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Mutation Research. Reviews in Mutation... 2014Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA... (Review)
Review
Eukaryotic cells utilize various RNA quality control mechanisms to ensure high fidelity of gene expression, thus protecting against the accumulation of nonfunctional RNA and the subsequent production of abnormal peptides. Messenger RNAs (mRNAs) are largely responsible for protein production, and mRNA quality control is particularly important for protecting the cell against the downstream effects of genetic mutations. Nonsense-mediated decay (NMD) is an evolutionarily conserved mRNA quality control system in all eukaryotes that degrades transcripts containing premature termination codons (PTCs). By degrading these aberrant transcripts, NMD acts to prevent the production of truncated proteins that could otherwise harm the cell through various insults, such as dominant negative effects or the ER stress response. Although NMD functions to protect the cell against the deleterious effects of aberrant mRNA, there is a growing body of evidence that mutation-, codon-, gene-, cell-, and tissue-specific differences in NMD efficiency can alter the underlying pathology of genetic disease. In addition, the protective role that NMD plays in genetic disease can undermine current therapeutic strategies aimed at increasing the production of full-length functional protein from genes harboring nonsense mutations. Here, we review the normal function of this RNA surveillance pathway and how it is regulated, provide current evidence for the role that it plays in modulating genetic disease phenotypes, and how NMD can be used as a therapeutic target.
Topics: Animals; Disease; Gene Expression Regulation; Humans; Nonsense Mediated mRNA Decay; Organ Specificity; RNA, Messenger
PubMed: 25485595
DOI: 10.1016/j.mrrev.2014.05.001 -
Environmental Research Jul 2015Simulate how the effect of exposure on disease occurrence and fatality influences the presence and magnitude of bias in survivor cohorts, motivated by an actual survivor...
OBJECTIVES
Simulate how the effect of exposure on disease occurrence and fatality influences the presence and magnitude of bias in survivor cohorts, motivated by an actual survivor cohort under study.
METHODS
We simulated a cohort of 50,000 subjects exposed to a disease-causing exposure over time and followed forty years, where disease incidence was the outcome of interest. We simulated this 'inception' cohort under different assumptions about the effect of exposure on disease occurrence and fatality after disease occurrence. We then created a corresponding 'survivor' (or 'cross-sectional') cohort, where cohort enrollment took place at a specific date after exposure began in the inception cohort; subjects dying prior to that enrollment date were excluded. The disease of interest caused all deaths in our simulations, but was not always fatal. In the survivor cohort, person-time at risk began before enrollment for all subjects who did not die prior to enrollment. We compared exposure-disease associations in each inception cohort to those in corresponding survivor cohorts to determine how different assumptions impacted bias in the survivor cohorts. All subjects in both inception and survivor cohorts were considered equally susceptible to the effect of exposure in causing disease. We used Cox proportional hazards regression to calculate effect measures.
RESULTS
There was no bias in survivor cohort estimates when case fatality among diseased subjects was independent of exposure. This was true even when the disease was highly fatal and more highly exposed subjects were more likely to develop disease and die. Assuming a positive exposure-response in the inception cohort, survivor cohort rate ratios were biased downwards when case fatality was greater with higher exposure.
CONCLUSIONS
Survivor cohort effect estimates for fatal outcomes are not always biased, although precision can decrease.
Topics: Cohort Studies; Disease; Environmental Exposure; Humans; Mortality; Probability; Survival Rate
PubMed: 25880887
DOI: 10.1016/j.envres.2015.03.039 -
Cell Metabolism Feb 2016Perturbation of an organism's homeostasis by stress can trigger biological or behavioral adaptation and accelerate onset and course of several diseases. Signaling...
Perturbation of an organism's homeostasis by stress can trigger biological or behavioral adaptation and accelerate onset and course of several diseases. Signaling triggered by norepinephrine or epinephrine (via adrenergic receptors) and cortisol (through glucocorticoid receptors) has profound effects on dampening immune responses, accelerating cancer progression and increasing the risk of cardiovascular, metabolic, and colonic diseases. To view this SnapShot, open or download the PDF.
Topics: Disease; Humans; Organ Specificity; Stress, Psychological
PubMed: 26863488
DOI: 10.1016/j.cmet.2016.01.015 -
International Review of Cell and... 2019Adaptive immune responses that occur in infection, cancer, and autoimmune as well as allergic diseases involve the participation of T cells. T cells travel throughout... (Review)
Review
Adaptive immune responses that occur in infection, cancer, and autoimmune as well as allergic diseases involve the participation of T cells. T cells travel throughout the body searching for antigens, which are recognized via the major histocompatibility complexes. In the healthy organism, these T cells maintain metabolic quiescence until they encounter a potentially cognate antigen. Once activated, e.g., during an infection or tissue damage, T cells switch their metabolic program to gain energy and building blocks to maintain cellular homeostasis and to fulfill their specific immune functions involving clonal expansion and/or differentiation into effector and memory T cells to ultimately ensure host survival. Thus, differences in metabolism in healthy and pathogenic T cells provide an explanation for dysfunctionality of T-cell responses in metabolic disorders, autoimmunity, and cancer. Here, we summarize current knowledge on T-cell metabolism during the maintenance of homeostasis, activation, and differentiation as well as over the course of time that memory is generated in health and in diseased states such as autoimmunity and cancer.
Topics: Animals; Disease; Health; Humans; T-Lymphocytes
PubMed: 30635095
DOI: 10.1016/bs.ircmb.2018.06.002 -
The American Journal of Clinical... Jun 1999Whether such epidemiologic descriptors as relative risk, dose response, and threshold points convey meaningful information is often the subject of debate. Thus, using... (Review)
Review
Whether such epidemiologic descriptors as relative risk, dose response, and threshold points convey meaningful information is often the subject of debate. Thus, using these descriptors to juxtapose the many disease-specific effects of nutritional exposures becomes problematic. In this article it is argued that epidemiologic patterns of disease-exposure associations must be interpreted in light of the profound imprecision of exposure assessment that characterizes nutritional epidemiology. In general, this imprecision leads to substantial attenuation of disease-exposure associations, such that relative risk, dose response, and the extent to which there are thresholds in disease-exposure associations can be seriously underestimated. Linking disease-specific relative risks, especially when derived from different studies with different methods of assessing exposure, is made increasingly difficult. The most critical tasks for lessening bias in these epidemiologic descriptors are first, to lessen imprecision in measuring exposures, and second, to adjust association estimates for attenuation due to measurement imprecision.
Topics: Diet; Disease; Epidemiologic Methods; Epidemiology; Humans; Prevalence; Reproducibility of Results; Risk
PubMed: 10359236
DOI: 10.1093/ajcn/69.6.1351S -
International Review of Cell and... 2013The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness.... (Review)
Review
The endoplasmic reticulum (ER) is a dynamic intracellular organelle with multiple functions essential for cellular homeostasis, development, and stress responsiveness. In response to cellular stress, a well-established signaling cascade, the unfolded protein response (UPR), is activated. This intricate mechanism is an important means of re-establishing cellular homeostasis and alleviating the inciting stress. Now, emerging evidence has demonstrated that the UPR influences cellular metabolism through diverse mechanisms, including calcium and lipid transfer, raising the prospect of involvement of these processes in the pathogenesis of disease, including neurodegeneration, cancer, diabetes mellitus and cardiovascular disease. Here, we review the distinct functions of the ER and UPR from a metabolic point of view, highlighting their association with prevalent pathologies.
Topics: Animals; Disease; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Humans; Proteolysis; Unfolded Protein Response
PubMed: 23317820
DOI: 10.1016/B978-0-12-407704-1.00005-1 -
Cellular & Molecular Immunology Apr 2018For the past twenty years, chemokines have emerged as a family of critical mediators of cell migration during immune surveillance, development, inflammation and cancer... (Review)
Review
For the past twenty years, chemokines have emerged as a family of critical mediators of cell migration during immune surveillance, development, inflammation and cancer progression. Chemokines bind to seven transmembrane G protein-coupled receptors (GPCRs) that are expressed by a wide variety of cell types and cause conformational changes in trimeric G proteins that trigger the intracellular signaling pathways necessary for cell movement and activation. Although chemokines have evolved to benefit the host, inappropriate regulation or utilization of these small proteins may contribute to or even cause diseases. Therefore, understanding the role of chemokines and their GPCRs in the complex physiological and diseased microenvironment is important for the identification of novel therapeutic targets. This review introduces the functional array and signals of multiple chemokine GPCRs in guiding leukocyte trafficking as well as their roles in homeostasis, inflammation, immune responses and cancer.
Topics: Animals; Chemokines; Disease; Homeostasis; Humans; Inflammation; Ligands; Receptors, G-Protein-Coupled
PubMed: 29375126
DOI: 10.1038/cmi.2017.134 -
Actas Luso-espanolas de Neurologia,... 1991In the study of psychosocial stress, three different types of factors can be established: external related to the induction of the stress response and pertaining to the... (Review)
Review
In the study of psychosocial stress, three different types of factors can be established: external related to the induction of the stress response and pertaining to the environment, such as life events; internal related to the individual response to stressors such as stress reactivity, and modulators, which are not directly related to the induction or response to stress, but which condition, modify or modulate, nevertheless, the interaction of external and internal factors, such as social support or depression. The adaptation of Holmes life-event questionnaire to Spanish and the development of the stress reactivity index are reviewed.
Topics: Adolescent; Adult; Aged; Behavior; Cognition; Disease; Emotions; Female; Humans; Life Change Events; Male; Middle Aged; Psychological Tests; Social Adjustment; Spain; Stress, Psychological; Surveys and Questionnaires
PubMed: 1807101
DOI: No ID Found -
Annual Review of Pathology 2008Autophagy is a process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. In yeast,... (Review)
Review
Autophagy is a process by which cytoplasmic components are sequestered in double membrane vesicles and degraded upon fusion with lysosomal compartments. In yeast, autophagy is activated in response to changes in the extracellular milieu. Depending upon the stimulus, autophagy can degrade cytoplasmic contents nonspecifically or can target the degradation of specific cellular components. Both of these have been adopted in higher eukaryotes and account for the expanding role of autophagy in various cellular processes, as well as contribute to the variation in cellular outcomes after induction of autophagy. In some cases, autophagy appears to be an adaptive response, whereas under other circumstances it is involved in cell death. In mammals, autophagy has been implicated in either the pathogenesis or response to a wide variety of diseases, including neurodegenerative disease, chronic bacterial and viral infections, atherosclerosis, and cancer. As the basic molecular pathways that regulate autophagy are elucidated, the relationship of autophagy to the pathogenesis of various disease states emerges.
Topics: Animals; Autophagy; Disease; Humans; Lysosomes
PubMed: 18039129
DOI: 10.1146/annurev.pathmechdis.2.010506.091842 -
Trends in Cell Biology Sep 2020Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to...
Recent work provides evidence for the new terminology, 'endoplasmic reticulum (ER) stress response or sensing failure', in relation to metabolic disease. We seek to identify and amass possible conditions of ER stress response failure in various metabolic and age-related pathogenesis, including obesity and diabetes.
Topics: Animals; Disease; Endoplasmic Reticulum Stress; Humans; Mice; Models, Biological; Unfolded Protein Response
PubMed: 32561138
DOI: 10.1016/j.tcb.2020.05.004