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Journal of the American Heart... Oct 2023The medial layer of the arterial wall is composed mainly of vascular smooth muscle cells (VSMCs). Under physiological conditions, VSMCs assume a contractile phenotype,... (Review)
Review
The medial layer of the arterial wall is composed mainly of vascular smooth muscle cells (VSMCs). Under physiological conditions, VSMCs assume a contractile phenotype, and their primary function is to regulate vascular tone. In contrast with terminally differentiated cells, VSMCs possess phenotypic plasticity, capable of transitioning into other cellular phenotypes in response to changes in the vascular environment. Recent research has shown that VSMC phenotypic switching participates in the pathogenesis of atherosclerosis, where the various types of dedifferentiated VSMCs accumulate in the atherosclerotic lesion and participate in the associated vascular remodeling by secreting extracellular matrix proteins and proteases. This review article discusses the 9 VSMC phenotypes that have been reported in atherosclerotic lesions and classifies them into differentiated VSMCs, intermediately dedifferentiated VSMCs, and dedifferentiated VSMCs. It also provides an overview of several methodologies that have been developed for studying VSMC phenotypic switching and discusses their respective advantages and limitations.
Topics: Humans; Muscle, Smooth, Vascular; Atherosclerosis; Phenotype; Cell Differentiation; Myocytes, Smooth Muscle; Cells, Cultured; Cell Proliferation
PubMed: 37815057
DOI: 10.1161/JAHA.123.031121 -
JAMA Psychiatry Aug 2023Assessing the link between whole-brain activity and individual differences in cognition and behavior has the potential to offer insights into psychiatric disorder... (Review)
Review
IMPORTANCE
Assessing the link between whole-brain activity and individual differences in cognition and behavior has the potential to offer insights into psychiatric disorder etiology and change the practice of psychiatry, from diagnostic clarification to intervention. To this end, recent application of predictive modeling to link brain activity to phenotype has generated significant excitement, but clinical applications have largely not been realized. This Review explores explanations for the as yet limited practical utility of brain-phenotype modeling and proposes a path forward to fulfill this clinical potential.
OBSERVATIONS
Clinical applications of brain-phenotype models are proposed and will require coordinated collaboration across the relatively siloed fields of psychometrics and computational neuroscience. Such interdisciplinary work will maximize the reliability and validity of modeled phenotypic measures, ensuring that resulting brain-based models are interpretable and useful. The models, in turn, may shed additional light on the neurobiological systems into which each phenotypic measure taps, permitting further phenotype refinement.
CONCLUSIONS AND RELEVANCE
Together, these observations reflect an opportunity: bridging the divide between phenotypic measure development and validation and measure end use for brain-phenotype modeling holds the promise that each may inform the other, yielding more precise and useful brain-phenotype models. Such models can in turn be used to reveal the macroscale neural bases of a given phenotype, advancing basic neuroscientific understanding and identifying circuits that can be targeted (eg, via closed-loop neurofeedback or brain stimulation) to slow, reverse, or even prevent functional impairment.
Topics: Humans; Reproducibility of Results; Mental Disorders; Brain; Cognition; Phenotype
PubMed: 37314790
DOI: 10.1001/jamapsychiatry.2023.1419 -
Biotechnology Advances 2024Cells execute biological functions to support phenotypes such as growth, migration, and secretion. Complementarily, each function of a cell has resource costs that... (Review)
Review
Cells execute biological functions to support phenotypes such as growth, migration, and secretion. Complementarily, each function of a cell has resource costs that constrain phenotype. Resource allocation by a cell allows it to manage these costs and optimize their phenotypes. In fact, the management of resource constraints (e.g., nutrient availability, bioenergetic capacity, and macromolecular machinery production) shape activity and ultimately impact phenotype. In mammalian systems, quantification of resource allocation provides important insights into higher-order multicellular functions; it shapes intercellular interactions and relays environmental cues for tissues to coordinate individual cells to overcome resource constraints and achieve population-level behavior. Furthermore, these constraints, objectives, and phenotypes are context-dependent, with cells adapting their behavior according to their microenvironment, resulting in distinct steady-states. This review will highlight the biological insights gained from probing resource allocation in mammalian cells and tissues.
Topics: Animals; Resource Allocation; Mammals; Phenotype
PubMed: 38215956
DOI: 10.1016/j.biotechadv.2023.108305 -
Heart Failure Reviews Sep 2023The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular... (Review)
Review
The hypertrophic cardiomyopathy phenotype encompasses a heterogeneous spectrum of genetic and acquired diseases characterized by the presence of left ventricular hypertrophy in the absence of abnormal cardiac loading conditions. This "umbrella diagnosis" includes the "classic" hypertrophic cardiomyopathy (HCM), due to sarcomere protein gene mutations, and its phenocopies caused by intra- or extracellular deposits, such as Fabry disease (FD) and cardiac amyloidosis (CA). All these conditions share a wide phenotypic variability which results from the combination of genetic and environmental factors and whose pathogenic mediators are poorly understood so far. Accumulating evidence suggests that inflammation plays a critical role in a broad spectrum of cardiovascular conditions, including cardiomyopathies. Indeed, inflammation can trigger molecular pathways which contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation, and microvascular dysfunction. Growing evidence suggests that systemic inflammation is a possible key pathophysiologic process potentially involved in the pathogenesis of cardiac disease progression, influencing the severity of the phenotype and clinical outcome, including heart failure. In this review, we summarize current knowledge regarding the prevalence, clinical significance, and potential therapeutic implications of inflammation in HCM and two of its most important phenocopies, FD and CA.
Topics: Humans; Cardiomyopathy, Hypertrophic; Hypertrophy, Left Ventricular; Cardiomyopathies; Phenotype; Fabry Disease; Inflammation
PubMed: 37115472
DOI: 10.1007/s10741-023-10307-4 -
Emerging Topics in Life Sciences Dec 2023Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a...
Repeat expansion disorders (REDs) are monogenic diseases caused by a sequence of repetitive DNA expanding above a pathogenic threshold. A common feature of the REDs is a strong genotype-phenotype correlation in which a major determinant of age at onset (AAO) and disease progression is the length of the inherited repeat tract. Over a disease-gene carrier's life, the length of the repeat can expand in somatic cells, through the process of somatic expansion which is hypothesised to drive disease progression. Despite being monogenic, individual REDs are phenotypically variable, and exploring what genetic modifying factors drive this phenotypic variability has illuminated key pathogenic mechanisms that are common to this group of diseases. Disease phenotypes are affected by the cognate gene in which the expansion is found, the location of the repeat sequence in coding or non-coding regions and by the presence of repeat sequence interruptions. Human genetic data, mouse models and in vitro models have implicated the disease-modifying effect of DNA repair pathways via the mechanisms of somatic mutation of the repeat tract. As such, developing an understanding of these pathways in the context of expanded repeats could lead to future disease-modifying therapies for REDs.
Topics: Mice; Animals; Humans; Trinucleotide Repeat Expansion; Age of Onset; Genetic Association Studies; Phenotype; Disease Progression
PubMed: 37861103
DOI: 10.1042/ETLS20230015 -
Trends in Genetics : TIG Sep 2023Phenotypic plasticity, the ability of an organism to display different phenotypes across environments, is widespread in nature. Plasticity aids survival in novel... (Review)
Review
Phenotypic plasticity, the ability of an organism to display different phenotypes across environments, is widespread in nature. Plasticity aids survival in novel environments. Herein, we review studies from yeast that allow us to start uncovering the genetic architecture of phenotypic plasticity. Genetic variants and their interactions impact the phenotype in different environments, and distinct environments modulate the impact of genetic variants and their interactions on the phenotype. Because of this, certain hidden genetic variation is expressed in specific genetic and environmental backgrounds. A better understanding of the genetic mechanisms of phenotypic plasticity will help to determine short- and long-term responses to selection and how wide variation in disease manifestation occurs in human populations.
Topics: Humans; Quantitative Trait Loci; Phenotype; Saccharomyces cerevisiae; Adaptation, Physiological; Genetic Variation
PubMed: 37173192
DOI: 10.1016/j.tig.2023.04.002 -
Journal of Nepal Health Research Council Jul 2023Beta thalassemias are extremely heterogenous hereditary monogenic blood disorders and preventable genetic hemolytic anemia caused by >200 mutations in HBB gene. In...
BACKGROUND
Beta thalassemias are extremely heterogenous hereditary monogenic blood disorders and preventable genetic hemolytic anemia caused by >200 mutations in HBB gene. In Nepal, it is more prevalent in Tharu tribe but it seen in other communities as well. Out of more than 200 mutations of beta globin gene, approximate 20 different alleles are responsible for >80% of the mutations. Mutations vary in different geographic population and are responsible for manifestation of different phenotypes. This study was done to find common mutations of HBB gene in Nepal which were responsible for different phenotypic manifestations and to know clinical severity according to the mutations.
METHODS
This was a descriptive, cross sectional study conducted in the pediatric and medicine department of Nepalgunj Medical College and Bheri Zonal Hospital, Nepalgunj from January 2020 to December 2020. The genotype and phenotype profiles of thalassemia cases were reported. The data was analyzed by SPSS 20.
RESULTS
The results obtained showed that clinical presentation differed with different β-globin gene mutations present. Individuals with HBB:c.47G>A and HBB:c.20A>T/ c.79G>A mutations showed milder presentation than those with HBB:c.47G>A/-619del and HBB:c.20A>T/c.47G>A.
CONCLUSIONS
Therefore, these findings can be used to predict clinical severity so that we can take appropriate measures by early genotype identification for prenatal diagnosis of beta thalassemia.
Topics: Female; Pregnancy; Humans; beta-Thalassemia; Cross-Sectional Studies; Nepal; Phenotype; Genotype
PubMed: 37489663
DOI: 10.33314/jnhrc.v20i4.3719 -
ELife Sep 2023Experiments on worms suggest that a statistical measure called the G matrix can accurately predict how phenotypes will adapt to a novel environment over multiple...
Experiments on worms suggest that a statistical measure called the G matrix can accurately predict how phenotypes will adapt to a novel environment over multiple generations.
Topics: Phenotype; Biological Evolution; Adaptation, Biological; Animals
PubMed: 37671937
DOI: 10.7554/eLife.91450 -
Proceedings. Biological Sciences Aug 2023Ecological interactions influence evolutionary dynamics by selecting upon fitness variation within species. Antagonistic interactions often promote genetic and species... (Review)
Review
Ecological interactions influence evolutionary dynamics by selecting upon fitness variation within species. Antagonistic interactions often promote genetic and species diversity, despite the inherently suppressive effect they can have on the species experiencing them. A central aim of evolutionary ecology is to understand how diversity is maintained in systems experiencing antagonism. In this review, we address how certain single-celled and dimorphic fungi have evolved allelopathic killer phenotypes that engage in antagonistic interactions. We discuss the evolutionary pathways to the production of lethal toxins, the functions of killer phenotypes and the consequences of competition for toxin producers, their competitors and toxin-encoding endosymbionts. Killer phenotypes are powerful models because many appear to have evolved independently, enabling across-phylogeny comparisons of the origins, functions and consequences of allelopathic antagonism. Killer phenotypes can eliminate host competitors and influence evolutionary dynamics, yet the evolutionary ecology of killer phenotypes remains largely unknown. We discuss what is known and what remains to be ascertained about killer phenotype ecology and evolution, while bringing their model system properties to the reader's attention.
Topics: Phylogeny; Fungi; Models, Biological; Phenotype; Ecology; Biological Evolution
PubMed: 37583325
DOI: 10.1098/rspb.2023.1108 -
Cell Reports Oct 2023Following viral infection, the human immune system generates CD8 T cell responses to virus antigens that differ in specificity, abundance, and phenotype. A...
Following viral infection, the human immune system generates CD8 T cell responses to virus antigens that differ in specificity, abundance, and phenotype. A characterization of virus-specific T cell responses allows one to assess infection history and to understand its contribution to protective immunity. Here, we perform in-depth profiling of CD8 T cells binding to CMV-, EBV-, influenza-, and SARS-CoV-2-derived antigens in peripheral blood samples from 114 healthy donors and 55 cancer patients using high-dimensional mass cytometry and single-cell RNA sequencing. We analyze over 500 antigen-specific T cell responses across six different HLA alleles and observed unique phenotypes of T cells specific for antigens from different virus categories. Using machine learning, we extract phenotypic signatures of antigen-specific T cells, predict virus specificity for bulk CD8 T cells, and validate these predictions, suggesting that machine learning can be used to accurately predict antigen specificity from T cell phenotypes.
Topics: Humans; CD8-Positive T-Lymphocytes; Herpesvirus 4, Human; T-Cell Antigen Receptor Specificity; Antigens, Viral; Phenotype
PubMed: 37837618
DOI: 10.1016/j.celrep.2023.113250