validée in vitro et chez H. pylori. A la différence de la protéine RNase R de E. coli, la protéine HpRNase R ne présente ni les domaines hélicase à ARN ni l'activité correspondante. Nous avons montré que HpRNase R et RhpA forment un complexe fonctionnel in vitro. Nous postulons que chez H. pylori et d’autres bactéries du phylum Campylobacterota, auquel elle appartient, la protéine RNase R a « coopté » la protéine RhpA pour compenser son absence d'activité hélicase. En conclusion, nous avons mis en évidence, chez H. pylori, différentes propriétés originales du dégradosome à ARN et de ses partenaires révélant ainsi des nouveaux modes de régulation de cette importante machine moléculaire.Helicobacter pylori is a bacterial pathogen that chronically colonizes the stomach of half of the human population and causes gastritis that can evolve into gastro-duodenal ulcers, MALT lymphoma or gastric adenocarcinoma that leads to more than 800,000 deaths/year. In the laboratory, we study the mechanisms that allow H. pylori to adapt to the stomach and persistently colonize it. Post-transcriptional regulation is a major level of control of gene expression that relies on multi-protein complexes, some of which include ribonucleases and, in bacteria, are called RNA degradosomes, central for RNA processing and degradation. Our lab previously established that H. pylori possesses a minimal RNA degradosome, composed of the essential endo- and 5'-3' exoribonuclease RNase J and the DEAD-box RNA helicase, RhpA. This complex plays a major role in mRNA decay. During my PhD work, different aspects of the functioning of this molecular machine were addressed. Firstly, the subcellular localization of RNase J and RhpA in H. pylori was found to be membrane-associated by cellular fractionation and Western blot. In addition, we showed that the RNase J-GFP protein assembles into clusters that we characterized by super-resolution microscopy and that we found to be regulated by the amount of free RNA inside the cell. We postulate that the RNA degradosome forms active clusters at the membrane. Second, RNase J was shown to be acetylated at multiple sites in H. pylori, suggesting that the RNA degradosome is post-translationally regulated. Acetylation of RNase J at lysine 649 was shown to modulate the oligomerization state and activity of RNase J in vitro, and replacement by alanine of other acetylated residues led to deficient RNase J variants which affect H. pylori cell morphology. Lastly, using bacterial two hybrid, we identified an additional interactor of RhpA, the 3'-5'exoribonuclease RNase R. This interaction was validated in vitro and in H. pylori. HpRNase R was demonstrated to lack helicase domains and activity, which are both features of E. coli RNase R. We found that HpRNase R and RhpA form a functional complex in vitro. We propose that in H. pylori and other members of the Campylobacterota, RNase R has co-opted the RhpA protein to compensate for the loss of its helicase activity. In conclusion, we have unraveled several original properties of the H. pylori RNA degradosome and of its partners that point to multiple levels of regulation of this important molecular machine machinery

Bacterial RNA Degradosomes: Molecular Machines under Tight Control

International audienceBacterial RNA degradosomes are multienzyme molecular machines that act as hubs for post-transcriptional regulation of gene expression. The ribonuclease activities of these complexes require tight regulation, as they are usually essential for cell survival while potentially destructive. Recent studies have unveiled a wide variety of regulatory mechanisms including autoregulation, post-translational modifications, and protein compartmentalization. Recently, the subcellular organization of bacterial RNA degradosomes was found to present similarities with eukaryotic messenger ribonucleoprotein (mRNP) granules, membraneless compartments that are also involved in mRNA and protein storage and/or mRNA degradation. In this review, we present the current knowledge on the composition and targets of RNA degradosomes, the most recent developments regarding the regulation of these machineries, and their similarities with the eukaryotic mRNP granules