Neutrophils play fundamental roles in innate immune response, shape adaptive immunity, and are a potentially causal cell type underpinning genetic associations with immune system traits and diseases. ...Here, we profile the binding of myeloid master regulator PU.1 in primary neutrophils across nearly a hundred volunteers. We show that variants associated with differential PU.1 binding underlie genetically-driven differences in cell count and susceptibility to autoimmune and inflammatory diseases. We integrate these results with other multi-individual genomic readouts, revealing coordinated effects of PU.1 binding variants on the local chromatin state, enhancer-promoter contacts and downstream gene expression, and providing a functional interpretation for 27 genes underlying immune traits. Collectively, these results demonstrate the functional role of PU.1 and its target enhancers in neutrophil transcriptional control and immune disease susceptibility.
Neutrophils are short-lived blood cells that play a critical role in host defense against infections. To better comprehend neutrophil functions and their regulation, we provide a complete epigenetic ...overview, assessing important functional features of their differentiation stages from bone marrow-residing progenitors to mature circulating cells. Integration of chromatin modifications, methylation, and transcriptome dynamics reveals an enforced regulation of differentiation, for cellular functions such as release of proteases, respiratory burst, cell cycle regulation, and apoptosis. We observe an early establishment of the cytotoxic capability, while the signaling components that activate these antimicrobial mechanisms are transcribed at later stages, outside the bone marrow, thus preventing toxic effects in the bone marrow niche. Altogether, these data reveal how the developmental dynamics of the chromatin landscape orchestrate the daily production of a large number of neutrophils required for innate host defense and provide a comprehensive overview of differentiating human neutrophils.
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•Dynamic acetylation enforces human neutrophil progenitor differentiation•Neutrophils’ cytotoxic capability is established early at the (pro)myelocyte stage•Coordinated signaling component expression prevents toxic effects to the bone marrow
Grassi et al. report that the establishment of transcriptional enhancers drives neutrophil differentiation. Coordinated waves of gene expression establish the cytotoxic capability of these cells at early stages of maturation. A set of super-enhancers is specifically opened at the end of the differentiation process to control neutrophil activation.
COVID 19 pandemic is the worst crisis that mankind has seen since World War-II. It has exposed glaring loopholes in the healthcare system and led to a global health crisis. In absence of any specific ...treatment or vaccine, countries began to enforce strict lockdown measures leading to a complete shutdown of economic activities. The purpose of this study is to identify key exit strategies that can be implemented to mitigate the impacts of COVID 19. Identification and categorisation of parameters have been achieved using multi criterion decision making techniques of Interpretive Structural Modelling (ISM) and Cross-impact matrix multiplication applied to classification MICMAC analysis. < br/>< br/> The study highlights a classification of key strategies based on their driving power and dependence which may enable Government to strengthen the disease surveillance system and effectively reduce the impact of the disease. The findings of the study suggest that Environmental Sustainability and Human Well-being; Online Awareness and Capacity Building Programme; Graded Surveillance- Targeted Restrictions and Stricter norms for Inter-State Mobility; and Harmonization between Centre, State and Local Authorities are the most important strategies that needs to be factored in while planning for the post lockdown economic recovery. With countries eager to resume economic activities, the strategies identified in our study can assist the governments and policymakers across the world in devising their exit plans while giving due consideration to each of the strategies to counter the disruptions brought about by the COVID 19 pandemic.
Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art ...method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones’ dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.
COVID-19 pandemic is the worst humanitarian crisis that economies across the globe have witnessed. Forced lockdowns, social distancing, and restricted mobility have contributed to large scale ...disruptions in the supply chain network. The purpose of the paper is to identify critical factors affecting global supply chain and evaluate strategies for risk reduction in the supply chain network by making it resilient.
Our study incorporates multi-criteria decision approach using Analytic Hierarchy Process (AHP) and Decision-Making Trial and Evaluation Laboratory (DEMATEL) to analyze factors that affected the supply chain networks with the onset of COVID-19. The AHP method enabled to hierarchically rank the factors based on the relative weightage while DEMATEL ascertained the inter-relationships among the factors and classified them into cause and effect groups. The findings of our study identified the cost–optimization as the most significant factor and the human resource management as the least important factor in reducing vulnerabilities of the supply chain network. Our analysis from DEMATEL approach indicate that government support is a significant causal factor which can effectively eliminate the issues plaguing supply chains during this pandemic. The results from our study aim to help policymakers in developing a risk resilient framework that can enhance performance and operational capability of the supply chain, thereby ensuring sustainability and socio-economic well-being of all the stakeholders involved in the entire network.
Abstract
This paper presents a mathematical model of a power controller for a high-frequency induction heating system based on a modified half-bridge series resonant inverter. The output real power ...is precise over the heating coil, and this real power is processed as a feedback signal that contends a closed-loop topology with a proportional-integral-derivative controller. This technique enables both control of the closed-loop power and determination of the stability of the high-frequency inverter. Unlike the topologies of existing power controllers, the proposed topology enables direct control of the real power of the high-frequency inverter.
Long-range interactions between regulatory elements and gene promoters play key roles in transcriptional regulation. The vast majority of interactions are uncharted, constituting a major missing link ...in understanding genome control. Here, we use promoter capture Hi-C to identify interacting regions of 31,253 promoters in 17 human primary hematopoietic cell types. We show that promoter interactions are highly cell type specific and enriched for links between active promoters and epigenetically marked enhancers. Promoter interactomes reflect lineage relationships of the hematopoietic tree, consistent with dynamic remodeling of nuclear architecture during differentiation. Interacting regions are enriched in genetic variants linked with altered expression of genes they contact, highlighting their functional role. We exploit this rich resource to connect non-coding disease variants to putative target promoters, prioritizing thousands of disease-candidate genes and implicating disease pathways. Our results demonstrate the power of primary cell promoter interactomes to reveal insights into genomic regulatory mechanisms underlying common diseases.
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•High-resolution maps of promoter interactions in 17 human primary blood cell types•Interaction patterns are cell type specific and segregate with the hematopoietic tree•Promoter-interacting regions enriched for regulatory chromatin features and eQTLs•Promoter interactions link non-coding GWAS variants with putative target genes
This study deploys a promoter capture Hi-C approach in 17 primary blood cell types to match collaborating regulatory regions and identify genes regulated by noncoding disease-associated variants. Explore this and other papers at the Cell Press IHEC webportal at http://www.cell.com/consortium/IHEC.
Characterizing the multifaceted contribution of genetic and epigenetic factors to disease phenotypes is a major challenge in human genetics and medicine. We carried out high-resolution genetic, ...epigenetic, and transcriptomic profiling in three major human immune cell types (CD14+ monocytes, CD16+ neutrophils, and naive CD4+ T cells) from up to 197 individuals. We assess, quantitatively, the relative contribution of cis-genetic and epigenetic factors to transcription and evaluate their impact as potential sources of confounding in epigenome-wide association studies. Further, we characterize highly coordinated genetic effects on gene expression, methylation, and histone variation through quantitative trait locus (QTL) mapping and allele-specific (AS) analyses. Finally, we demonstrate colocalization of molecular trait QTLs at 345 unique immune disease loci. This expansive, high-resolution atlas of multi-omics changes yields insights into cell-type-specific correlation between diverse genomic inputs, more generalizable correlations between these inputs, and defines molecular events that may underpin complex disease risk.
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•Genome, transcriptome, and epigenome reference panel in three human immune cell types•Identified 4,418 genes associated with epigenetic changes independent of genetics•Described genome-epigenome coordination defining cell-type-specific regulatory events•Functionally mapped disease mechanisms at 345 unique autoimmune disease loci
As part of the IHEC consortium, this study integrates genetic, epigenetic, and transcriptomic profiling in three immune cell types from nearly 200 people to characterize the distinct and cooperative contributions of diverse genomic inputs to transcriptional variation. Explore the Cell Press IHEC web portal at http://www.cell.com/consortium/IHEC.
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