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  • Evolving Concepts of Mitochondrial Dynamics
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Gerald W. Dorn II

    The concept that mitochondria are highly dynamic is as widely accepted as it is untrue for a number of important contexts. Healthy mitochondria of the most energy-dependent and mitochondrial-rich mammalian organ, the heart, only rarely undergo fusion or fission and are seemingly static within cardiac myocytes. Here, we revisit mitochondrial dynamism with a fresh perspective developed from the recently discovered multifunctionality of mitochondrial fusion proteins and newly defined mechanisms for direct cross talk between mitochondrial dynamics, biogenesis, quality control, and trafficking pathways. Insights gained from comparing static mitochondrial biology in cardiac myocytes and dynamic mitochondrial biology in neurons are reviewed with the goal of understanding contextual fallacies of overly generalized characterizations of these essential and intriguing organelles.

    更新日期:2019-11-18
  • Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    David A. Hood, Jonathan M. Memme, Ashley N. Oliveira, Matthew Triolo

    Mitochondria are critical organelles responsible for regulating the metabolic status of skeletal muscle. These organelles exhibit remarkable plasticity by adapting their volume, structure, and function in response to chronic exercise, disuse, aging, and disease. A single bout of exercise initiates signaling to provoke increases in mitochondrial biogenesis, balanced by the onset of organelle turnover carried out by the mitophagy pathway. This accelerated turnover ensures the presence of a high functioning network of mitochondria designed for optimal ATP supply, with the consequence of favoring lipid metabolism, maintaining muscle mass, and reducing apoptotic susceptibility over the longer term. Conversely, aging and disuse are associated with reductions in muscle mass that are in part attributable to dysregulation of the mitochondrial network and impaired mitochondrial function. Therefore, exercise represents a viable, nonpharmaceutical therapy with the potential to reverse and enhance the impaired mitochondrial function observed with aging and chronic muscle disuse.

    更新日期:2019-11-18
  • ATP-Gated P2X Receptor Channels: Molecular Insights into Functional Roles
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Ralf Schmid, Richard J. Evans

    In the nervous system, ATP is co-stored in vesicles with classical transmitters and released in a regulated manner. ATP from the intracellular compartment can also exit the cell through hemichannels and following shear stress or membrane damage. In the past 30 years, the action of ATP as an extracellular transmitter at cell-surface receptors has evolved from somewhat of a novelty that was treated with skepticism to purinergic transmission being accepted as having widespread important functional roles mediated by ATP-gated ionotropic P2X receptors (P2XRs). This review focuses on work published in the last five years and provides an overview of (a) structural studies, (b) the molecular basis of channel properties and regulation of P2XRs, and (c) the physiological and pathophysiological roles of ATP acting at defined P2XR subtypes.

    更新日期:2019-11-18
  • Cysteine-Based Redox Sensing and Its Role in Signaling by Cyclic Nucleotide–Dependent Kinases in the Cardiovascular System
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Friederike Cuello, Philip Eaton

    Oxidant molecules are produced in biological systems and historically have been considered causal mediators of damage and disease. While oxidants may contribute to the pathogenesis of disease, evidence continues to emerge that shows these species also play important regulatory roles in health. A major mechanism of oxidant sensing and signaling involves their reaction with reactive cysteine thiols within proteins, inducing oxidative posttranslational modifications that can couple to altered function to enable homeostatic regulation. Protein kinase A and protein kinase G are regulated by oxidants in this way, and this review focuses on our molecular-level understanding of these events and their role in regulating cardiovascular physiology during health and disease.

    更新日期:2019-11-18
  • Plasticity of the Maternal Vasculature During Pregnancy
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    George Osol, Nga Ling Ko, Maurizio Mandalà

    Maternal cardiovascular changes during pregnancy include an expansion of plasma volume, increased cardiac output, decreased peripheral resistance, and increased uteroplacental blood flow. These adaptations facilitate the progressive increase in uteroplacental perfusion that is required for normal fetal growth and development, prevent the development of hypertension, and provide a reserve of blood in anticipation of the significant blood loss associated with parturition. Each woman's genotype and phenotype determine her ability to adapt in response to molecular signals that emanate from the fetoplacental unit. Here, we provide an overview of the major hemodynamic and cardiac changes and then consider regional changes in the splanchnic, renal, cerebral, and uterine circulations in terms of endothelial and vascular smooth muscle cell plasticity. Although consideration of gestational disease is beyond the scope of this review, aberrant signaling and/or maternal responsiveness contribute to the etiology of several common gestational diseases such as preeclampsia, intrauterine growth restriction, and gestational diabetes.

    更新日期:2019-11-18
  • Regulation of BK Channels by Beta and Gamma Subunits
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2016-03-18
    Vivian Gonzalez-Perez, Christopher J. Lingle

    Ca2+- and voltage-gated K+ channels of large conductance (BK channels) are expressed in a diverse variety of both excitable and inexcitable cells, with functional properties presumably uniquely calibrated for the cells in which they are found. Although some diversity in BK channel function, localization, and regulation apparently arises from cell-specific alternative splice variants of the single pore–forming α subunit (KCa1.1, Kcnma1, Slo1) gene, two families of regulatory subunits, β and γ, define BK channels that span a diverse range of functional properties. We are just beginning to unravel the cell-specific, physiological roles served by BK channels of different subunit composition.

    更新日期:2019-11-18
  • Branched Chain Amino Acids
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Michael Neinast, Danielle Murashige, Zoltan Arany

    Branched chain amino acids (BCAAs) are building blocks for all life-forms. We review here the fundamentals of BCAA metabolism in mammalian physiology. Decades of studies have elicited a deep understanding of biochemical reactions involved in BCAA catabolism. In addition, BCAAs and various catabolic products act as signaling molecules, activating programs ranging from protein synthesis to insulin secretion. How these processes are integrated at an organismal level is less clear. Inborn errors of metabolism highlight the importance of organismal regulation of BCAA physiology. More recently, subtle alterations of BCAA metabolism have been suggested to contribute to numerous prevalent diseases, including diabetes, cancer, and heart failure. Understanding the mechanisms underlying altered BCAA metabolism and how they contribute to disease pathophysiology will keep researchers busy for the foreseeable future.

    更新日期:2019-11-18
  • Phospholipid Remodeling in Physiology and Disease
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Bo Wang, Peter Tontonoz

    Phospholipids are major constituents of biological membranes. The fatty acyl chain composition of phospholipids determines the biophysical properties of membranes and thereby affects their impact on biological processes. The composition of fatty acyl chains is also actively regulated through a deacylation and reacylation pathway called Lands’ cycle. Recent studies of mouse genetic models have demonstrated that lysophosphatidylcholine acyltransferases (LPCATs), which catalyze the incorporation of fatty acyl chains into the sn-2 site of phosphatidylcholine, play important roles in pathophysiology. Two LPCAT family members, LPCAT1 and LPCAT3, have been particularly well studied. LPCAT1 is crucial for proper lung function due to its role in pulmonary surfactant biosynthesis. LPCAT3 maintains systemic lipid homeostasis by regulating lipid absorption in intestine, lipoprotein secretion, and de novo lipogenesis in liver. Mounting evidence also suggests that changes in LPCAT activity may be potentially involved in pathological conditions, including nonalcoholic fatty liver disease, atherosclerosis, viral infections, and cancer. Pharmacological manipulation of LPCAT activity and membrane phospholipid composition may provide new therapeutic options for these conditions.

    更新日期:2019-11-18
  • Contribution of Wound-Associated Cells and Mediators in Orchestrating Gastrointestinal Mucosal Wound Repair
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Miguel Quirós, Asma Nusrat

    The gastrointestinal mucosa, structurally formed by the epithelium and lamina propria, serves as a selective barrier that separates luminal contents from the underlying tissues. Gastrointestinal mucosal wound repair is orchestrated by a series of spatial and temporal events that involve the epithelium, recruited immune cells, resident stromal cells, and the microbiota present in the wound bed. Upon injury, repair of the gastrointestinal barrier is mediated by collective migration, proliferation, and subsequent differentiation of epithelial cells. Epithelial repair is intimately regulated by a number of wound-associated cells that include immune cells and stromal cells in addition to mediators released by luminal microbiota. The highly regulated interaction of these cell types is perturbed in chronic inflammatory diseases that are associated with impaired wound healing. An improved understanding of prorepair mechanisms in the gastrointestinal mucosa will aid in the development of novel therapeutics that promote mucosal healing and reestablish the critical epithelial barrier function.

    更新日期:2019-11-18
  • Epithelial-Stromal Interactions in Pancreatic Cancer
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Yaqing Zhang, Howard C. Crawford, Marina Pasca di Magliano

    Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment.

    更新日期:2019-11-18
  • Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Sabine Schneider, Christina M. Wright, Robert O. Heuckeroth

    At the most fundamental level, the bowel facilitates absorption of small molecules, regulates fluid and electrolyte flux, and eliminates waste. To successfully coordinate this complex array of functions, the bowel relies on the enteric nervous system (ENS), an intricate network of more than 500 million neurons and supporting glia that are organized into distinct layers or plexi within the bowel wall. Neuron and glial diversity, as well as neurotransmitter and receptor expression in the ENS, resembles that of the central nervous system. The most carefully studied ENS functions include control of bowel motility, epithelial secretion, and blood flow, but the ENS also interacts with enteroendocrine cells, influences epithelial proliferation and repair, modulates the intestinal immune system, and mediates extrinsic nerve input. Here, we review the many different cell types that communicate with the ENS, integrating data about ENS function into a broader view of human health and disease. In particular, we focus on exciting new literature highlighting relationships between the ENS and its lesser-known interacting partners.

    更新日期:2019-11-18
  • Visceral Pain
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Luke Grundy, Andelain Erickson, Stuart M. Brierley

    Most of us live blissfully unaware of the orchestrated function that our internal organs conduct. When this peace is interrupted, it is often by routine sensations of hunger and urge. However, for >20% of the global population, chronic visceral pain is an unpleasant and often excruciating reminder of the existence of our internal organs. In many cases, there is no obvious underlying pathological cause of the pain. Accordingly, chronic visceral pain is debilitating, reduces the quality of life of sufferers, and has large concomitant socioeconomic costs. In this review, we highlight key mechanisms underlying chronic abdominal and pelvic pain associated with functional and inflammatory disorders of the gastrointestinal and urinary tracts. This includes how the colon and bladder are innervated by specialized subclasses of spinal afferents, how these afferents become sensitized in highly dynamic signaling environments, and the subsequent development of neuroplasticity within visceral pain pathways. We also highlight key contributing factors, including alterations in commensal bacteria, altered mucosal permeability, epithelial interactions with afferent nerves, alterations in immune or stress responses, and cross talk between these two adjacent organs.

    更新日期:2019-11-18
  • Central Mechanisms for Thermoregulation
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    S.F. Morrison, K. Nakamura

    Maintenance of a homeostatic body core temperature is a critical brain function accomplished by a central neural network. This orchestrates a complex behavioral and autonomic repertoire in response to environmental temperature challenges or declining energy homeostasis and in support of immune responses and many behavioral states. This review summarizes the anatomical, neurotransmitter, and functional relationships within the central neural network that controls the principal thermoeffectors: cutaneous vasoconstriction regulating heat loss and shivering and brown adipose tissue for heat production. The core thermoregulatory network regulating these thermoeffectors consists of parallel but distinct central efferent pathways that share a common peripheral thermal sensory input. Delineating the neural circuit mechanism underlying central thermoregulation provides a useful platform for exploring its functional organization, elucidating the molecular underpinnings of its neuronal interactions, and discovering novel therapeutic approaches to modulating body temperature and energy homeostasis.

    更新日期:2019-11-18
  • Biomarkers of Acute and Chronic Kidney Disease
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    William R. Zhang, Chirag R. Parikh

    The current unidimensional paradigm of kidney disease detection is incompatible with the complexity and heterogeneity of renal pathology. The diagnosis of kidney disease has largely focused on glomerular filtration, while assessment of kidney tubular health has notably been absent. Following insult, the kidney tubular cells undergo a cascade of cellular responses that result in the production and accumulation of low-molecular-weight proteins in the urine and systemic circulation. Modern advancements in molecular analysis and proteomics have allowed the identification and quantification of these proteins as biomarkers for assessing and characterizing kidney diseases. In this review, we highlight promising biomarkers of kidney tubular health that have strong underpinnings in the pathophysiology of kidney disease. These biomarkers have been applied to various specific clinical settings from the spectrum of acute to chronic kidney diseases, demonstrating the potential to improve patient care.

    更新日期:2019-11-18
  • Generating Kidney from Stem Cells
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Melissa H. Little, Lorna J. Hale, Sara E. Howden, Santhosh V. Kumar

    Human kidney tissue can now be generated via the directed differentiation of human pluripotent stem cells. This advance is anticipated to facilitate the modeling of human kidney diseases, provide platforms for nephrotoxicity screening, enable cellular therapy, and potentially generate tissue for renal replacement. All such applications will rely upon the accuracy and reliability of the model and the capacity for stem cell–derived kidney tissue to recapitulate both normal and diseased states. In this review, we discuss the models available, how well they recapitulate the human kidney, and how far we are from application of these cells for use in cellular therapies.

    更新日期:2019-11-18
  • Regulation of Thirst and Vasopressin Release
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Daniel G. Bichet

    Recent experiments using optogenetic tools facilitate the identification and functional analysis of thirst neurons and vasopressin-producing neurons. Four major advances provide a detailed anatomy and physiology of thirst, taste for water, and arginine-vasopressin (AVP) release: (a) Thirst and AVP release are regulated by the classical homeostatic, interosensory plasma osmolality negative feedback as well as by novel, exterosensory, anticipatory signals. These anticipatory signals for thirst and vasopressin release concentrate on the same homeostatic neurons and circumventricular organs that monitor the composition of blood. (b) Acid-sensing taste receptor cells (TRCs) expressing otopetrin 1 on type III presynaptic TRCs on the tongue, which were previously suggested as the sour taste sensors, also mediate taste responses to water. (c) Dehydration is aversive, and median preoptic nucleus (MnPO) neuron activity is proportional to the intensity of this aversive state. (d) MnPOGLP1R neurons serve as a central detector that discriminates fluid ingestion from solid ingestion, which promotes acute satiation of thirst through the subfornical organ and other downstream targets.

    更新日期:2019-11-18
  • Cell Death in the Lung: The Apoptosis–Necroptosis Axis
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Maor Sauler, Isabel S. Bazan, Patty J. Lee

    Regulated cell death is a major mechanism to eliminate damaged, infected, or superfluous cells. Previously, apoptosis was thought to be the only regulated cell death mechanism; however, new modalities of caspase-independent regulated cell death have been identified, including necroptosis, pyroptosis, and autophagic cell death. As an understanding of the cellular mechanisms that mediate regulated cell death continues to grow, there is increasing evidence that these pathways are implicated in the pathogenesis of many pulmonary disorders. This review summarizes our understanding of regulated cell death as it pertains to the pathogenesis of chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, acute respiratory distress syndrome, and pulmonary arterial hypertension.

    更新日期:2019-11-18
  • Cellular Metabolism in Lung Health and Disease
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Gang Liu, Ross Summer

    The lung is often overlooked as a metabolically active organ, yet biochemical studies have long demonstrated that glucose utilization surpasses that of many other organs, including the heart, kidney, and brain. For most cells in the lung, energy consumption is relegated to performing common cellular tasks, like mRNA transcription and protein translation. However, certain lung cell populations engage in more specialized types of energy-consuming behaviors, such as the beating of cilia or the production of surfactant. While many extrapulmonary diseases are now linked to abnormalities in cellular metabolism, the pulmonary community has only recently embraced the concept of metabolic dysfunction as a driver of respiratory pathology. Herein, we provide an overview of the major metabolic pathways in the lung and discuss how cells sense and adapt to low-energy states. Moreover, we review some of the emerging evidence that links alterations in cellular metabolism to the pathobiology of several common respiratory diseases.

    更新日期:2019-11-18
  • Innate Lymphoid Cells of the Lung
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Jillian L. Barlow, Andrew N.J. McKenzie

    Although, as the major organ of gas exchange, the lung is considered a nonlymphoid organ, an interconnected network of lung-resident innate cells, including epithelial cells, dendritic cells, macrophages, and natural killer cells is crucial for its protection. These cells provide defense against a daily assault by airborne bacteria, viruses, and fungi, as well as prevent the development of cancer, allergy, and the outgrowth of commensals. Our understanding of this innate immune environment has recently changed with the discovery of a family of innate lymphoid cells (ILCs): ILC1s, ILC2s, and ILC3s. All lack adaptive antigen receptors but can provide a substantial and rapid source of IFN-γ, IL-5 and IL-13, and IL-17A or IL-22, respectively. Their ability to afford immediate protection to the lung and to influence subsequent adaptive immune responses highlights the importance of understanding ILC-regulated immunity for the design of future therapeutic interventions.

    更新日期:2019-11-18
  • Mitochondrial Iron in Human Health and Disease
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Diane M. Ward, Suzanne M. Cloonan

    Mitochondria are an iconic distinguishing feature of eukaryotic cells. Mitochondria encompass an active organellar network that fuses, divides, and directs a myriad of vital biological functions, including energy metabolism, cell death regulation, and innate immune signaling in different tissues. Another crucial and often underappreciated function of these dynamic organelles is their central role in the metabolism of the most abundant and biologically versatile transition metals in mammalian cells, iron. In recent years, cellular and animal models of mitochondrial iron dysfunction have provided vital information in identifying new proteins that have elucidated the pathways involved in mitochondrial homeostasis and iron metabolism. Specific signatures of mitochondrial iron dysregulation that are associated with disease pathogenesis and/or progression are becoming increasingly important. Understanding the molecular mechanisms regulating mitochondrial iron pathways will help better define the role of this important metal in mitochondrial function and in human health and disease.

    更新日期:2019-11-18
  • Metabolic Pathways Fueling the Endothelial Cell Drive
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Xuri Li, Anil Kumar, Peter Carmeliet

    Endothelial cell (EC) metabolism is important for health and disease. Metabolic pathways, such as glycolysis, fatty acid oxidation, and amino acid metabolism, determine vasculature formation. These metabolic pathways have different roles in securing the production of energy and biomass and the maintenance of redox homeostasis in vascular migratory tip cells, proliferating stalk cells, and quiescent phalanx cells, respectively. Emerging evidence demonstrates that perturbation of EC metabolism results in EC dysfunction and vascular pathologies. Here, we summarize recent insights into EC metabolic pathways and their deregulation in vascular diseases. We further discuss the therapeutic implications of targeting EC metabolism in various pathologies.

    更新日期:2019-11-18
  • Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    John D. Martin, Giorgio Seano, Rakesh K. Jain

    Abnormal blood and lymphatic vessels create a hostile tumor microenvironment characterized by hypoxia, low pH, and elevated interstitial fluid pressure. These abnormalities fuel tumor progression, immunosuppression, and treatment resistance. In 2001, we proposed a novel hypothesis that the judicious use of antiangiogenesis agents—originally developed to starve tumors—could transiently normalize tumor vessels and improve the outcome of anticancer drugs administered during the window of normalization. In addition to providing preclinical and clinical evidence in support of this hypothesis, we also revealed the underlying molecular mechanisms. In parallel, we demonstrated that desmoplasia could also impair vascular function by compressing vessels, and that normalizing the extracellular matrix could improve vascular function and treatment outcome in both preclinical and clinical settings. Here, we summarize the progress made in understanding and applying the normalization concept to cancer and outline opportunities and challenges ahead to improve patient outcomes using various normalizing strategies.

    更新日期:2019-11-18
  • Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Massimiliano Mazzone, Gabriele Bergers

    Research over the last decades has provided strong evidence for the pivotal role of the tumor-associated blood and lymphatic vasculature in supporting immunoevasion and in subverting T cell–mediated immunosurveillance. Conversely, tumor blood and lymphatic vessel growth is in part regulated by the immune system, with infiltrating innate as well as adaptive immune cells providing both immunosuppressive and various angiogenic signals. Thus, tumor angiogenesis and escape of immunosurveillance are two cancer hallmarks that are tightly linked and interregulated by cell constituents from compartments secreting both chemokines and cytokines. In this review, we discuss the implication and regulation of innate and adaptive immune cells in regulating blood and lymphatic angiogenesis in tumor progression and metastases. Moreover, we also highlight novel therapeutic approaches that target the tumor vasculature as well as the immune compartment to sustain and improve therapeutic efficacy in cancer.

    更新日期:2019-11-18
  • Evolved Mechanisms of Aerobic Performance and Hypoxia Resistance in High-Altitude Natives
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Grant B. McClelland, Graham R. Scott

    Comparative physiology studies of high-altitude species provide an exceptional opportunity to understand naturally evolved mechanisms of hypoxia resistance. Aerobic capacity (VO2max) is a critical performance trait under positive selection in some high-altitude taxa, and several high-altitude natives have evolved to resist the depressive effects of hypoxia on VO2max. This is associated with enhanced flux capacity through the O2 transport cascade and attenuation of the maladaptive responses to chronic hypoxia that can impair O2 transport. Some highlanders exhibit elevated rates of carbohydrate oxidation during exercise, taking advantage of its high ATP yield per mole of O2. Certain highland native animals have also evolved more oxidative muscles and can sustain high rates of lipid oxidation to support thermogenesis. The underlying mechanisms include regulatory adjustments of metabolic pathways and to gene expression networks. Therefore, the evolution of hypoxia resistance in high-altitude natives involves integrated functional changes in the pathways for O2 and substrate delivery and utilization by mitochondria.

    更新日期:2019-11-18
  • Steps in Mechanotransduction Pathways that Control Cell Morphology
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Haguy Wolfenson, Bo Yang, Michael P. Sheetz

    It is increasingly clear that mechanotransduction pathways play important roles in regulating fundamental cellular functions. Of the basic mechanical functions, the determination of cellular morphology is critical. Cells typically use many mechanosensitive steps and different cell states to achieve a polarized shape through repeated testing of the microenvironment. Indeed, morphology is determined by the microenvironment through periodic activation of motility, mechanotesting, and mechanoresponse functions by hormones, internal clocks, and receptor tyrosine kinases. Patterned substrates and controlled environments with defined rigidities limit the range of cell behavior and influence cell state decisions and are thus very useful for studying these steps. The recently defined rigidity sensing process provides a good example of how cells repeatedly test their microenvironment and is also linked to cancer. In general, aberrant extracellular matrix mechanosensing is associated with numerous conditions, including cardiovascular disease, aging, and fibrosis, that correlate with changes in tissue morphology and matrix composition. Hence, detailed descriptions of the steps involved in sensing and responding to the microenvironment are needed to better understand both the mechanisms of tissue homeostasis and the pathomechanisms of human disease.

    更新日期:2019-11-18
  • The Physiology of Optimizing Health with a Focus on Exercise as Medicine
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-02-11
    Bente Klarlund Pedersen

    Physical inactivity is one of the leading health problems in the world. Strong epidemiological and clinical evidence demonstrates that exercise decreases the risk of more than 35 different disorders and that exercise should be prescribed as medicine for many chronic diseases. The physiology and molecular biology of exercise suggests that exercise activates multiple signaling pathways of major health importance. An anti-inflammatory environment is produced with each bout of exercise, and long-term anti-inflammatory effects are mediated via an effect on abdominal adiposity. There is, however, a need to close the gap between knowledge and practice and assure that basic research is translated, implemented, and anchored in society, leading to change of praxis and political statements. In order to make more people move, we need a true translational perspective on exercise as medicine, from molecular and physiological events to infrastructure and architecture, with direct implications for clinical practice and public health.

    更新日期:2019-11-18
  • Cardiac Pacemaker Activity and Aging.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-23
    Colin H Peters,Emily J Sharpe,Catherine Proenza

    A progressive decline in maximum heart rate (mHR) is a fundamental aspect of aging in humans and other mammals. This decrease in mHR is independent of gender, fitness, and lifestyle, affecting in equal measure women and men, athletes and couch potatoes, spinach eaters and fast food enthusiasts. Importantly, the decline in mHR is the major determinant of the age-dependent decline in aerobic capacity that ultimately limits functional independence for many older individuals. The gradual reduction in mHR with age reflects a slowing of the intrinsic pacemaker activity of the sinoatrial node of the heart, which results from electrical remodeling of individual pacemaker cells along with structural remodeling and a blunted β-adrenergic response. In this review, we summarize current evidence about the tissue, cellular, and molecular mechanisms that underlie the reduction in pacemaker activity with age and highlight key areas for future work. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Regulation and Effects of FGF23 in Chronic Kidney Disease.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-20
    John Musgrove,Myles Wolf

    Chronic kidney disease (CKD) is a global health epidemic that accelerates cardiovascular disease, increases risk of infection, and causes anemia and bone disease, among other complications that collectively increase risk of premature death. Alterations in calcium and phosphate homeostasis have long been considered nontraditional risk factors for many of the most morbid outcomes of CKD. The discovery of fibroblast growth factor 23 (FGF23), which revolutionized the diagnosis and treatment of rare hereditary disorders of FGF23 excess that cause hypophosphatemic rickets, has also driven major paradigm shifts in our understanding of the pathophysiology and downstream end-organ complications of disordered mineral metabolism in CKD. As research of FGF23 in CKD has rapidly advanced, major new questions about its regulation and effects continuously emerge. These are promoting exciting innovations in laboratory, patient-oriented, and epidemiological research and stimulating clinical trials of new therapies and repurposing of existing ones to target FGF23. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-19
    Dinushan Nesan,Deborah M Kurrasch

    Endocrine disrupting chemicals are common in our environment and act on hormone systems and signaling pathways to alter physiological homeostasis. Gestational exposure can disrupt developmental programs, permanently altering tissues with impacts lasting into adulthood. The brain is a critical target for developmental endocrine disruption, resulting in altered neuroendocrine control of hormonal signaling, altered neurotransmitter control of nervous system function, and fundamental changes in behaviors such as learning, memory, and social interactions. Human cohort studies reveal correlations between maternal/fetal exposure to endocrine disruptors and incidence of neurodevelopmental disorders. Here, we summarize the major literature findings of endocrine disruption of neurodevelopment and concomitant changes in behavior by four major endocrine disruptor classes: bisphenol A, polychlorinated biphenyls, organophosphates, and polybrominated diphenyl ethers. We specifically review studies of gestational and/or lactational exposure to understand the effects of early life exposure to these compounds and summarize animal studies that help explain human correlative data. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • The Acidic Tumor Microenvironment as a Driver of Cancer.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-16
    Ebbe Boedtkjer,Stine F Pedersen

    Acidic metabolic waste products accumulate in the tumor microenvironment because of high metabolic activity and insufficient perfusion. In tumors, the acidity of the interstitial space and the relatively well-maintained intracellular pH influence cancer and stromal cell function, their mutual interplay, and their interactions with the extracellular matrix. Tumor pH is spatially and temporally heterogeneous, and the fitness advantage of cancer cells adapted to extracellular acidity is likely particularly evident when they encounter less acidic tumor regions, for instance, during invasion. Through complex effects on genetic stability, epigenetics, cellular metabolism, proliferation, and survival, the compartmentalized pH microenvironment favors cancer development. Cellular selection exacerbates the malignant phenotype, which is further enhanced by acid-induced cell motility, extracellular matrix degradation, attenuated immune responses, and modified cellular and intercellular signaling. In this review, we discuss how the acidity of the tumor microenvironment influences each stage in cancer development, from dysplasia to full-blown metastatic disease. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Genetics of COPD.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-16
    Edwin K Silverman

    Although chronic obstructive pulmonary disease (COPD) risk is strongly influenced by cigarette smoking, genetic factors are also important determinants of COPD. In addition to Mendelian syndromes such as alpha-1 antitrypsin deficiency, many genomic regions that influence COPD susceptibility have been identified in genome-wide association studies. Similarly, multiple genomic regions associated with COPD-related phenotypes, such as quantitative emphysema measures, have been found. Identifying the functional variants and key genes within these association regions remains a major challenge. However, newly identified COPD susceptibility genes are already providing novel insights into COPD pathogenesis. Network-based approaches that leverage these genetic discoveries have the potential to assist in decoding the complex genetic architecture of COPD. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • IP3 Receptor Plasticity Underlying Diverse Functions.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-16
    Kozo Hamada,Katsuhiko Mikoshiba

    In the body, extracellular stimuli produce inositol 1,4,5-trisphosphate (IP3), an intracellular chemical signal that binds to the IP3 receptor (IP3R) to release calcium ions (Ca2+) from the endoplasmic reticulum. In the past 40 years, the wide-ranging functions mediated by IP3R and its genetic defects causing a variety of disorders have been unveiled. Recent cryo-electron microscopy and X-ray crystallography have resolved IP3R structures and begun to integrate with concurrent functional studies, which can explicate IP3-dependent opening of Ca2+-conducting gates placed ∼90 Å away from IP3-binding sites and its regulation by Ca2+. This review highlights recent research progress on the IP3R structure and function. We also propose how protein plasticity within IP3R, which involves allosteric gating and assembly transformations accompanied by rapid and chronic structural changes, would enable it to regulate diverse functions at cellular microdomains in pathophysiological states. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Aging and Lung Disease.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-16
    Soo Jung Cho,Heather W Stout-Delgado

    People worldwide are living longer, and it is estimated that by 2050, the proportion of the world's population over 60 years of age will nearly double. Natural lung aging is associated with molecular and physiological changes that cause alterations in lung function, diminished pulmonary remodeling and regenerative capacity, and increased susceptibility to acute and chronic lung diseases. As the aging population rapidly grows, it is essential to examine how alterations in cellular function and cell-to-cell interactions of pulmonary resident cells and systemic immune cells contribute to a higher risk of increased susceptibility to infection and development of chronic diseases, such as chronic obstructive pulmonary disease and interstitial pulmonary fibrosis. This review provides an overview of physiological, structural, and cellular changes in the aging lung and immune system that facilitate the development and progression of disease. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-10-23
    Christi M Gendron,Tuhin S Chakraborty,Brian Y Chung,Zachary M Harvanek,Kristina J Holme,Jacob C Johnson,Yang Lyu,Allyson S Munneke,Scott D Pletcher

    Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and/or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • APOL1 and Kidney Disease: From Genetics to Biology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 2019-11-12
    David J Friedman,Martin R Pollak

    Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic Trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropathy spectrum. We then explore the origins of the APOL1 risk variants and evolutionary struggle between humans and trypanosomes at both the molecular and population genetic level. Finally, we survey the rapidly growing literature investigating APOL1 biology as elucidated from experiments in cell-based systems, cell-free systems, mouse and lower organism models of disease, and through illuminating natural experiments in humans. Expected final online publication date for the Annual Review of Physiology, Volume 82 is February 10, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

    更新日期:2019-11-01
  • Pharmacology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    M L TAINTER,L C MILLER,T J BECKER

    更新日期:2019-11-01
  • Applied physiology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    R E JOHNSON

    更新日期:2019-11-01
  • Physiological psychology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    R H SEASHORE

    更新日期:2019-11-01
  • Aviation physiology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    C L GEMMILL

    更新日期:2019-11-01
  • Reproduction.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    C W HOOKER

    更新日期:2019-11-01
  • Metabolic functions of the endocrine glands.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    E W DEMPSEY

    更新日期:2019-11-01
  • Audition.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    E G WEVER

    更新日期:2019-11-01
  • The somatic functions of the central nervous system.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    A E WALKER

    更新日期:2019-11-01
  • The visceral functions of the nervous system.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    K HARE

    更新日期:2019-11-01
  • Nerve and synaptic conduction.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    G H BISHOP

    更新日期:2019-11-01
  • Shock.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    M I GREGERSEN

    更新日期:2019-11-01
  • Heart.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    H E HOFF

    更新日期:2019-11-01
  • The lymphatic system.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    O COPE,L ROSENFELD

    更新日期:2019-11-01
  • Blood cytology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    G M HIGGINS

    更新日期:2019-11-01
  • 更新日期:2019-11-01
  • Kidney.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    R F PITTS

    更新日期:2019-11-01
  • Liver and bile.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    S FREEMAN

    更新日期:2019-11-01
  • Digestive system.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    J P QUIGLEY

    更新日期:2019-11-01
  • The physiology of the skin.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    S ROTHMAN,Z FELSHER

    更新日期:2019-11-01
  • Respiration.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    L F NIMS

    更新日期:2019-11-01
  • Energy metabolism.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    T M CARPENTER

    更新日期:2019-11-01
  • Physiology of heat and cold.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    J R BROBECK

    更新日期:2019-11-01
  • Developmental physiology.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    L B FLEXNER

    更新日期:2019-11-01
  • Physiological aspects of genetics.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    C H DANFORTH

    更新日期:2019-11-01
  • Effects of ultraviolet radiation.
    Annu. Rev. Physiol. (IF 17.902) Pub Date : 1946-01-01
    A HOLLAENDER

    更新日期:2019-11-01
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