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AMA Journal of Ethics Dec 2019This image of a silhouetted figure looking out over a body of water at sunset aims to promote reflection about patients' feelings of sadness, despair, helplessness, and...
This image of a silhouetted figure looking out over a body of water at sunset aims to promote reflection about patients' feelings of sadness, despair, helplessness, and uncertainty upon being diagnosed.
Topics: Disease; Emotions; Humans; Medicine in the Arts; Sadness
PubMed: 31876476
DOI: 10.1001/amajethics.2019.1103 -
Journal of Vascular Surgery. Venous and... Sep 2020
Topics: Disease; Humans; Iliac Vein; Lasers; Patients; Saphenous Vein
PubMed: 32800262
DOI: 10.1016/j.jvsv.2020.03.001 -
Cell Death and Differentiation Mar 2020Autophagy is a process in which intracellular components and dysfunctional organelles are delivered to the lysosome for degradation and recycling. Autophagy has various... (Review)
Review
Autophagy is a process in which intracellular components and dysfunctional organelles are delivered to the lysosome for degradation and recycling. Autophagy has various connections to a large number of human diseases, as its functions are essential for cell survival, bioenergetic homeostasis, organism development, and cell death regulation. In the past two decades, substantial effort has been made to identify the roles of autophagy in tumor suppression and promotion, neurodegenerative disorders, and other pathophysiologies. This review summarizes the current advances and discusses the unanswered questions in understanding the involvement of autophagy in pathogenic mechanisms of disease, primarily focusing on cancer and neurodegenerative diseases.
Topics: Animals; Autophagy; Disease; Humans; Models, Biological; Neoplasms; Neurodegenerative Diseases
PubMed: 31900427
DOI: 10.1038/s41418-019-0480-9 -
Nature Mar 2021Many sequence variants have been linked to complex human traits and diseases, but deciphering their biological functions remains challenging, as most of them reside in...
Many sequence variants have been linked to complex human traits and diseases, but deciphering their biological functions remains challenging, as most of them reside in noncoding DNA. Here we have systematically assessed the binding of 270 human transcription factors to 95,886 noncoding variants in the human genome using an ultra-high-throughput multiplex protein-DNA binding assay, termed single-nucleotide polymorphism evaluation by systematic evolution of ligands by exponential enrichment (SNP-SELEX). The resulting 828 million measurements of transcription factor-DNA interactions enable estimation of the relative affinity of these transcription factors to each variant in vitro and evaluation of the current methods to predict the effects of noncoding variants on transcription factor binding. We show that the position weight matrices of most transcription factors lack sufficient predictive power, whereas the support vector machine combined with the gapped k-mer representation show much improved performance, when assessed on results from independent SNP-SELEX experiments involving a new set of 61,020 sequence variants. We report highly predictive models for 94 human transcription factors and demonstrate their utility in genome-wide association studies and understanding of the molecular pathways involved in diverse human traits and diseases.
Topics: Binding Sites; Disease; Genome, Human; Humans; Ligands; Polymorphism, Single Nucleotide; Protein Binding; SELEX Aptamer Technique; Support Vector Machine; Transcription Factors
PubMed: 33505025
DOI: 10.1038/s41586-021-03211-0 -
Cell Death and Differentiation Mar 2020Autophagy regulates the degradation of unnecessary or dysfunctional cellular components. This catabolic process requires the formation of a double-membrane vesicle, the... (Review)
Review
Autophagy regulates the degradation of unnecessary or dysfunctional cellular components. This catabolic process requires the formation of a double-membrane vesicle, the autophagosome, that engulfs the cytosolic material and delivers it to the lysosome. Substrate specificity is achieved by autophagy receptors, which are characterized by the presence of at least one LC3-interaction region (LIR) or GABARAP-interaction motif (GIM). Only recently, several receptors that mediate the specific degradation of endoplasmic reticulum (ER) components via autophagy have been identified (the process known as ER-phagy or reticulophagy). Here, we give an update on the current knowledge about the role of ER-phagy receptors in health and disease.
Topics: Animals; Autophagy; Disease; Endoplasmic Reticulum; Homeostasis; Humans
PubMed: 31659280
DOI: 10.1038/s41418-019-0444-0 -
Nature Medicine Jun 2023Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the...
Alcohol consumption accounts for ~3 million annual deaths worldwide, but uncertainty persists about its relationships with many diseases. We investigated the associations of alcohol consumption with 207 diseases in the 12-year China Kadoorie Biobank of >512,000 adults (41% men), including 168,050 genotyped for ALDH2- rs671 and ADH1B- rs1229984 , with >1.1 million ICD-10 coded hospitalized events. At baseline, 33% of men drank alcohol regularly. Among men, alcohol intake was positively associated with 61 diseases, including 33 not defined by the World Health Organization as alcohol-related, such as cataract (n = 2,028; hazard ratio 1.21; 95% confidence interval 1.09-1.33, per 280 g per week) and gout (n = 402; 1.57, 1.33-1.86). Genotype-predicted mean alcohol intake was positively associated with established (n = 28,564; 1.14, 1.09-1.20) and new alcohol-associated (n = 16,138; 1.06, 1.01-1.12) diseases, and with specific diseases such as liver cirrhosis (n = 499; 2.30, 1.58-3.35), stroke (n = 12,176; 1.38, 1.27-1.49) and gout (n = 338; 2.33, 1.49-3.62), but not ischemic heart disease (n = 8,408; 1.04, 0.94-1.14). Among women, 2% drank alcohol resulting in low power to assess associations of self-reported alcohol intake with disease risks, but genetic findings in women suggested the excess male risks were not due to pleiotropic genotypic effects. Among Chinese men, alcohol consumption increased multiple disease risks, highlighting the need to strengthen preventive measures to reduce alcohol intake.
Topics: Adult; Female; Humans; Male; Alcohol Drinking; Aldehyde Dehydrogenase, Mitochondrial; East Asian People; Ethanol; Genotype; Gout; Risk Factors; Disease; China
PubMed: 37291211
DOI: 10.1038/s41591-023-02383-8 -
Genome Biology Apr 2020Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many...
BACKGROUND
Cellular senescence, a permanent state of replicative arrest in otherwise proliferating cells, is a hallmark of aging and has been linked to aging-related diseases. Many genes play a role in cellular senescence, yet a comprehensive understanding of its pathways is still lacking.
RESULTS
We develop CellAge (http://genomics.senescence.info/cells), a manually curated database of 279 human genes driving cellular senescence, and perform various integrative analyses. Genes inducing cellular senescence tend to be overexpressed with age in human tissues and are significantly overrepresented in anti-longevity and tumor-suppressor genes, while genes inhibiting cellular senescence overlap with pro-longevity and oncogenes. Furthermore, cellular senescence genes are strongly conserved in mammals but not in invertebrates. We also build cellular senescence protein-protein interaction and co-expression networks. Clusters in the networks are enriched for cell cycle and immunological processes. Network topological parameters also reveal novel potential cellular senescence regulators. Using siRNAs, we observe that all 26 candidates tested induce at least one marker of senescence with 13 genes (C9orf40, CDC25A, CDCA4, CKAP2, GTF3C4, HAUS4, IMMT, MCM7, MTHFD2, MYBL2, NEK2, NIPA2, and TCEB3) decreasing cell number, activating p16/p21, and undergoing morphological changes that resemble cellular senescence.
CONCLUSIONS
Overall, our work provides a benchmark resource for researchers to study cellular senescence, and our systems biology analyses reveal new insights and gene regulators of cellular senescence.
Topics: Aging; Animals; Cellular Senescence; Databases, Genetic; Disease; Evolution, Molecular; Gene Expression; Genes, Neoplasm; Humans; Longevity; Oligonucleotide Array Sequence Analysis; Organ Specificity; Protein Interaction Mapping; RNA-Seq; Systems Biology
PubMed: 32264951
DOI: 10.1186/s13059-020-01990-9 -
Cells May 2020Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play...
Mitochondria are subcellular organelles evolved by endosymbiosis of bacteria with eukaryotic cells characteristics. They are the main source of ATP in the cell and play a pivotal role in cell life and cell death. Mitochondria are engaged in the pathogenesis of human diseases and aging directly or indirectly through a broad range of signaling pathways. However, despite an increased interest in mitochondria over the past decades, the mechanisms of mitochondria-mediated cell/organ dysfunction in response to pathological stimuli remain unknown. The Special Issue, "Mitochondria in Health and Diseases," organized by includes 24 review and original articles that highlight the latest achievements in elucidating the role of mitochondria under physiological (healthy) conditions and, in various cell/animal models of human diseases and, in patients. Altogether, the Special Issue summarizes and discusses different aspects of mitochondrial metabolism and function that open new avenues in understanding mitochondrial biology.
Topics: Animals; Disease; Health; Humans; Mitochondria; Models, Biological; Molecular Targeted Therapy
PubMed: 32397376
DOI: 10.3390/cells9051177 -
Science (New York, N.Y.) Apr 2023Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern...
Thousands of genomic regions have been associated with heritable human diseases, but attempts to elucidate biological mechanisms are impeded by an inability to discern which genomic positions are functionally important. Evolutionary constraint is a powerful predictor of function, agnostic to cell type or disease mechanism. Single-base phyloP scores from 240 mammals identified 3.3% of the human genome as significantly constrained and likely functional. We compared phyloP scores to genome annotation, association studies, copy-number variation, clinical genetics findings, and cancer data. Constrained positions are enriched for variants that explain common disease heritability more than other functional annotations. Our results improve variant annotation but also highlight that the regulatory landscape of the human genome still needs to be further explored and linked to disease.
Topics: Animals; Humans; Biological Evolution; Genetic Variation; Genome, Human; Genome-Wide Association Study; Genomics; Molecular Sequence Annotation; Polymorphism, Single Nucleotide; Disease
PubMed: 37104612
DOI: 10.1126/science.abn2937 -
International Journal of Molecular... Jun 2021Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular... (Review)
Review
Long noncoding RNAs exceeding a length of 200 nucleotides play an important role in ensuring cell functions and proper organism development by interacting with cellular compounds such as miRNA, mRNA, DNA and proteins. However, there is an additional level of lncRNA regulation, called lncRNA epigenetics, in gene expression control. In this review, we describe the most common modified nucleosides found in lncRNA, 6-methyladenosine, 5-methylcytidine, pseudouridine and inosine. The biosynthetic pathways of these nucleosides modified by the writer, eraser and reader enzymes are important to understanding these processes. The characteristics of the individual methylases, pseudouridine synthases and adenine-inosine editing enzymes and the methods of lncRNA epigenetics for the detection of modified nucleosides, as well as the advantages and disadvantages of these methods, are discussed in detail. The final sections are devoted to the role of modifications in the most abundant lncRNAs and their functions in pathogenic processes.
Topics: Disease; Epigenesis, Genetic; Humans; MicroRNAs; RNA, Long Noncoding; RNA, Messenger
PubMed: 34200507
DOI: 10.3390/ijms22116166