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Nature Aug 2021Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for... (Review)
Review
Deciphering the principles and mechanisms by which gene activity orchestrates complex cellular arrangements in multicellular organisms has far-reaching implications for research in the life sciences. Recent technological advances in next-generation sequencing- and imaging-based approaches have established the power of spatial transcriptomics to measure expression levels of all or most genes systematically throughout tissue space, and have been adopted to generate biological insights in neuroscience, development and plant biology as well as to investigate a range of disease contexts, including cancer. Similar to datasets made possible by genomic sequencing and population health surveys, the large-scale atlases generated by this technology lend themselves to exploratory data analysis for hypothesis generation. Here we review spatial transcriptomic technologies and describe the repertoire of operations available for paths of analysis of the resulting data. Spatial transcriptomics can also be deployed for hypothesis testing using experimental designs that compare time points or conditions-including genetic or environmental perturbations. Finally, spatial transcriptomic data are naturally amenable to integration with other data modalities, providing an expandable framework for insight into tissue organization.
Topics: Animals; Data Analysis; Disease; Gene Expression Profiling; Humans; Organ Specificity; Transcription, Genetic; Transcriptome
PubMed: 34381231
DOI: 10.1038/s41586-021-03634-9 -
Science (New York, N.Y.) Nov 2021Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic...
Characterization of the genetic regulation of proteins is essential for understanding disease etiology and developing therapies. We identified 10,674 genetic associations for 3892 plasma proteins to create a cis-anchored gene-protein-disease map of 1859 connections that highlights strong cross-disease biological convergence. This proteo-genomic map provides a framework to connect etiologically related diseases, to provide biological context for new or emerging disorders, and to integrate different biological domains to establish mechanisms for known gene-disease links. Our results identify proteo-genomic connections within and between diseases and establish the value of cis-protein variants for annotation of likely causal disease genes at loci identified in genome-wide association studies, thereby addressing a major barrier to experimental validation and clinical translation of genetic discoveries.
Topics: Aging; Alternative Splicing; Blood Proteins; COVID-19; Connective Tissue Diseases; Disease; Drug Development; Female; Gallstones; Genetic Association Studies; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Humans; Internet; Male; Phenotype; Proteins; Proteome; Quantitative Trait Loci; Sex Characteristics
PubMed: 34648354
DOI: 10.1126/science.abj1541 -
Science (New York, N.Y.) Jan 2020Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the... (Review)
Review
Despite extensive evidence showing that exposure to specific chemicals can lead to disease, current research approaches and regulatory policies fail to address the chemical complexity of our world. To safeguard current and future generations from the increasing number of chemicals polluting our environment, a systematic and agnostic approach is needed. The "exposome" concept strives to capture the diversity and range of exposures to synthetic chemicals, dietary constituents, psychosocial stressors, and physical factors, as well as their corresponding biological responses. Technological advances such as high-resolution mass spectrometry and network science have allowed us to take the first steps toward a comprehensive assessment of the exposome. Given the increased recognition of the dominant role that nongenetic factors play in disease, an effort to characterize the exposome at a scale comparable to that of the human genome is warranted.
Topics: Dietary Supplements; Disease; Exposome; Genome, Human; Health; Humans; Organic Chemicals; Physical Phenomena; Risk Assessment; Stress, Psychological
PubMed: 31974245
DOI: 10.1126/science.aay3164 -
Zeitschrift Fur Rheumatologie Nov 2022The VEXAS syndrome is a recently identified autoinflammatory systemic disease. The acronym VEXAS stands for Vacuoles, E1 enzyme, X‑linked, Autoinflammatory, Somatic.... (Review)
Review
The VEXAS syndrome is a recently identified autoinflammatory systemic disease. The acronym VEXAS stands for Vacuoles, E1 enzyme, X‑linked, Autoinflammatory, Somatic. The disease is due to an acquired somatic mutation of the UBA1 gene, which encodes for the E‑1 enzyme, which in turn is responsible for the ubiquitination of proteins. Due to its location on the X chromosome, the disease predominantly affects men (in the second half of life). The patients present with a plethora of inflammatory clinical symptoms, often with overlap of hematologic, dermatologic, and rheumatologic syndromes. In particular, the presence of cytoplasmic vacuoles in the bone marrow is characteristic. In this article we report the clinical case of a VEXAS patient and give an overview of the pathophysiology, clinical symptoms and diagnostics of the disease.
Topics: Male; Humans; Syndrome; Mutation
PubMed: 35179640
DOI: 10.1007/s00393-022-01169-6 -
The EMBO Journal Mar 2021Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their... (Review)
Review
Various forms of cell death have been identified over the last decades with each relying on a different subset of proteins for the activation and execution of their respective pathway(s). In addition to the three best characterized pathways-apoptosis, necroptosis, and pyroptosis-other forms of regulated cell death including autophagy-dependent cell death (ADCD), mitochondrial permeability transition pore (MPTP)-mediated necrosis, parthanatos, NETosis and ferroptosis, and their relevance for organismal homeostasis are becoming better understood. Importantly, it is increasingly clear that none of these pathways operate alone. Instead, a more complex picture is emerging with many pathways sharing components and signaling principles. Finally, a number of cell death regulators are implicated in human diseases and represent attractive therapeutic targets. Therefore, better understanding of physiological and mechanistic aspects of cell death signaling should yield improved reagents for addressing unmet medical needs.
Topics: Cell Death; Disease; Humans; Signal Transduction
PubMed: 33439509
DOI: 10.15252/embj.2020106700 -
Science (New York, N.Y.) Sep 2020The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory...
The Genotype-Tissue Expression (GTEx) project was established to characterize genetic effects on the transcriptome across human tissues and to link these regulatory mechanisms to trait and disease associations. Here, we present analyses of the version 8 data, examining 15,201 RNA-sequencing samples from 49 tissues of 838 postmortem donors. We comprehensively characterize genetic associations for gene expression and splicing in cis and trans, showing that regulatory associations are found for almost all genes, and describe the underlying molecular mechanisms and their contribution to allelic heterogeneity and pleiotropy of complex traits. Leveraging the large diversity of tissues, we provide insights into the tissue specificity of genetic effects and show that cell type composition is a key factor in understanding gene regulatory mechanisms in human tissues.
Topics: Datasets as Topic; Disease; Female; Gene Expression Regulation; Genome-Wide Association Study; Humans; Male; Organ Specificity; Quantitative Trait Loci; Sequence Analysis, RNA
PubMed: 32913098
DOI: 10.1126/science.aaz1776 -
American Journal of Physiology.... Nov 2020Altered intestinal permeability plays a role in many pathological conditions. Intestinal permeability is a component of the intestinal barrier. This barrier is a dynamic... (Review)
Review
Altered intestinal permeability plays a role in many pathological conditions. Intestinal permeability is a component of the intestinal barrier. This barrier is a dynamic interface between the body and the food and pathogens that enter the gastrointestinal tract. Therefore, dietary components can directly affect this interface, and many metabolites produced by the host enzymes or the gut microbiota can act as signaling molecules or exert direct effects on this barrier. Our aim was to examine the effects of diet components on the intestinal barrier in health and disease states. Herein, we conducted an in-depth PubMed search based on specific key words (diet, permeability, barrier, health, disease, and disorder), as well as cross references from those articles. The normal intestinal barrier consists of multiple components in the lumen, epithelial cell layer and the lamina propria. Diverse methods are available to measure intestinal permeability. We focus predominantly on human in vivo studies, and the literature is reviewed to identify dietary factors that decrease (e.g., emulsifiers, surfactants, and alcohol) or increase (e.g., fiber, short-chain fatty acids, glutamine, and vitamin D) barrier integrity. Effects of these dietary items in disease states, such as metabolic syndrome, liver disease, or colitis are documented as examples of barrier dysfunction in the multifactorial diseases. Effects of diet on intestinal barrier function are associated with precise mechanisms in some instances; further research of those mechanisms has potential to clarify the role of dietary interventions in treating diverse pathologic states.
Topics: Animals; Diet; Disease; Food; Gastrointestinal Tract; Health; Humans; Intestines; Permeability
PubMed: 32902315
DOI: 10.1152/ajpgi.00245.2020 -
Science (New York, N.Y.) Oct 2022Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic... (Review)
Review
Cellular barcodes are distinct DNA sequences that enable one to track specific cells across time or space. Recent advances in our ability to detect natural or synthetic cellular barcodes, paired with single-cell readouts of cell state, have markedly increased our knowledge of clonal dynamics and genealogies of the cells that compose a variety of tissues and organs. These advances hold promise to redefine our view of human disease. Here, we provide an overview of cellular barcoding approaches, discuss applications to gain new insights into disease mechanisms, and provide an outlook on future applications. We discuss unanticipated insights gained through barcoding in studies of cancer and blood cell production and describe how barcoding can be applied to a growing array of medical fields, particularly with the increasing recognition of clonal contributions in human diseases.
Topics: Humans; DNA Barcoding, Taxonomic; Clonal Evolution; Disease; Single-Cell Analysis
PubMed: 36227997
DOI: 10.1126/science.abm5874 -
The American Journal of Pathology Feb 2020Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway... (Review)
Review
Over the past 15 years, elegant studies have demonstrated that in certain conditions, programed cell death resembles necrosis and depends on a unique molecular pathway with no overlap with apoptosis. This form of regulated necrosis is represented by necroptosis, in which the receptor-interacting protein kinase-3 and its substrate mixed-lineage kinase domain-like protein play a crucial role. With the development of knockout mouse models and molecular inhibitors unique to necroptotic proteins, this cell death has been found to occur in virtually all tissues and diseases evaluated. There are different immunologic consequences depending on whether cells die through apoptosis or necroptosis. Therefore, distinguishing between these two forms of cell death may be crucial during pathologic evaluations. In this review, we provide an understanding of necroptotic cell-death and highlight diseases in which necroptosis has been found to play a role. We also discuss the inhibitors of necroptosis and the ways these inhibitors have been used in preclinical models of diseases. These two discussions offer an understanding of the role of necroptosis in diseases and will foster efforts to pharmacologically target this unique yet pervasive form of programed cell death in the clinic.
Topics: Animals; Chronic Disease; Disease; Humans; Inflammation; Necroptosis
PubMed: 31783008
DOI: 10.1016/j.ajpath.2019.10.012 -
Annual Review of Pathology Jan 2020The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research... (Review)
Review
The human eosinophil has long been thought to favorably influence innate mucosal immunity but at times has also been incriminated in disease pathophysiology. Research into eosinophil biology has uncovered a number of interesting contributions by eosinophils to health and disease. However, it appears that not all eosinophils from all species are created equal. It remains unclear, for example, exactly how having eosinophils benefits the human host when helminth infections in the developed world have become scarce. This review focuses on our current state of knowledge as it relates to human eosinophils. When information is lacking, we discuss lessons learned from mouse studies that may or may not directly apply to human biology and disease. It is an exciting time to be an "eosinophilosopher" because the use of biologic agents that selectively target eosinophils provides an unprecedented opportunity to define the contribution of this cell to eosinophil-associated human diseases.
Topics: Animals; Disease; Eosinophils; Helminthiasis; Humans; Immunity, Innate; Leukocyte Count; Mice
PubMed: 31977298
DOI: 10.1146/annurev-pathmechdis-012419-032756