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Experimental Cell Research Nov 2014DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various... (Review)
Review
DNA replication is a fundamental process of the cell that ensures accurate duplication of the genetic information and subsequent transfer to daughter cells. Various pertubations, originating from endogenous or exogenous sources, can interfere with proper progression and completion of the replication process, thus threatening genome integrity. Coordinated regulation of replication and the DNA damage response is therefore fundamental to counteract these challenges and ensure accurate synthesis of the genetic material under conditions of replication stress. In this review, we summarize the main sources of replication stress and the DNA damage signaling pathways that are activated in order to preserve genome integrity during DNA replication. We also discuss the association of replication stress and DNA damage in human disease and future perspectives in the field.
Topics: Animals; DNA Damage; DNA Replication; Disease; Genomic Instability; Humans
PubMed: 25281304
DOI: 10.1016/j.yexcr.2014.09.030 -
Cellular and Molecular Life Sciences :... Dec 2021Inflammation is vital to protect the host against foreign organism invasion and cellular damage. It requires tight and concise gene expression for regulation of pro- and... (Review)
Review
Inflammation is vital to protect the host against foreign organism invasion and cellular damage. It requires tight and concise gene expression for regulation of pro- and anti-inflammatory gene expression in immune cells. Dysregulated immune responses caused by gene mutations and errors in post-transcriptional regulation can lead to chronic inflammatory diseases and cancer. The mechanisms underlying post-transcriptional gene expression regulation include mRNA splicing, mRNA export, mRNA localisation, mRNA stability, RNA/protein interaction, and post-translational events such as protein stability and modification. The majority of studies to date have focused on transcriptional control pathways. However, post-transcriptional regulation of mRNA in eukaryotes is equally important and related information is lacking. In this review, we will focus on the mechanisms involved in the pre-mRNA splicing events, mRNA surveillance, RNA degradation pathways, disorders or symptoms caused by mutations or errors in post-transcriptional regulation during innate immunity especially toll-like receptor mediated pathways.
Topics: Animals; Disease; Humans; Immunity; Inflammation; Nonsense Mediated mRNA Decay; Pathogen-Associated Molecular Pattern Molecules; RNA
PubMed: 34971439
DOI: 10.1007/s00018-021-04073-5 -
Cellular and Molecular Life Sciences :... Jan 2017The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle... (Review)
Review
The vasculature is one of the most dynamic tissues that encounter numerous mechanical cues derived from pulsatile blood flow, blood pressure, activity of smooth muscle cells in the vessel wall, and transmigration of immune cells. The inner layer of blood and lymphatic vessels is covered by the endothelium, a monolayer of cells which separates blood from tissue, an important function that it fulfills even under the dynamic circumstances of the vascular microenvironment. In addition, remodeling of the endothelial barrier during angiogenesis and trafficking of immune cells is achieved by specific modulation of cell-cell adhesion structures between the endothelial cells. In recent years, there have been many new discoveries in the field of cellular mechanotransduction which controls the formation and destabilization of the vascular barrier. Force-induced adaptation at endothelial cell-cell adhesion structures is a crucial node in these processes that challenge the vascular barrier. One of the key examples of a force-induced molecular event is the recruitment of vinculin to the VE-cadherin complex upon pulling forces at cell-cell junctions. Here, we highlight recent advances in the current understanding of mechanotransduction responses at, and derived from, endothelial cell-cell junctions. We further discuss their importance for vascular barrier function and remodeling in development, inflammation, and vascular disease.
Topics: Disease; Endothelial Cells; Humans; Intercellular Junctions; Mechanotransduction, Cellular; Neovascularization, Physiologic; Vascular Stiffness
PubMed: 27506620
DOI: 10.1007/s00018-016-2325-8 -
Cells Jun 2023Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional... (Review)
Review
Apathy is commonly defined as a loss of motivation leading to a reduction in goal-directed behaviors. This multidimensional syndrome, which includes cognitive, emotional and behavioral components, is one of the most prevalent neuropsychiatric features of Parkinson's disease (PD). It has been established that the prevalence of apathy increases as PD progresses. However, the pathophysiology and anatomic substrate of this syndrome remain unclear. Apathy seems to be underpinned by impaired anatomical structures that link the prefrontal cortex with the limbic system. It can be encountered in the prodromal stage of the disease and in fluctuating PD patients receiving bilateral chronic subthalamic nucleus stimulation. In these stages, apathy may be considered as a disorder of motivation that embodies amotivational behavioral syndrome, is underpinned by combined dopaminergic and serotonergic denervation and is dopa-responsive. In contrast, in advanced PD patients, apathy may be considered as cognitive apathy that announces cognitive decline and PD dementia, is underpinned by diffuse neurotransmitter system dysfunction and Lewy pathology spreading and is no longer dopa-responsive. In this review, we discuss the clinical patterns of apathy and their treatment, the neurobiological basis of apathy, the potential role of the anatomical structures involved and the pathways in motivational and cognitive apathy.
Topics: Humans; Apathy; Parkinson Disease; Depression; Limbic System; Syndrome; Dihydroxyphenylalanine
PubMed: 37371068
DOI: 10.3390/cells12121599 -
Nucleic Acids Research Jan 2018Enhancers, as specialized genomic cis-regulatory elements, activate transcription of their target genes and play an important role in pathogenesis of many human complex...
Enhancers, as specialized genomic cis-regulatory elements, activate transcription of their target genes and play an important role in pathogenesis of many human complex diseases. Despite recent systematic identification of them in the human genome, currently there is an urgent need for comprehensive annotation databases of human enhancers with a focus on their disease connections. In response, we built the Human Enhancer Disease Database (HEDD) to facilitate studies of enhancers and their potential roles in human complex diseases. HEDD currently provides comprehensive genomic information for ∼2.8 million human enhancers identified by ENCODE, FANTOM5 and RoadMap with disease association scores based on enhancer-gene and gene-disease connections. It also provides Web-based analytical tools to visualize enhancer networks and score enhancers given a set of selected genes in a specific gene network. HEDD is freely accessible at http://zdzlab.einstein.yu.edu/1/hedd.php.
Topics: Chromosomes, Human, Pair 9; Databases, Nucleic Acid; Disease; Enhancer Elements, Genetic; Gene Regulatory Networks; Genome, Human; Genome-Wide Association Study; Humans; Internet; Molecular Sequence Annotation; Multifactorial Inheritance; Polymorphism, Single Nucleotide
PubMed: 29077884
DOI: 10.1093/nar/gkx988 -
Autophagy Apr 2021Proteome profiling and global protein-interaction approaches have significantly improved our knowledge of the protein interactomes of autophagy and other cellular...
Proteome profiling and global protein-interaction approaches have significantly improved our knowledge of the protein interactomes of autophagy and other cellular stress-response pathways. New discoveries regarding protein complexes, interaction partners, interaction domains, and biological roles of players that are part of these pathways are emerging. The fourth Vancouver Autophagy Symposium showcased research that expands our understanding of the protein interaction networks and molecular mechanisms underlying autophagy and other cellular stress responses in the context of distinct stressors. In the keynote presentation, Dr. Wade Harper described his team's recent discovery of a novel reticulophagy receptor for selective autophagic degradation of the endoplasmic reticulum, and discussed molecular mechanisms involved in ribophagy and non-autophagic ribosomal turnover. In other presentations, both omic and targeted approaches were used to reveal molecular players of other cellular stress responses including amyloid body and stress granule formation, anastasis, and extracellular vesicle biogenesis. Additional topics included the roles of autophagy in disease pathogenesis, autophagy regulatory mechanisms, and crosstalk between autophagy and cellular metabolism in anti-tumor immunity. The relationship between autophagy and other cell stress responses remains a relatively unexplored area in the field, with future investigations required to understand how the various processes are coordinated and connected in cells and tissues. A-bodies: amyloid bodies; ACM: amyloid-converting motif; AMFR/gp78: autocrine motility factor receptor; ATG: autophagy-related; ATG4B: autophagy related 4B cysteine peptidase; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAR T: chimeric antigen receptor T; CASP3: caspase 3; CCPG1: cell cycle progression 1; CAR: chimeric antigen receptor; CML: chronic myeloid leukemia; CCOCs: clear cell ovarian cancers; CVB3: coxsackievirus B3; CRISPR-Cas9: clustered regularly interspaced short palindromic repeats-CRISPR associated protein 9; DDXs: DEAD-box helicases; EIF2S1/EIF-2alpha: eukaryotic translation initiation factor 2 subunit alpha; EIF2AK3: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; EV: extracellular vesicle; FAO: fatty acid oxidation; GABARAP: GABA type A receptor-associated protein; ILK: integrin linked kinase; ISR: integrated stress response; MTOR: mechanistic target of rapamycin kinase; MPECs: memory precursory effector T cells; MAVS: mitochondrial antiviral signaling protein; NBR1: NBR1 autophagy cargo receptor; PI4KB/PI4KIIIβ: phosphatidylinositol 4-kinase beta; PLEKHM1: pleckstrin homology and RUN domain containing M1; RB1CC1: RB1 inducible coiled-coil 1; RTN3: reticulon 3; rIGSRNAs: ribosomal intergenic noncoding RNAs; RPL29: ribosomal protein L29; RPS3: ribosomal protein S3; ; sEV: small extracellular vesicles; ; SQSTM1: sequestosome 1; SF3B1: splicing factor 3b subunit 1; SILAC-MS: stable isotope labeling with amino acids in cell culture-mass spectrometry; SNAP29: synaptosome associated protein 29; TEX264: testis expressed 264, ER-phagy receptor; TNBC: triple-negative breast cancer; ULK1: unc-51 like autophagy activating kinase 1; VAS: Vancouver Autophagy Symposium.
Topics: Animals; Autophagy; Autophagy-Related Proteins; Disease; Humans; Proteome; Proteomics; Stress, Physiological
PubMed: 32507070
DOI: 10.1080/15548627.2020.1775394 -
Current Opinion in Biotechnology Feb 2019Synthetic biology aims to repurpose cells to sense a wide range of input signals and respond by conditionally expressing user-defined output genes. In this review, we... (Review)
Review
Synthetic biology aims to repurpose cells to sense a wide range of input signals and respond by conditionally expressing user-defined output genes. In this review, we highlight the latest developments in synthetic-biology-inspired in vitro and in vivo diagnostics and therapeutics employing engineered mammalian cells. Recent work has led to the creation of modular synthetic receptors with adaptable ligand-binding domains whose recognition specificity can be easily tailored to target various diseases. Engineered cells can now sense a great variety of soluble and surface-bound antigens with unprecedented selectivity and sensitivity, and implanted designer cells equipped with appropriate response modules can successfully treat diabetes, cancer and autoimmune diseases in animal models. Recently, the first immunotherapies using chimeric-antigen receptor (CAR)-T cells were approved to treat lymphoma patients. As this milestone paves the way for translating state-of-the-art synthetic biology approaches into clinical benefit, we also discuss the challenges facing engineered cell therapies.
Topics: Animals; Cell Engineering; Disease; Humans; Mammals; Receptors, Cell Surface; Synthetic Biology
PubMed: 30195188
DOI: 10.1016/j.copbio.2018.08.008 -
International Review of Cell and... 2015Aneuploidy is widely acknowledged as a leading cause of miscarriage and birth defects in humans, and is generally known to be deleterious to the survival of individual... (Review)
Review
Aneuploidy is widely acknowledged as a leading cause of miscarriage and birth defects in humans, and is generally known to be deleterious to the survival of individual cells. However, aneuploidy is also ubiquitous in cancer and is found to arise as an adaptive response in certain contexts. This dichotomy of aneuploidy has attracted the interest of researchers for over a century, but many studies have reached conflicting conclusions. The emergence of new technology has allowed scientists to revisit the aneuploidy problem and has fueled a number of recent studies aimed at understanding the effects of aneuploidy on cell physiology. Here, we review these studies, in light of previous observations and knowledge, specifically focusing on the effects of aneuploidy on cellular homeostasis, chromosome stability, and adaptation.
Topics: Adaptation, Physiological; Aneuploidy; Animals; Chromosomal Instability; Disease; Homeostasis; Humans
PubMed: 25708466
DOI: 10.1016/bs.ircmb.2014.11.002 -
Annual Review of Pathology 2015The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics.... (Review)
Review
The ultimate goal of most biomedical research is to gain greater insight into mechanisms of human disease or to develop new and improved therapies or diagnostics. Although great advances have been made in terms of developing disease models in animals, such as transgenic mice, many of these models fail to faithfully recapitulate the human condition. In addition, it is difficult to identify critical cellular and molecular contributors to disease or to vary them independently in whole-animal models. This challenge has attracted the interest of engineers, who have begun to collaborate with biologists to leverage recent advances in tissue engineering and microfabrication to develop novel in vitro models of disease. As these models are synthetic systems, specific molecular factors and individual cell types, including parenchymal cells, vascular cells, and immune cells, can be varied independently while simultaneously measuring system-level responses in real time. In this article, we provide some examples of these efforts, including engineered models of diseases of the heart, lung, intestine, liver, kidney, cartilage, skin and vascular, endocrine, musculoskeletal, and nervous systems, as well as models of infectious diseases and cancer. We also describe how engineered in vitro models can be combined with human inducible pluripotent stem cells to enable new insights into a broad variety of disease mechanisms, as well as provide a test bed for screening new therapies.
Topics: Animals; Disease; Humans; In Vitro Techniques; Models, Biological; Pathology
PubMed: 25621660
DOI: 10.1146/annurev-pathol-012414-040418 -
The Journal of Physiological Sciences :... May 2019An organism stems from assemblies of a variety of cells and proteins. This complex system serves as a unit, and it exhibits highly sophisticated functions in response to... (Review)
Review
An organism stems from assemblies of a variety of cells and proteins. This complex system serves as a unit, and it exhibits highly sophisticated functions in response to exogenous stimuli that change over time. The complete sequencing of the entire human genome has allowed researchers to address the enigmas of life and disease at the gene- or molecular-based level. The consequence of such studies is the rapid accumulation of a multitude of data at multiple levels, ranging from molecules to the whole body, that has necessitated the development of entirely new concepts, tools, and methodologies to analyze and integrate these data. This necessity has given birth to systems biology, an advanced theoretical and practical research framework that has totally changed the directions of not only basic life science but also medicine. During the symposium of the 95th Annual Meeting of The Physiological Society of Japan 2018, five researchers reported on their respective studies on systems biology. The topics included reactions of drugs, ion-transport architecture in an epithelial system, multi-omics in renal disease, cardiac electrophysiological systems, and a software platform for computer simulation. In this review article these authors have summarized recent achievements in the field and discuss next-generation studies on health and disease.
Topics: Animals; Computational Biology; Computer Simulation; Disease; Humans; Japan; Research; Software; Systems Biology
PubMed: 30868372
DOI: 10.1007/s12576-019-00667-8