-
Immunology Dec 2021
Topics: Cell Communication; Disease Susceptibility; Homeostasis; Humans; Immunity; Immunomodulation; Lymphocytes; Neutrophils
PubMed: 34725825
DOI: 10.1111/imm.13415 -
Human Molecular Genetics Oct 2021The Y chromosome is the most gene-deficient chromosome in the human genome (though not the smallest chromosome) and has largely been sequestered away from large-scale... (Review)
Review
The Y chromosome is the most gene-deficient chromosome in the human genome (though not the smallest chromosome) and has largely been sequestered away from large-scale studies of the effects of genetics on human health. Here I review the literature, focusing on the last 2 years, for recent evidence of the role of the Y chromosome in protecting from or contributing to disease. Although many studies have focused on Y chromosome gene copy number and variants in fertility, the role of the Y chromosome in human health is now known to extend too many other conditions including the development of multiple cancers and Alzheimer's disease. I further include the discussion of current technology and methods for analyzing Y chromosome variation. The true role of the Y chromosome and associated genetic variants in human disease will only become clear when the Y chromosome is integrated into larger studies of human genetic variation, rather than being analyzed in isolation.
Topics: Chromosomes, Human, Y; Disease Susceptibility; Evolution, Molecular; Gene Expression Regulation; Genes, Y-Linked; Genetic Predisposition to Disease; Genetic Testing; Genome, Human; Homeostasis; Humans; Male
PubMed: 34328177
DOI: 10.1093/hmg/ddab215 -
Viruses Jan 2021Although mobile genetic elements, or transposons, have played an important role in genome evolution, excess activity of mobile elements can have detrimental... (Review)
Review
Although mobile genetic elements, or transposons, have played an important role in genome evolution, excess activity of mobile elements can have detrimental consequences. Already, the enhanced expression of transposons-derived nucleic acids can trigger autoimmune reactions that may result in severe autoinflammatory disorders. Thus, cells contain several layers of protective measures to restrict transposons and to sense the enhanced activity of these "intragenomic pathogens". This review focuses on our current understanding of immunogenic patterns derived from the most active elements in humans, the retrotransposons long interspersed element (LINE)-1 and Alu. We describe the role of known pattern recognition receptors in nucleic acid sensing of LINE-1 and Alu and the possible consequences for autoimmune diseases.
Topics: Alu Elements; Animals; Disease Susceptibility; Genetic Predisposition to Disease; Host-Pathogen Interactions; Humans; Long Interspersed Nucleotide Elements; Retroelements
PubMed: 33445593
DOI: 10.3390/v13010094 -
Open Biology Mar 2019Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize... (Review)
Review
Ageing is considered as a snowballing phenotype of the accumulation of damaged dysfunctional or toxic proteins and silent mutations (polymorphisms) that sensitize relevant proteins to oxidative damage as inborn predispositions to age-related diseases. Ageing is not a disease, but it causes (or shares common cause with) age-related diseases as suggested by similar slopes of age-related increase in the incidence of diseases and death. Studies of robust and more standard species revealed that dysfunctional oxidatively damaged proteins are the root cause of radiation-induced morbidity and mortality. Oxidized proteins accumulate with age and cause reversible ageing-like phenotypes with some irreversible consequences (e.g. mutations). Here, we observe in yeast that aggregation rate of damaged proteins follows the Gompertz law of mortality and review arguments for a causal relationship between oxidative protein damage, ageing and disease. Aerobes evolved proteomes remarkably resistant to oxidative damage, but imperfectly folded proteins become sensitive to oxidation. We show that α-synuclein mutations that predispose to early-onset Parkinson's disease bestow an increased intrinsic sensitivity of α-synuclein to in vitro oxidation. Considering how initially silent protein polymorphism becomes phenotypic while causing age-related diseases and how protein damage leads to genome alterations inspires a vision of predictive diagnostic, prognostic, prevention and treatment of degenerative diseases.
Topics: Aging; Animals; Disease Susceptibility; Humans; Mutation; Neurodegenerative Diseases; Oxidative Stress; Protein Aggregation, Pathological; Protein Folding; Proteins
PubMed: 30914006
DOI: 10.1098/rsob.180249 -
Anesthesiology Jan 2018
Review
Topics: Anesthesia; Disease Susceptibility; Humans; Malignant Hyperthermia
PubMed: 28902673
DOI: 10.1097/ALN.0000000000001877 -
British Journal of Clinical Pharmacology Oct 2019The pharmacological effects of a drug depend on its concentration at the site of action, and therefore on the concentration in blood and on the dose. The relationship... (Review)
Review
The pharmacological effects of a drug depend on its concentration at the site of action, and therefore on the concentration in blood and on the dose. The relationship between the concentration or dose and the corresponding effect can usually be represented mathematically as a rectangular hyperbola; when effect is plotted against log concentration or log dose, the curve is sigmoidal. Inevitably, the effect size and the doses causing benefit and harm will differ among individuals, since they are biological phenomena: some individuals are more likely than others to suffer harm at any given dose. Some harmful effects can occur at much lower doses than those used in therapeutics; that is, the log dose-response curve for harm lies far to the left of the log dose-response curve for benefit. Those who suffer such reactions are hypersusceptible. When the dose-response curves for harm and therapeutic effect are in the same range, dose cannot separate the harmful effects from the therapeutic effects, and adverse reactions are collateral. Toxic effects occur when harmful doses are above the doses needed for benefit. In this review we consider factors that influence a subject's susceptibility to adverse drug reactions. Determinants of susceptibility include Immunological, Genetic, demographic (Age and Sex), Physiological and Exogenous factors (drug-drug interactions, for example), and Diseases and disorders such as renal failure, giving the mnemonic I GASPED. Some susceptibility factors are discrete (for example, all-or-none) and some are continuous; susceptibility can therefore be discrete or continuous; and the factors can interact to determine a person's overall susceptibility to harm.
Topics: Animals; Disease Susceptibility; Dose-Response Relationship, Drug; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Genetic Predisposition to Disease; Humans; Pharmaceutical Preparations
PubMed: 31169324
DOI: 10.1111/bcp.14015 -
Current Environmental Health Reports Sep 2020Arsenic is associated with cancer, heart disease, diabetes, and other outcomes that are also related to obesity. These similar effects raise the possibility that arsenic... (Review)
Review
PURPOSE OF REVIEW
Arsenic is associated with cancer, heart disease, diabetes, and other outcomes that are also related to obesity. These similar effects raise the possibility that arsenic plays a role in obesity causation. They also raise the possibility that obesity may be an important effect modifier of arsenic-caused disease. This review summarizes the complex relationship between arsenic and obesity, with an emphasis on current research from human studies.
RECENT FINDINGS
Experimental studies provide some evidence that arsenic could play a role in obesity pathogenesis. To date, however, these associations have not been confirmed in human studies. In contrast, several epidemiologic studies have shown that the risks of arsenic-caused disease are markedly higher in obese individuals, highlighting obesity as an important susceptibility factor. Arsenic exposure and obesity are prevalent and widespread. Research identifying vulnerable populations, including obese individuals, could lead to new interventions having broad public health effects.
Topics: Arsenic; Disease Susceptibility; Environmental Exposure; Humans; Obesity
PubMed: 32766950
DOI: 10.1007/s40572-020-00288-z -
Current Opinion in Nephrology and... May 2021Allelic variants in the gene for apolipoprotein L1 (APOL1), found only in individuals of African ancestry, explain a majority of the excess risk of kidney disease in... (Review)
Review
PURPOSE OF REVIEW
Allelic variants in the gene for apolipoprotein L1 (APOL1), found only in individuals of African ancestry, explain a majority of the excess risk of kidney disease in African Americans. However, a clear understanding how the disease-associated APOL1 variants cause kidney injury and the identity of environmental stressors that trigger the injury process have not been determined.
RECENT FINDINGS
Basic mechanistic studies of APOL1 biochemistry and cell biology, bolstered by new antibody reagents and inducible pluripotent stem cell-derived cell systems, have focused on the cytotoxic effect of the risk variants when APOL1 gene expression is induced. Since the APOL1 variants evolved to alter a key protein-protein interaction with the trypanosome serum resistance-associated protein, additional studies have begun to address differences in APOL1 interactions with other proteins expressed in podocytes, including new observations that APOL1 variants may alter podocyte cytoskeleton dynamics.
SUMMARY
A unified mechanism of pathogenesis for the various APOL1 nephropathies still remains unclear and controversial. As ongoing studies have consistently implicated the pathogenic gain-of-function effects of the variant proteins, novel therapeutic development inhibiting the synthesis or function of APOL1 proteins is moving toward clinical trials.
Topics: Apolipoprotein L1; Disease Susceptibility; Genetic Predisposition to Disease; Humans; Kidney Diseases; Podocytes
PubMed: 33767059
DOI: 10.1097/MNH.0000000000000704 -
Frontiers in Immunology 2021
Topics: Animals; Autoimmunity; Disease Susceptibility; Humans; Scleroderma, Systemic
PubMed: 33828566
DOI: 10.3389/fimmu.2021.663381 -
Neoplasia (New York, N.Y.) Dec 2020Cancers are complex, adaptive ecosystems. They remain the leading cause of disease-related death among children in North America. As we approach computational oncology... (Review)
Review
Cancers are complex, adaptive ecosystems. They remain the leading cause of disease-related death among children in North America. As we approach computational oncology and Deep Learning Healthcare, our mathematical models of cancer dynamics must be revised. Recent findings support the perspective that cancer-microenvironment interactions may consist of chaotic gene expressions and turbulent protein flows during pattern formation. As such, cancer pattern formation, protein-folding and metastatic invasion are discussed herein as processes driven by chemical turbulence within the framework of complex systems theory. To conclude, cancer stem cells are presented as strange attractors of the Waddington landscape.
Topics: Algorithms; Animals; Disease Susceptibility; Energy Metabolism; Gene Expression Regulation, Neoplastic; Genetic Predisposition to Disease; Humans; Models, Biological; Neoplasms; Neoplastic Stem Cells; Systems Biology; Tumor Microenvironment
PubMed: 33142240
DOI: 10.1016/j.neo.2020.09.008