Regulation and Effects of FGF23 in Chronic Kidney Disease.
Abstract 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 ...
Source: Annual Review of Physiology - November 19, 2019 Category: Physiology Authors: Musgrove J, Wolf M Tags: Annu Rev Physiol Source Type: research

Gestational Exposure to Common Endocrine Disrupting Chemicals and Their Impact on Neurodevelopment and Behavior.
Abstract 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 matern...
Source: Annual Review of Physiology - November 18, 2019 Category: Physiology Authors: Nesan D, Kurrasch DM Tags: Annu Rev Physiol Source Type: research

Aging and Lung Disease.
Abstract 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 inc...
Source: Annual Review of Physiology - November 15, 2019 Category: Physiology Authors: Jung Cho S, Stout-Delgado HW Tags: Annu Rev Physiol Source Type: research

IP3 Receptor Plasticity Underlying Diverse Functions.
Abstract 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...
Source: Annual Review of Physiology - November 15, 2019 Category: Physiology Authors: Hamada K, Mikoshiba K Tags: Annu Rev Physiol Source Type: research

Genetics of COPD.
Abstract 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 ide...
Source: Annual Review of Physiology - November 15, 2019 Category: Physiology Authors: Silverman EK Tags: Annu Rev Physiol Source Type: research

The Acidic Tumor Microenvironment as a Driver of Cancer.
Abstract 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 e...
Source: Annual Review of Physiology - November 15, 2019 Category: Physiology Authors: Boedtkjer E, Pedersen SF Tags: Annu Rev Physiol Source Type: research

APOL1 and Kidney Disease: From Genetics to Biology.
Abstract 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 nephropa...
Source: Annual Review of Physiology - November 11, 2019 Category: Physiology Authors: Friedman DJ, Pollak MR Tags: Annu Rev Physiol Source Type: research

Marrow Adipocytes: Origin, Structure, and Function.
Abstract The skeleton harbors an array of lineage cells that have an essential role in whole body homeostasis. Adipocytes start the colonization of marrow space early in postnatal life, expanding progressively and influencing other components of the bone marrow through paracrine signaling. In this unique, closed, and hypoxic environment close to the endosteal surface and adjacent to the microvascular space the marrow adipocyte can store or provide energy, secrete adipokines, and target neighboring bone cells. Adipocyte progenitors can also migrate from the bone marrow to populate white adipose tissue, a process th...
Source: Annual Review of Physiology - November 8, 2019 Category: Physiology Authors: de Paula FJA, Rosen CJ Tags: Annu Rev Physiol Source Type: research

New Approaches to Target Inflammation in Heart Failure: Harnessing Insights from Studies of Immune Cell Diversity.
Abstract Despite mounting evidence implicating inflammation in cardiovascular diseases, attempts at clinical translation have shown mixed results. Recent preclinical studies have reenergized this field and provided new insights into how to favorably modulate cardiac macrophage function in the context of acute myocardial injury and chronic disease. In this review, we discuss the origins and roles of cardiac macrophage populations in the steady-state and diseased heart, focusing on the human heart and mouse models of ischemia, hypertensive heart disease, and aortic stenosis. Specific attention is given to delineatin...
Source: Annual Review of Physiology - October 28, 2019 Category: Physiology Authors: Rhee AJ, Lavine KJ Tags: Annu Rev Physiol Source Type: research

Autophagy in Kidney Disease.
Abstract Autophagy is a cellular homeostatic program for the turnover of cellular organelles and proteins, in which double-membraned vesicles (autophagosomes) sequester cytoplasmic cargos, which are subsequently delivered to the lysosome for degradation. Emerging evidence implicates autophagy as an important modulator of human disease. Macroautophagy and selective autophagy (e.g., mitophagy, aggrephagy) can influence cellular processes, including cell death, inflammation, and immune responses, and thereby exert both adaptive and maladaptive roles in disease pathogenesis. Autophagy has been implicated in acute kidn...
Source: Annual Review of Physiology - October 22, 2019 Category: Physiology Authors: Choi ME Tags: Annu Rev Physiol Source Type: research

Diurnal Regulation of Renal Electrolyte Excretion: The Role of Paracrine Factors.
Abstract Many physiological processes, including most kidney-related functions, follow specific rhythms tied to a 24-h cycle. This is largely because circadian genes operate in virtually every cell type in the body. In addition, many noncanonical genes have intrinsic circadian rhythms, especially within the liver and kidney. This new level of complexity applies to the control of renal electrolyte excretion. Furthermore, there is growing evidence that paracrine and autocrine factors, especially the endothelin system, are regulated by clock genes. We have known for decades that excretion of electrolytes is dependent...
Source: Annual Review of Physiology - October 21, 2019 Category: Physiology Authors: Zhang D, Pollock DM Tags: Annu Rev Physiol Source Type: research

Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.
Abstract 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 mo...
Source: Annual Review of Physiology - October 21, 2019 Category: Physiology Authors: Gendron CM, Chakraborty TS, Chung BY, Harvanek ZM, Holme KJ, Johnson JC, Lyu Y, Munneke AS, Pletcher SD Tags: Annu Rev Physiol Source Type: research

Contributions of Aging to Cerebral Small Vessel Disease.
Abstract Cerebral small vessel disease (SVD) is characterized by changes in the pial and parenchymal microcirculations. SVD produces reductions in cerebral blood flow and impaired blood-brain barrier function, which are leading contributors to age-related reductions in brain health. End-organ effects are diverse, resulting in both cognitive and noncognitive deficits. Underlying phenotypes and mechanisms are multifactorial, with no specific treatments at this time. Despite consequences that are already considerable, the impact of SVD is predicted to increase substantially with the growing aging population. In the f...
Source: Annual Review of Physiology - October 16, 2019 Category: Physiology Authors: De Silva TM, Faraci FM Tags: Annu Rev Physiol Source Type: research

Physiology of the Carotid Body: From Molecules to Disease.
ez-Barneo J Abstract The carotid body (CB) is an arterial chemoreceptor organ located in the carotid bifurcation and has a well-recognized role in cardiorespiratory regulation. The CB contains neurosecretory sensory cells (glomus cells), which release transmitters in response to hypoxia, hypercapnia, and acidemia to activate afferent sensory fibers terminating in the respiratory and autonomic brainstem centers. Knowledge of the physiology of the CB has progressed enormously in recent years. Herein we review advances concerning the organization and function of the cellular elements of the CB, with emphasis on the m...
Source: Annual Review of Physiology - October 16, 2019 Category: Physiology Authors: Ortega-Sáenz P, López-Barneo J Tags: Annu Rev Physiol Source Type: research

BMP Signaling in Development, Stem Cells, and Diseases of the Gastrointestinal Tract.
Abstract The bone morphogenetic protein (BMP) pathway is essential for the morphogenesis of multiple organs in the digestive system. Abnormal BMP signaling has also been associated with disease initiation and progression in the gastrointestinal (GI) tract and associated organs. Recent studies using animal models, tissue organoids, and human pluripotent stem cells have significantly expanded our understanding of the roles played by BMPs in the development and homeostasis of GI organs. It is clear that BMP signaling regulates GI function and disease progression that involve stem/progenitor cells and inflammation in ...
Source: Annual Review of Physiology - October 16, 2019 Category: Physiology Authors: Zhang Y, Que J Tags: Annu Rev Physiol Source Type: research

Intestinal Stem Cell Aging: Origins and Interventions.
Abstract Regenerative processes that maintain the function of the gastrointestinal (GI) epithelium are critical for health and survival of multicellular organisms. In insects and vertebrates, intestinal stem cells (ISCs) regenerate the GI epithelium. ISC function is regulated by intrinsic, local, and systemic stimuli to adjust regeneration to tissue demands. These control mechanisms decline with age, resulting in significant perturbation of intestinal homeostasis. Processes that lead to this decline have been explored intensively in Drosophila melanogaster in recent years and are now starting to be characterized i...
Source: Annual Review of Physiology - October 14, 2019 Category: Physiology Authors: Jasper H Tags: Annu Rev Physiol Source Type: research

Circadian Regulation of Cardiac Physiology: Rhythms That Keep the Heart Beating.
Abstract On Earth, all life is exposed to dramatic changes in the environment over the course of the day; consequently, organisms have evolved strategies to both adapt to and anticipate these 24-h oscillations. As a result, time of day is major regulator of mammalian physiology and processes, including transcription, signaling, metabolism, and muscle contraction, all of which oscillate over the course of the day. In particular, the heart is subject to wide fluctuations in energetic demand throughout the day as a result of waking, physical activity, and food intake patterns. Daily rhythms in cardiovascular function...
Source: Annual Review of Physiology - October 7, 2019 Category: Physiology Authors: Zhang J, Chatham J, Young ME Tags: Annu Rev Physiol Source Type: research

Cardiomyocyte Polyploidy and Implications for Heart Regeneration.
Abstract In mammals, most cardiomyocytes (CMs) become polyploid (they have more than two complete sets of chromosomes). The purpose of this review is to evaluate assumptions about CM ploidy that are commonly discussed, even if not experimentally demonstrated, and to highlight key issues that are still to be resolved. Topics discussed here include (a) technical and conceptual difficulties in defining a polyploid CM, (b) the candidate role of reactive oxygen as a proximal trigger for the onset of polyploidy, (c) the relationship between polyploidization and other aspects of CM maturation, (d ) recent insights...
Source: Annual Review of Physiology - October 4, 2019 Category: Physiology Authors: Gan P, Patterson M, Sucov HM Tags: Annu Rev Physiol Source Type: research

Why Lungs Keep Time: Circadian Rhythms and Lung Immunity.
Abstract Circadian rhythms are daily cycles in biological function that are ubiquitous in nature. Understood as a means for organisms to anticipate daily environmental changes, circadian rhythms are also important for orchestrating complex biological processes such as immunity. Nowhere is this more evident than in the respiratory system, where circadian rhythms in inflammatory lung disease have been appreciated since ancient times. In this focused review we examine how emerging research on circadian rhythms is being applied to the study of fundamental lung biology and respiratory disease. We begin with a general i...
Source: Annual Review of Physiology - September 27, 2019 Category: Physiology Authors: Nosal C, Ehlers A, Haspel JA Tags: Annu Rev Physiol Source Type: research

Osteoclasts Provide Coupling Signals to Osteoblast Lineage Cells Through Multiple Mechanisms.
Abstract Bone remodeling is essential for the repair and replacement of damaged and old bone. The major principle underlying this process is that osteoclast-mediated resorption of a quantum of bone is followed by osteoblast precursor recruitment; these cells differentiate to matrix-producing osteoblasts, which form new bone to replace what was resorbed. Evidence from osteopetrotic syndromes indicate that osteoclasts not only resorb bone, but also provide signals to promote bone formation. Osteoclasts act upon osteoblast lineage cells throughout their differentiation by facilitating growth factor release from resor...
Source: Annual Review of Physiology - September 25, 2019 Category: Physiology Authors: Sims NA, Martin TJ Tags: Annu Rev Physiol Source Type: research

Regulation of Blood and Lymphatic Vessels by Immune Cells in Tumors and Metastasis.
Abstract 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 ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Mazzone M, Bergers G Tags: Annu Rev Physiol Source Type: research

Normalizing Function of Tumor Vessels: Progress, Opportunities, and Challenges.
Abstract 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 ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Martin JD, Seano G, Jain RK Tags: Annu Rev Physiol Source Type: research

Biomarkers of Acute and Chronic Kidney Disease.
Abstract 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 a...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Zhang WR, Parikh CR Tags: Annu Rev Physiol Source Type: research

Plasticity of the Maternal Vasculature During Pregnancy.
ve; M Abstract 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 fetoplace...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Osol G, Ko NL, Mandalà M Tags: Annu Rev Physiol Source Type: research

Regulation of Thirst and Vasopressin Release.
Abstract 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 ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Bichet DG Tags: Annu Rev Physiol Source Type: research

Innate Lymphoid Cells of the Lung.
Abstract 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 lac...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Barlow JL, McKenzie ANJ Tags: Annu Rev Physiol Source Type: research

Metabolic Pathways Fueling the Endothelial Cell Drive.
Abstract 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 a...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Li X, Kumar A, Carmeliet P Tags: Annu Rev Physiol Source Type: research

Regulation of BK Channels by Beta and Gamma Subunits.
Abstract 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 ...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Gonzalez-Perez V, Lingle CJ Tags: Annu Rev Physiol Source Type: research

Generating Kidney from Stem Cells.
Abstract 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 fr...
Source: Annual Review of Physiology - February 10, 2019 Category: Physiology Authors: Little MH, Hale LJ, Howden SE, Kumar SV Tags: Annu Rev Physiol Source Type: research

The Physiology of Optimizing Health with a Focus on Exercise as Medicine.
Abstract 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 clos...
Source: Annual Review of Physiology - December 10, 2018 Category: Physiology Authors: Pedersen BK Tags: Annu Rev Physiol Source Type: research

Cellular Metabolism in Lung Health and Disease.
Abstract 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,...
Source: Annual Review of Physiology - November 28, 2018 Category: Physiology Authors: Liu G, Summer R Tags: Annu Rev Physiol Source Type: research

Branched Chain Amino Acids.
Abstract 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 alteratio...
Source: Annual Review of Physiology - November 28, 2018 Category: Physiology Authors: Neinast M, Murashige D, Arany Z Tags: Annu Rev Physiol Source Type: research

Mitochondrial Iron in Human Health and Disease.
Abstract 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 info...
Source: Annual Review of Physiology - November 28, 2018 Category: Physiology Authors: Ward DM, Cloonan SM Tags: Annu Rev Physiol Source Type: research

Cell Death in the Lung: The Apoptosis-Necroptosis Axis.
Abstract 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...
Source: Annual Review of Physiology - November 28, 2018 Category: Physiology Authors: Sauler M, Bazan IS, Lee PJ Tags: Annu Rev Physiol Source Type: research

Epithelial-Stromal Interactions in Pancreatic Cancer.
Abstract 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 ...
Source: Annual Review of Physiology - November 12, 2018 Category: Physiology Authors: Zhang Y, Crawford HC, Pasca di Magliano M Tags: Annu Rev Physiol Source Type: research

Steps in Mechanotransduction Pathways that Control Cell Morphology.
Abstract 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 env...
Source: Annual Review of Physiology - November 7, 2018 Category: Physiology Authors: Wolfenson H, Yang B, Sheetz MP Tags: Annu Rev Physiol Source Type: research

Visceral Pain.
Abstract 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 underly...
Source: Annual Review of Physiology - October 31, 2018 Category: Physiology Authors: Grundy L, Erickson A, Brierley SM Tags: Annu Rev Physiol Source Type: research

Phospholipid Remodeling in Physiology and Disease.
Abstract 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...
Source: Annual Review of Physiology - October 31, 2018 Category: Physiology Authors: Wang B, Tontonoz P Tags: Annu Rev Physiol Source Type: research

Unexpected Roles for the Second Brain: Enteric Nervous System as Master Regulator of Bowel Function.
Abstract 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 moti...
Source: Annual Review of Physiology - October 31, 2018 Category: Physiology Authors: Schneider S, Wright CM, Heuckeroth RO Tags: Annu Rev Physiol Source Type: research

ATP-Gated P2X Receptor Channels: Molecular Insights into Functional Roles.
Abstract 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 ...
Source: Annual Review of Physiology - October 24, 2018 Category: Physiology Authors: Schmid R, Evans RJ Tags: Annu Rev Physiol Source Type: research

Contribution of Wound-Associated Cells and Mediators in Orchestrating Gastrointestinal Mucosal Wound Repair.
rat A Abstract 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...
Source: Annual Review of Physiology - October 24, 2018 Category: Physiology Authors: Quirós M, Nusrat A Tags: Annu Rev Physiol Source Type: research

Evolving Concepts of Mitochondrial Dynamics.
Abstract 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. Insigh...
Source: Annual Review of Physiology - September 26, 2018 Category: Physiology Authors: Dorn GW Tags: Annu Rev Physiol Source Type: research

Central Mechanisms for Thermoregulation.
Abstract 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 co...
Source: Annual Review of Physiology - September 26, 2018 Category: Physiology Authors: Morrison SF, Nakamura K Tags: Annu Rev Physiol Source Type: research

Evolved Mechanisms of Aerobic Performance and Hypoxia Resistance in High-Altitude Natives.
Abstract 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 du...
Source: Annual Review of Physiology - September 26, 2018 Category: Physiology Authors: McClelland GB, Scott GR Tags: Annu Rev Physiol Source Type: research

Maintenance of Skeletal Muscle Mitochondria in Health, Exercise, and Aging.
Abstract 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 optimalATPsupply, with the consequence of favoring lipid metaboli...
Source: Annual Review of Physiology - September 14, 2018 Category: Physiology Authors: Hood DA, Memme JM, Oliveira AN, Triolo M Tags: Annu Rev Physiol Source Type: research

Cysteine-Based Redox Sensing and Its Role in Signaling by Cyclic Nucleotide-Dependent Kinases in the Cardiovascular System.
Abstract 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 wa...
Source: Annual Review of Physiology - September 14, 2018 Category: Physiology Authors: Cuello F, Eaton P Tags: Annu Rev Physiol Source Type: research

The Work of Titin Protein Folding as a Major Driver in Muscle Contraction.
ez JM Abstract Single-molecule atomic force microscopy and magnetic tweezers experiments have demonstrated that titin immunoglobulin (Ig) domains are capable of folding against a pulling force, generating mechanical work that exceeds that produced by a myosin motor. We hypothesize that upon muscle activation, formation of actomyosin cross bridges reduces the force on titin, causing entropic recoil of the titin polymer and triggering the folding of the titin Ig domains. In the physiological force range of 4-15 pN under which titin operates in muscle, the folding contraction of a single Ig domain can generate 200% o...
Source: Annual Review of Physiology - February 10, 2018 Category: Physiology Authors: Eckels EC, Tapia-Rojo R, Rivas-Pardo JA, Fernández JM Tags: Annu Rev Physiol Source Type: research

Unraveling the Mechanobiology of Extracellular Matrix.
Abstract Cells need to be anchored to extracellular matrix (ECM) to survive, yet the role of ECM in guiding developmental processes, tissue homeostasis, and aging has long been underestimated. How ECM orchestrates the deterioration of healthy to pathological tissues, including fibrosis and cancer, also remains poorly understood. Inquiring how alterations in ECM fiber tension might drive these processes is timely, as mechanobiology is a rapidly growing field, and many novel mechanisms behind the mechanical forces that can regulate protein, cell, and tissue functions have recently been deciphered. The goal of this a...
Source: Annual Review of Physiology - February 10, 2018 Category: Physiology Authors: Vogel V Tags: Annu Rev Physiol Source Type: research

Mechanical Protein Unfolding and Degradation.
Abstract AAA+ proteolytic machines use energy from ATP hydrolysis to degrade damaged, misfolded, or unneeded proteins. Protein degradation occurs within a barrel-shaped self-compartmentalized peptidase. Before protein substrates can enter this peptidase, they must be unfolded and then translocated through the axial pore of an AAA+ ring hexamer. An unstructured region of the protein substrate is initially engaged in the axial pore, and conformational changes in the ring, powered by ATP hydrolysis, generate a mechanical force that pulls on and denatures the substrate. The same conformational changes in the hexameric...
Source: Annual Review of Physiology - February 10, 2018 Category: Physiology Authors: Olivares AO, Baker TA, Sauer RT Tags: Annu Rev Physiol Source Type: research

Bacterial Mechanosensors.
Abstract Bacteria represent one of the most evolutionarily successful groups of organisms to inhabit Earth. Their world is awash with mechanical cues, probably the most ancient form of which are osmotic forces. As a result, they have developed highly robust mechanosensors in the form of bacterial mechanosensitive (MS) channels. These channels are essential in osmoregulation, and in this setting, provide one of the simplest paradigms for the study of mechanosensory transduction. We explore the past, present, and future of bacterial MS channels, including the alternate mechanosensory roles that they may play in comp...
Source: Annual Review of Physiology - December 1, 2017 Category: Physiology Authors: Cox CD, Bavi N, Martinac B Tags: Annu Rev Physiol Source Type: research