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Volume 87, 2025
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Sex Differences in Electrophysiology and Calcium Handling in Atrial Health and Fibrillation
Vol. 87 (2025), pp. 1–24More LessThe importance of biological sex on disease etiology and outcomes has long been underinvestigated. While recent focus on characterizing sex differences in cardiac pathophysiology has led to improved inclusion of both sexes in scientific studies and clinical trials, much is still unknown about underlying differences in normal cardiac physiology. This is particularly true for the atria, where the most common arrhythmia, atrial fibrillation (AF), occurs. AF is associated with adverse structural, electrophysiological, and calcium handling remodeling that leads to patient morbidity and mortality. Differences in the onset, prevalence, presentation, and prognosis of AF are known to differ between males and females, yet the sex-specific baseline phenotypes from which AF arises are not well characterized. This review examines what is currently known about sex differences in atrial physiology, the alterations that occur in AF, potential mechanisms underlying sex divergence, and the need for sex-targeted therapeutic strategies.
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Mechanisms and Implications of Electrical Heterogeneity in Cardiac Function in Ischemic Heart Disease
Vol. 87 (2025), pp. 25–51More LessA healthy heart shows intrinsic electrical heterogeneities that play a significant role in cardiac activation and repolarization. However, cardiac diseases may perturb the baseline electrical properties of the healthy cardiac tissue, leading to increased arrhythmic risk and compromised cardiac functions. Moreover, biological variability among patients produces a wide range of clinical symptoms, which complicates the treatment and diagnosis of cardiac diseases. Ischemic heart disease is usually caused by a partial or complete blockage of a coronary artery. The onset of the disease begins with myocardial ischemia, which can develop into myocardial infarction if it persists for an extended period. The progressive regional tissue remodeling leads to increased electrical heterogeneities, with adverse consequences on arrhythmic risk, cardiac mechanics, and mortality. This review aims to summarize the key role of electrical heterogeneities in the heart on cardiac function and diseases. Ischemic heart disease has been chosen as an example to show how adverse electrical remodeling at different stages may lead to variable manifestations in patients. For this, we have reviewed the dynamic electrophysiological and structural remodeling from the onset of acute myocardial ischemia and reperfusion to acute and chronic stages post–myocardial infarction. The arrhythmic mechanisms, patient phenotypes, risk stratification at different stages, and patient management strategies are also discussed. Finally, we provide a brief review on how computational approaches incorporate human electrophysiological heterogeneity to facilitate basic and translational research.
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The Heart Is a Smart Pump: Mechanotransduction Mechanisms of the Frank-Starling Law and the Anrep Effect
Vol. 87 (2025), pp. 53–77More LessThe Frank-Starling law and Anrep effect describe two intrinsic mechanisms that regulate contraction force in the heart. Based on recent advancements and the historical literature, we propose new perspectives and address several critical issues in this review. (a) The Frank-Starling mechanism and Anrep effect are dynamically linked and act synergistically. (b) An open question is how cardiomyocytes sense mechanical load and transduce to biochemical signals (called mechano-chemo-transduction or MCT) to regulate contraction in response to load changes. (c) One research focus is to identify various mechanosensors and decipher their downstream MCT pathways. (d) Innovative experimental techniques engage different mechanosensors that detect different local strain and stress in the cell architecture. (e) Closed-loop MCT feedback in the dynamic excitation-Ca2+ signaling-contraction system enables autoregulation of contraction in response to physiological load changes. (f) However, pathological overload such as volume and pressure overload lead to excessive MCT-Ca2+ gain, cardiac remodeling, and heart diseases.
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Preterm Brain Injury: Mechanisms and Challenges
Vol. 87 (2025), pp. 79–106More LessPreterm fetuses and newborns have a high risk of neural injury and impaired neural maturation, leading to neurodevelopmental disability. Developing effective treatments is rather challenging, as preterm brain injury may occur at any time during pregnancy and postnatally, and many cases involve multiple pathogenic factors. This review examines research on how the preterm fetus responds to hypoxia-ischemia and how brain injury evolves after hypoxia-ischemia, offering windows of opportunity for treatment and insights into the mechanisms of injury during key phases. We highlight research showing that preterm fetuses can survive hypoxia-ischemia and continue development in utero with evolving brain injury. Early detection of fetal brain injury would provide an opportunity for treatments to reduce adverse neurodevelopmental outcomes, including cerebral palsy. However, this requires that we can detect injury using noninvasive methods. We discuss how circadian changes in fetal heart rate variability may offer utility as a biomarker for detecting injury and phases of injury.
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Exercise as Mitochondrial Medicine: How Does the Exercise Prescription Affect Mitochondrial Adaptations to Training?
Vol. 87 (2025), pp. 107–129More LessMitochondria are multifaceted organelles with several life-sustaining functions beyond energy transformation, including cell signaling, calcium homeostasis, hormone synthesis, programmed cell death (apoptosis), and others. A defining aspect of these dynamic organelles is their remarkable plasticity, which allows them to sense, respond, and adapt to various stressors. In particular, it is well-established that the stress of exercise provides a powerful stimulus that can trigger transient or enduring changes to mitochondrial molecular features, activities, integrated functions, behaviors, and cell-dependent mitochondrial phenotypes. Evidence documenting the many beneficial mitochondrial adaptations to exercise has led to the notion of exercise as a mitochondrial medicine. However, as with other medicines, it is important to understand the optimal prescription (i.e., type, dose, frequency, duration). In this review, we build on a systematic biological framework that distinguishes between domains of mitochondrial biology to critically evaluate how different exercise prescription variables influence mitochondrial adaptations to training.
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From Muscle-Based Nonshivering Thermogenesis to Malignant Hyperthermia in Mammals
Vol. 87 (2025), pp. 131–150More LessFor physiological processes in the vital organs of eutherian mammals to function, it is important to maintain constant core body temperature at ∼37°C. Mammals generate heat internally by thermogenesis. The focus of this review is on heat generated in resting skeletal muscles, using the same cellular components that muscles use to regulate cytoplasmic calcium concentrations [Ca2+] and contraction. Key to this process, known as muscle-based nonshivering thermogenesis (MB-NST), are tiny Ca2+ movements and associated ATP turnover coordinated by the plasma membrane, sarcoplasmic reticulum (SR), and the mitochondria. MB-NST has made mammals with gain-of-function SR ryanodine receptor (RyR) variants vulnerable to excessive heat generation that can be potentially lethal, known as malignant hyperthermia. Studies of RyR variants using recently developed techniques have advanced our understanding of MB-NST.
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Transport and Immune Functions of the Lymphatic System
Vol. 87 (2025), pp. 151–172More LessTwo major functions of the lymphatic system are the reabsorption of excess interstitial fluid/protein and the coordination of immune cell interactions and trafficking. Specialized junctions between lymphatic endothelial cells optimize reabsorption. The spontaneous contractions of collecting vessels provide active lymph propulsion. One-way valves prevent backflow, and chemokine gradients direct the migration of immune cells. Specialized compartments within the lymph node facilitate antigen-immune cell interactions to produce innate and acquired immunity. Lymphatic injury and/or mutations in genes controlling vessel/valve development result in contractile/valve dysfunction, reduced immune cell trafficking and, ultimately, lymph-edema. Activated CD4+ T cells produce inflammatory mediators that exacerbate these processes, potentially leading to interstitial and lymphatic vessel remodeling and negatively impacting overall function. Mouse models have advanced our knowledge of lymphatic disease, but clinical trials to reduce the impact of inflammatory mediators have yielded mixed success, implying that additional factors underlying human lymphedema are not yet understood.
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Store-Operated Calcium Channels in the Nervous System
Vol. 87 (2025), pp. 173–199More LessStore-operated Ca2+ entry (SOCE) is a widespread mechanism of cellular Ca2+ signaling that arises from Ca2+ influx across the plasma membrane through the Orai family of calcium channels in response to depletion of intracellular Ca2+ stores. Orai channels are a crucial Ca2+ entry mechanism in both neurons and glia and are activated by a unique inside-out gating process involving interactions with the endoplasmic reticulum Ca2+ sensors, STIM1 and STIM2. Recent evidence indicates that SOCE is broadly found across all areas of the nervous system where its physiology and pathophysiology is only now beginning to be understood. Here, we review the growing literature on the mechanisms of SOCE in the nervous system and contributions to gene expression, neuronal excitability, synaptic plasticity, and behavior. We also explore the burgeoning links between SOCE and neurological disease and discuss therapeutic implications of targeting SOCE for brain disorders.
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Inositol 1,4,5-Trisphosphate Receptor Mutations Associated with Human Disease: Insights into Receptor Function and Dysfunction
Vol. 87 (2025), pp. 201–228More LessInositol 1,4,5-trisphosphate receptors (IP3Rs) are ubiquitous intracellular Ca2+ release channels. Their activation, subcellular localization, abundance, and regulation play major roles in defining the spatiotemporal characteristics of intracellular Ca2+ signals, which are in turn fundamental to the appropriate activation of effectors that control a myriad of cellular events. Over the past decade, ∼100 mutations in ITPRs associated with human diseases have been documented. Mutations have been detailed in all three IP3R subtypes and all functional domains of the protein, resulting in both gain and loss of receptor function. IP3R mutations are associated with a diverse array of pathology including spinocerebellar ataxia, peripheral neuropathy, immunopathy, anhidrosis, hyperparathyroidism, and squamous cell carcinoma. This review focuses on how studying the altered activity of these mutations provides information relating to IP3R structure and function, the physiology underpinned by specific IP3R subtypes, and the pathological consequences of dysregulated Ca2+ signaling in human disease.
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Specialized Pulmonary Vascular Cells in Development and Disease
Vol. 87 (2025), pp. 229–255More LessEndothelial cells (ECs) develop organ-specific gene expression and function in response to signals from the surrounding tissue. In turn, ECs can affect organ development and morphogenesis and promote or hinder disease response. In the lung, ECs play an essential role in gas exchange with the external environment, requiring both a close physical connection and a strong axis of communication with alveolar epithelial cells. A complete picture of the composition of the pulmonary endothelium is therefore critical for a full understanding of development, maintenance, and repair of the gas exchange interface. Defining the factors that control lung-specific EC specification, establish EC heterogeneity within the lung, and promote the differing contributions of EC subtypes to development, health, and disease will facilitate the development of much-needed regenerative therapies. This includes targeting therapeutics directly to ECs, developing pluripotent or primary cell–derived ECs to replace damaged or diseased vasculature, and vascularizing engineered tissues for transplant.
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The Calcium Homeostasis of Human Red Blood Cells in Health and Disease: Interactions of PIEZO1, the Plasma Membrane Calcium Pump, and Gardos Channels
Vol. 87 (2025), pp. 257–277More LessCalcium ions mediate the volume homeostasis of human red blood cells (RBCs) in the circulation. The mechanism by which calcium ions affect RBC hydration states always follows the same sequence. Deformation of RBCs traversing capillaries briefly activates mechanosensitive PIEZO1 channels, allowing Ca2+ influx down its steep inward gradient transiently overcoming the calcium pump and elevating [Ca2+]i. Elevated [Ca2+]i activates the Ca2+-sensitive Gardos channels, inducing KCl loss and cell dehydration, a sequence operated with infinite variations in vivo and under experimental conditions. The selected health and disease themes for this review focus on landmark experimental results that led to the development of highly constrained models of the circulatory changes in RBC homeostasis. Based on model predictions, a new perspective emerged, pointing to PIEZO1 dysfunction as the main trigger in the formation of the profoundly dehydrated irreversible sickle cells, the main pathogenic participants in vaso-occlusion, the root cause of sickle cell disease.
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A Mechanistic Rationale for Incretin-Based Therapeutics in the Management of Obesity
Vol. 87 (2025), pp. 279–299More LessDriven by increased caloric intake relative to expenditure, obesity is a major health concern placing economic and operational strain on healthcare and social care worldwide. Pharmacologically, one of the most effective avenues for the management of excess adiposity is the suppression of appetite. However, owing to the body's natural physiological defense to weight loss and tolerability issues that typically accompany anorectic agents, leveraging this approach to induce sustained weight loss is often easier said than done. As such, to address these challenges, researchers have coupled a thorough understanding of the gut–brain axis with advancements in peptide engineering to design therapeutics mimicking the actions of endocrine hormones to promote a negative energy balance. Indeed, multireceptor agonists targeting the GLP-1, GIP, and glucagon receptors produce meaningful weight loss in people with obesity. Herein, we provide a rationale for how activation of the GIP receptor in the brain and the glucagon receptor in the liver and adipose tissue functions to synergize with GLP-1 receptor agonism to curb the drive to feed and ignite the combustion of excess calories for providing next-generation weight loss.
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Protein Tyrosine Phosphatases in Metabolism: A New Frontier for Therapeutics
Vol. 87 (2025), pp. 301–324More LessThe increased prevalence of chronic metabolic disorders, including obesity and type 2 diabetes and their associated comorbidities, are among the world's greatest health and economic challenges. Metabolic homeostasis involves a complex interplay between hormones that act on different tissues to elicit changes in the storage and utilization of energy. Such processes are mediated by tyrosine phosphorylation-dependent signaling, which is coordinated by the opposing actions of protein tyrosine kinases and protein tyrosine phosphatases (PTPs). Perturbations in the functions of PTPs can be instrumental in the pathophysiology of metabolic diseases. The goal of this review is to highlight key advances in our understanding of how PTPs control body weight and glucose metabolism, as well as their contributions to obesity and type 2 diabetes. The emerging appreciation of the integrated functions of PTPs in metabolism, coupled with significant advances in pharmaceutical strategies aimed at targeting this class of enzymes, marks the advent of a new frontier in combating metabolic disorders.
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At the Crossroads of Health and Disease: Consequences of Fat in the Liver
Vol. 87 (2025), pp. 325–352More LessThe liver plays a central role in regulating lipid and glucose metabolism, particularly in transitioning between energy storage and provision in fed and fasting states. Loss of metabolic flexibility, characterized by the impaired capacity to shift between different energy substrates, sets the stage for accumulation of hepatic triglyceride as lipid droplets and further metabolic perturbations. Cross talk between the liver and other organs, including adipose tissue, pancreas, and muscle, is relevant in this transition. In addition to the metabolic consequences of steatosis, there are significant liver risks related to triggered inflammatory and fibrotic processes. Steatotic liver diseases affect an estimated one in three adults globally and contribute to substantial morbidity and mortality. This review focuses on the liver's role in lipid metabolism, defining metabolic health and unhealth, the pathogenic underpinnings that lead to steatohepatitis and hepatic fibrosis, and the clinical features and therapies for the most common forms of steatotic liver diseases.
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The Physiology of Enteric Glia
Vol. 87 (2025), pp. 353–380More LessEnteric glia are the partners of neurons in the enteric nervous system throughout the gastrointestinal tract. Roles fulfilled by enteric glia are diverse and contribute to maintaining intestinal homeostasis through interactions with neurons, immune cells, and the intestinal epithelium. Glial influences optimize physiological gut processes such as intestinal motility and epithelial barrier integrity through actions that regulate the microenvironment of the enteric nervous system, the activity of enteric neurons, intestinal epithelial functions, and immune response. Changes to glial phenotype in disease switch glial functions and contribute to intestinal inflammation, dysmotility, pain, neuroplasticity, and tumorigenesis. This review summarizes current concepts regarding the physiological roles of enteric glial cells and their potential contributions to gut disease. The discussion is focused on recent evidence that suggests important glial contributions to gastrointestinal health and pathophysiology.
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Epithelial Na+ Channels, Immune Cells, and Salt
Vol. 87 (2025), pp. 381–395More LessEpithelial Na+ channels (ENaCs) are known to affect blood pressure through their role in transporting Na+ in the distal nephron of the kidney. While expressed in other epithelial tissues, there is growing evidence that ENaCs are also expressed in nonepithelial tissues where their activity influences blood pressure. This review provides an overview of ENaCs and key mechanisms that regulate channel activity. The role of ENaCs in antigen-presenting dendritic cells is discussed, where ENaC-dependent sensing of increases in the extracellular Na+ concentration leads to activation of a signaling cascade, T cell activation with the release of proinflammatory cytokines, and an increase in blood pressure. The potential contribution of this pathway to human hypertension is discussed.
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Chloride-Dependent Cation Transport via SLC12 Carriers at Atomic Resolution
Vol. 87 (2025), pp. 397–419More LessThe SLC12 family of genes encodes electroneutral Cl−-dependent cation transporters (i.e., Na-Cl, K-Cl, Na-K-2Cl cotransporters), which play significant roles in maintaining cell and body homeostasis. Recent resolution of their structures at the atomic level provides a new understanding how these transporters operate in health and disease and how they are targeted for therapeutic intervention. Overall, the SLC12 transporter cryo-EM structures confirm some key features established by traditional biochemical and molecular methods, such as the presence of 12 transmembrane domains and the formation of a functional dimer. Study of these structures also uncovers previously unknown features, such as the presence of strategic salt bridges that explain why transporters are stabilized in specific conformations. The cryo-EM structures show similarities with other transport protein structures, especially regarding the position of the cations. The structures also pose challenging questions regarding the number of ions bound and the strict electroneutrality that is conventional understanding.
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The Lymphatic Vasculature in Lung Homeostasis and Disease
Vol. 87 (2025), pp. 421–446More LessThe lymphatic vasculature maintains lung homeostasis via fluid drainage in the form of lymph and by facilitating immune surveillance and leukocyte trafficking to the draining lymph nodes. Previous studies in both humans and animal models have demonstrated an important role for lymphatics in lung function from the neonatal period through adulthood. In addition, changes in the lymphatic vasculature have been observed in many respiratory diseases, and there is emerging evidence of a causative role for lymphatic dysfunction in the initiation and progression of lung pathology. Despite advances in the field, there are still many unanswered questions, and a more comprehensive understanding of the mechanisms by which the lymphatics affect lung homeostasis and the response to lung injury is needed. In this review, we discuss our current knowledge of the structure, function, and role of the lymphatics in the lung and how these vessels are involved in respiratory disease.
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Spatial Transcriptomics of the Respiratory System
Vol. 87 (2025), pp. 447–470More LessOver the last decade, single-cell genomics has revealed remarkable heterogeneity and plasticity of cell types in the lungs and airways. The challenge now is to understand how these cell types interact in three-dimensional space to perform lung functions, facilitating airflow and gas exchange while simultaneously providing barrier function to avoid infection. An explosion in novel spatially resolved gene expression technologies, coupled with computational tools that harness machine learning and deep learning, now promise to address this challenge. Here, we review the most commonly used spatial analysis workflows, highlighting their advantages and limitations, and outline recent developments in machine learning and artificial intelligence that will augment how we interpret spatial data. Together these technologies have the potential to transform our understanding of the respiratory system in health and disease, and we showcase studies in lung development, COVID-19, lung cancer, and fibrosis where spatially resolved transcriptomics is already providing novel insights.
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Sex, Gender, and COPD
Vol. 87 (2025), pp. 471–490More LessSex and gender have emerged as critical considerations relevant to chronic obstructive pulmonary disease (COPD). Sex differences in lung development and physiologic response to hormones and environmental exposures influence COPD susceptibility, progression, severity, morbidity, and mortality. Gender has been poorly measured in the context of COPD, and gendered exposures further impact biology. The hormonal milieu is critical to study across the life course. Differences in immunity and inflammation likely impact sex- and gender-related features of COPD. Emerging evidence from multiple types of omics data is revealing new genes and pathways to consider as relevant to sex- and gender-divergent features of COPD. Much research to date has focused on autosomes, but the growing awareness of a role for allosomes is highlighting knowledge gaps. Reproductive aging impacts lung function and requires more investigation. Network medicine holds promise as an approach to sex and gender omics to uncover drivers of COPD in men and women.
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Previous Volumes
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Volume 87 (2025)
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Volume 86 (2024)
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Volume 85 (2023)
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Volume 84 (2022)
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Volume 83 (2021)
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Volume 82 (2020)
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Volume 81 (2019)
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Volume 80 (2018)
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Volume 79 (2017)
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Volume 78 (2016)
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Volume 77 (2015)
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Volume 76 (2014)
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Volume 75 (2013)
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Volume 74 (2012)
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Volume 73 (2011)
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Volume 72 (2010)
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Volume 71 (2009)
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Volume 70 (2008)
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Volume 69 (2007)
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Volume 68 (2006)
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Volume 67 (2005)
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Volume 66 (2004)
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Volume 65 (2003)
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Volume 64 (2002)
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Volume 63 (2001)
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Volume 62 (2000)
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Volume 61 (1999)
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Volume 60 (1998)
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Volume 59 (1997)
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Volume 58 (1996)
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Volume 57 (1995)
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Volume 56 (1994)
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Volume 55 (1993)
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Volume 54 (1992)
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Volume 53 (1991)
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Volume 52 (1990)
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Volume 51 (1989)
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Volume 50 (1988)
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Volume 49 (1987)
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Volume 48 (1986)
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Volume 47 (1985)
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Volume 46 (1984)
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Volume 45 (1983)
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Volume 44 (1982)
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Volume 43 (1981)
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Volume 42 (1980)
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Volume 41 (1979)
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Volume 40 (1978)
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Volume 39 (1977)
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Volume 38 (1976)
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Volume 37 (1975)
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Volume 36 (1974)
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Volume 35 (1973)
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Volume 34 (1972)
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Volume 33 (1971)
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Volume 32 (1970)
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Volume 31 (1969)
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Volume 30 (1968)
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Volume 29 (1967)
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Volume 28 (1966)
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Volume 27 (1965)
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Volume 26 (1964)
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Volume 25 (1963)
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Volume 24 (1962)
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Volume 23 (1961)
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Volume 22 (1960)
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Volume 21 (1959)
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Volume 20 (1958)
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Volume 19 (1957)
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Volume 18 (1956)
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Volume 17 (1955)
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Volume 16 (1954)
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Volume 15 (1953)
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Volume 14 (1952)
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Volume 13 (1951)
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Volume 12 (1950)
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Volume 11 (1949)
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Volume 10 (1948)
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Volume 9 (1947)
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Volume 8 (1946)
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Volume 7 (1945)
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Volume 6 (1944)
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Volume 5 (1943)
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Volume 4 (1942)
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Volume 3 (1941)
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Volume 2 (1940)
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Volume 1 (1939)
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Volume 0 (1932)