Estudio del efecto de la exposición a pesticidas en el neurodesarrollo mediante la integración de datos ómicos

[ES] El enfoque multiómico está ganando terreno en el campo de la biología de sistemas, ya que permite estudiar aspectos complementarios del funcionamiento de un sistema biológico. Sin embargo, la integración de datos ómicos en un modelo estadístico que ayude a entender los mecanismos de regulación en la célula es todavía un reto importante en bioinformática. En este proyecto, en el que colaboran los laboratorios de Genómica de la Expresión Génica y de Neurobiología del Centro de Investigación Príncipe Felipe, se ha abordado el análisis de datos multiómicos (proteómica, metabolómica) procedentes del proyecto europeo DENAMIC, en el que se investigaron los efectos neurotóxicos de distintos pesticidas de uso común en crías de ratas expuestas durante el embarazo y lactancia, integrándolos con los resultados de diversos tests que medían capacidades cognitivas y motoras. El objetivo de este trabajo es procesar los datos y realizar los análisis estadísticos apropiados que permitan integrar toda la información para entender los mecanismos celulares subyacentes al proceso biológico estudiado, así como interpretar los resultados obtenidos desde el punto de vista biológico para poder obtener finalmente un conjunto de biomarcadores sensibles y representativos de alteraciones cognitivas o motoras.[EN] The multi-omic approach is gaining ground in the field of systems biology, since it allows to study complementary aspects of how a biological system works. However, the integration of omic data into a statistical model that helps to understand the mechanisms of regulation in the cell is still a major challenge in bioinformatics. This project, which is a collaboration between the Genomics of Gene Expression Laboratory and the Neurobiology Laboratory at the Príncipe Felipe Research Center, tackles the analysis of multi-omic data (proteomics and metabolomics) from the European project DENAMIC, in which the neurotoxic effects of several commonly used pesticides on the offspring of rats exposed during pregnancy and lactation were studied by means of integrating these multi-omic data with the results of various tests that measured cognitive and motor skills. The goal of this work is to process the data and to perform the appropriate statistical analyses that allow to integrate all the information to understand the cellular mechanisms underlying the biological process studied, as well as to interpret the results obtained from the biological point of view in order to finally obtain a set of sensitive and representative biomarkers for cognitive or motor alterations.Sánchez Gaya, V. (2017). Estudio del efecto de la exposición a pesticidas en el neurodesarrollo mediante la integración de datos ómicos. http://hdl.handle.net/10251/86404TFG

A study of situational circumstances related to Spain’s occupational accident rates in the metal sector from 2009 to 2019

Producción CientíficaThe metal sector encompasses a variety of economic activities, such as metallurgy and the manufacturing of metallic elements. These activities represent great diversity in production processes. Worker-related characteristics are particularly important in these processes and the accident rate. In view of the metal sector’s importance and that the latest annual report (2019) reveals the sector to be among the ten sectors with Spain’s highest accident rates, the purpose of this study is to explore the evolution of work accidents in the metal-mechanical sector in Spain for the period of 2009–2019 and to analyse the relationship between the associated variables. Data for this study come from occupational accident reports, which are required to be sent to the relevant administrative bodies using the Spanish Delt@ (electronic declaration of injured workers) computer system. The study variables were selected from the official occupational accident data and classified into four groups: personal, business, material, and time period. The relationships between severity and other variables were explored via contingency tables in which the chi-squared value (χ2) was calculated. This study shows a slight improvement in the accident rate over the last decade, but a high percentage of serious and fatal accidents in the Spanish industrial sector remains. The Monday effect, meal breaks, and being near retirement age are the most important factors influencing the number of serious accidents in this sector.Ministerio de Economía, Industria y Competitividad (project DPI2016-79824-R

A 5S Lean Strategy for a Sustainable Welding Process

[EN] The correct performance of the welding processes used to join metal parts or structural elements is considered to be of vital importance to guarantee the reliability of these products during their useful lives. Adequate workstation design ensures a safe environment in which an operator can perform these processes correctly. In order to guarantee the quality of welding seams, which are used to join metal parts and structural elements, a series of standards have been developed; these standards establish requirements to guarantee the correct performance of welding processes, and the inspection of the metal welds obtained. The 5S methodology has proven to be a valid tool for improving workplaces in industrial and service activities; it is a capstone methodology when companies implement lean production approaches. This work presents a framework for applying the 5S methodology in metal welding workplaces. It defines an index to evaluate the degree of implementation of the 5S methodology, and the application of the important performance analysis methodology (IPA). Fuzzy logic is used to treat the uncertainty in evaluating the different evaluation indicators proposed. This framework is applied to a real practical case, to provide an example of its use in establishing good manufacturing practices that guarantee compliance with the requirements of welding standards, and guaranteeing the correct handling and storage of the materials and tools used in welding processes for the manufacture of welded parts and structural elements.This research was funded by the Annual Grants Call of the International Doctorate School of the Spanish National Distance-Learning University (EIDUNED).Manzanares-Cañizares, C.; Sánchez-Lite, A.; Rosales-Prieto, VF.; Fuentes Bargues, JL.; González-Gaya, C. (2022). A 5S Lean Strategy for a Sustainable Welding Process. Sustainability. 14(11):1-17. https://doi.org/10.3390/su14116499117141

Elucidating the regulation of the Yeast Metabolic Cycle through the integration of gene expression and chromatin status

The Yeast Metabolic Cycle (YMC) has become a model to study how changes in the metabolic landscape can affect the chromatin status to regulate gene expression. Previous studies have shown how the YMC is divided in three main phases and have described the effect of certain histone modifications in gene regulation. This project constitutes a novel application of different statistical methodologies for the integration of chromatin status data (ChIP-Seq) and gene expression data (RNA-Seq) to better understand the YMC. The usage of regression models (N-PLS and MORE methodologies) for the omics integration allowed us for assessing the relevance of histone modifications and transcription factors on the regulation of gene expression changes in the YMC. H3K18ac and H3K9ac turned out to be the most important of the studied histone modifications, whereas YLR403W, YPL254W, YOR363C, YGL209W and YDR451C emerged as the most relevant transcription factors. A significant association of co-regulation of gene expression was found between H3K18ac and the transcription factors YPL254W (involved in the formation of the SAGA complex) and YLR403W (involved in the process of histones exchange), which evinced the crucial role of the acetylation levels to regulate gene expression in the YMC through a coordinated action of transcription factors and histone modification levels. Thus, in this study, new connections were established between metabolome, chromatin status and gene expression, as well as the basis to identify potential regulators of hidden regulatory mechanisms that connect histone modifications and gene expression changes.El Cicle Metabòlic del Llevat (YMC) s'ha convertit en un model d'estudi per analitzar la influència dels canvis metabòlics sobre l'estat de la cromatina per a la regulació de l'expressió gènica. Estudis previs han demostrat que el YMC es divideix en tres fases principals i han descrit l'efecte de certes modificacions d'histones en la regulació gènica. Aquest projecte constitueix una aplicació innovadora de diferents metodologies estadístiques per a la integració de dades d'estat de la cromatina (ChIP-Seq) i d'expressió gènica (RNA-Seq). L'ús de models de regressió (metodologies N-PLS i MORE) per a la integració d'òmiques ens ha permés avaluar la rellevància de les modificacions d'histones i els factors de transcripció en la regulació dels canvis d'expressió gènica en el YMC. H3K18ac i H3K9ac van resultar ser les més importants de les modificacions estudiades, mentre que YLR403W, YPL254W, YOR363C, YGL209W i YDR451C van ser els factors de transcripció més rellevants. Es va trobar una associació significativa de co-regulació de l'expressió gènica entre H3K18ac i els factors de transcripció YPL254W (implicat en la formació del complex SAGA) i YLR403W (involucrat en el procés d'intercanvi d'histones), que evidenciava el paper crucial dels nivells d'acetilació a l'hora de regular l'expressió gènica al YMC mitjançant l'acció coordinada dels factors de transcripció i els nivells de les modificacions d'histones. D'aquesta manera, en aquest estudi s'estableixen noves connexions entre el metaboloma, l'estat de la cromatina i l'expressió gènica, així com la base per identificar els possibles reguladors dels mecanismes de regulació que connecten les modificacions d'histones amb els canvis d'expressió gènica.El Ciclo Metabólico de la Levadura (YMC) se ha convertido en un modelo de estudio para analizar la influencia de los cambios metabólicos sobre el estado de la cromatina para la regulación de la expresión génica. Estudios previos han demostrado que el YMC se divide en tres fases principales y han descrito el efecto de ciertas modificaciones de histonas en la regulación génica. Este proyecto constituye una aplicación innovadora de diferentes metodologías estadísticas para la integración de datos de estado de la cromatina (ChIP-Seq) y de expresión génica (RNA-Seq). El uso de modelos de regresión (metodologías N-PLS y MORE) para la integración de ómicas nos ha permitido evaluar la relevancia de las modificaciones de histonas y los factores de transcripción en la regulación de los cambios de expresión génica en el YMC. H3K18ac y H3K9ac resultaron ser las más importantes de las modificaciones estudiadas, mientras que YLR403W, YPL254W, YOR363C, YGL209W y YDR451C fueron los factores de transcripción más relevantes. Se encontró una asociación significativa de co-regulación de la expresión génica entre H3K18ac y los factores de transcripción YPL254W (implicado en la formación del complejo SAGA) y YLR403W (involucrado en el proceso de intercambio de histonas), que evidenciaba el papel crucial de los niveles de acetilació a la hora de regular la expresión génica al YMC mediante la acción coordinada de los factores de transcripción y los niveles de las modificaciones de histonas. De este modo, en este estudio se establecen nuevas conexiones entre el metaboloma, el estado de la cromatina y la expresión génica, así como la base para identificar los posibles reguladores de los mecanismos de regulación que conectan las modificaciones de histonas con los cambios de expresión génica

POSTRE: a tool to predict the pathological effects of human structural variants

Understanding the pathological impact of non-coding genetic variation is a major challenge in medical genetics. Accumulating evidences indicate that a significant fraction of genetic alterations, including structural variants (SVs), can cause human disease by altering the function of non-coding regulatory elements, such as enhancers. In the case of SVs, described pathomechanisms include changes in enhancer dosage and long-range enhancer-gene communication. However, there is still a clear gap between the need to predict and interpret the medical impact of non-coding variants, and the existence of tools to properly perform these tasks. To reduce this gap, we have developed POSTRE (Prediction Of STRuctural variant Effects), a computational tool to predict the pathogenicity of SVs implicated in a broad range of human congenital disorders. By considering disease-relevant cellular contexts, POSTRE identifies SVs with either coding or long-range pathological consequences with high specificity and sensitivity. Furthermore, POSTRE not only identifies pathogenic SVs, but also predicts the disease-causative genes and the underlying pathological mechanism (e.g, gene deletion, enhancer disconnection, enhancer adoption, etc.). POSTRE is available at https://github.com/vicsanga/Postre.Funding: Víctor Sánchez-Gaya is supported by a doctoral fellow-ship from the University of Cantabria (Spain); Work in the Rada-Iglesias laboratory is supported by the EMBO Young Investigator Programme [PGC2018- 095301-B-I00, PID2021-123030NB-I00] funded by MCIN/AEI/10.13039/501 100 011 033 and by ‘ERDF A way of making Europe’ [RED2018-102553-T (REDE-VNEURAL 3.0)] funded by MCIN/AEI/10.13039/501 100 011 033; ERC CoG ‘PoisedLogic’ [862 022] funded by the European Research Council and grant ‘ENHPATHY’ H2020-MSCA-ITN-2019-860002 funded by the European Commission. Funding for open access charge: Grants. Conflict of interest statement. None declared. Acknowledgements: We would like to thank Maria Mariner Fauli for her advice on POSTRE’s graphical design and help with the elaboration of some figures. We would also like to thank Magdalena Laugsch, Julia Baptista, Ayat Essabi, Judith Zaugg and all the Rada-Iglesias lab members for insightful comments and suggestions

Rare or Overlooked? Structural Disruption of Regulatory Domains in Human Neurocristopathies

© 2020 Sánchez-Gaya, Mariner-Faulí and Rada-Iglesias.In the last few years, the role of non-coding regulatory elements and their involvement in human disease have received great attention. Among the non-coding regulatory sequences, enhancers are particularly important for the proper establishment of cell type–specific gene-expression programs. Furthermore, the disruption of enhancers can lead to human disease through two main mechanisms: (i) Mutations or copy number variants can directly alter the enhancer sequences and thereby affect expression of their target genes; (ii) structural variants can provoke changes in 3-D chromatin organization that alter neither the enhancers nor their target genes, but rather the physical communication between them. In this review, these pathomechanisms are mostly discussed in the context of neurocristopathies, congenital disorders caused by defects that occur during neural crest development. We highlight why, due to its contribution to multiple tissues and organs, the neural crest represents an important, yet understudied, cell type involved in multiple congenital disorders. Moreover, we discuss currently available resources and experimental models for the study of human neurocristopathies. Last, we provide some practical guidelines that can be followed when investigating human neurocristopathies caused by structural variants. Importantly, these guidelines can be useful not only to uncover the etiology of human neurocristopathies, but also of other human congenital disorders in which enhancer disruption is involved.VS-G is supported by a Ph.D fellowship from the University of Cantabria (Spain). AR-I is supported by the “Programa STAR-Santander Universidades, Campus Cantabria Internacional de la convocatoria CEI 2015 de Campus de Excelencia Internacional” (Spain)

Properties of Green Mortar Containing Granite Sawmill

The cement industry is one of the world’s largest CO2 emitters. The need to minimize these emissions, and assimilate by substitution and different types of waste, are challenges faced in the European Union. The use of granite sawmill from the ornamental stone industry allows for the manufacturing of pozzolanic cements, in which 10% and 20% of ordinary Portland cement (OPC) has been replaced by waste. In the present paper, properties of cements and mortars have been tested (when fresh and once set), such as workability, setting, retraction, mechanical resistance to bending and compression, elastic modulus to compression, creep, retraction, and durability. In all cases and substitution proportions, the results have been as satisfactory as those achieved with OPC, even better, allowing a second life to the waste, and participating in the principles of the circular economy. Bot substitutions are very resistant and have great durability for the gelifraction processes from the new green cements. Using this waste—granite sawmill—its volume is minimized and transfer to a landfill is avoided

Elucidating the Role of Chromatin State and Transcription Factors on the Regulation of the Yeast Metabolic Cycle: A Multi-Omic Integrative Approach

The Yeast Metabolic Cycle (YMC) is a model system in which levels of around 60% of the yeast transcripts cycle over time. The spatial and temporal resolution provided by the YMC has revealed that changes in the yeast metabolic landscape and chromatin status can be related to cycling gene expression. However, the interplay between histone modifications and transcription factor activity during the YMC is still poorly understood. Here we apply an innovative statistical approach to integrate chromatin state (ChIP-seq) and gene expression (RNA-seq) data to investigate the transcriptional control during the YMC. By using the multivariate regression models N-PLS (Partial Least Squares) and MORE (Multi-Omics REgulation) methodologies, we assessed the contribution of histone marks and transcription factors to the regulation of gene expression in the YMC. We found that H3K18ac and H3K9ac were the most important histone modifications, whereas Sfp1, Hfi1, Pip2, Mig2, and Yhp1 emerged as the most relevant transcription factors. A significant association in the co-regulation of gene expression was found between H3K18ac and the transcription factors Pip2 (involved in fatty acids metabolism), Xbp1 (cyclin implicated in the regulation of carbohydrate and amino acid metabolism), and Hfi1 (involved in the formation of the SAGA complex). These results evidence the crucial role of histone lysine acetylation levels in the regulation of gene expression in the YMC through the coordinated action of transcription factors and lysine acetyltransferases

An approach to Sustainability Risk Assessment in Industrial Assets

[EN] Asset management, as a global process through which value is added to a company, is a managerial model that involves major changes in strategies, technologies, and resources; risk management; and a change in the attitude of the people involved. The growing commitment of companies to sustainability results in them applying this approach to all their activities. For this reason, it is relevant to develop sustainability risk assessment procedures in industrial assets. This paper presents a methodological framework for the inclusion of sustainability aspects in the risk management of industrial assets. This approach presents a procedure to provide general criteria, methodology, and essential mandatory requirements to be adopted for the identification, analysis, and evaluation of sustainability aspects, impacts, and risks related to assets owned and managed by an industrial company. The proposed procedure is based on ISO 55,000 and ISO 31,000 standards and was developed following three steps: a preliminary study, identification of sustainability aspects and sustainability risks/opportunities, and impact assessment and residual risks management. Our results could serve as a model that facilitates the improvement of sustainability analysis risks in industrial assets and could be used as a basis for future developments in the application of the standards to optimize management of these assets.This research was funded by the ETSII-Universidad Nacional de Educacion a Distancia (UNED) of Spain.García-Gómez, FJ.; Rosales-Prieto, VF.; Sánchez-Lite, A.; Fuentes Bargues, JL.; González-Gaya, C. (2021). An approach to Sustainability Risk Assessment in Industrial Assets. Sustainability. 13(12):1-23. https://doi.org/10.3390/su13126538S123131

Influence of the length of hospitalisation in post-discharge outcomes in patients with acute heart failure: Results of the LOHRCA study.

To investigate the relationship between length of hospitalisation (LOH) and post-discharge outcomes in acute heart failure (AHF) patients and to ascertain whether there are different patterns according to department of initial hospitalisation. Consecutive AHF patients hospitalised in 41 Spanish centres were grouped based on the LOH (15 days). Outcomes were defined as 90-day post-discharge all-cause mortality, AHF readmissions, and the combination of both. Hazard ratios (HRs), adjusted by chronic conditions and severity of decompensation, were calculated for groups with LOH >6 days vs. LOH 6 days vs. LOH We included 8563 patients (mean age: 80 (SD = 10) years, 55.5% women), with a median LOH of 7 days (IQR 4-11): 2934 (34.3%) had a LOH 15 days. The 90-day post-discharge mortality was 11.4%, readmission 32.2%, and combined endpoint 37.4%. Mortality was increased by 36.5% (95%CI = 13.0-64.9) when LOH was 11-15 days, and by 72.0% (95%CI = 42.6-107.5) when >15 days. Conversely, no differences were found in readmission risk, and the combined endpoint only increased 21.6% (95%CI = 8.4-36.4) for LOH >15 days. Stratified analysis by hospitalisation departments rendered similar post-discharge outcomes, with all exhibiting increased mortality for LOH >15 days and no significant increments in readmission risk. Short hospitalisations are not associated with worse outcomes. While post-discharge readmissions are not affected by LOH, mortality risk increases as the LOH lengthens. These findings were similar across hospitalisation departments