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- Volume 60, 1998
Annual Review of Physiology - Volume 60, 1998
Volume 60, 1998
- Review Articles
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PREBÖTZINGER COMPLEX AND PACEMAKER NEURONS: Hypothesized Site and Kernel for Respiratory Rhythm Generation
Vol. 60 (1998), pp. 385–405More Less▪ AbstractIdentification of the sites and mechanisms underlying the generation of respiratory rhythm is of longstanding interest to physiologists and neurobiologists. Recently, with the development of novel experimental preparations, especially in vitro en bloc and slice preparations of rodent brainstem, progress has been made. In particular, a site in the ventrolateral medulla, the preBötzinger Complex, is hypothesized to contain neuronal circuits generating respiratory rhythm. Lesions or disruption of synaptic transmission within the preBötzinger Complex, either in vivo or in vitro, can abolish respiratory activity. Furthermore, the persistence of respiratory rhythm following interference with postsynaptic inhibition and the subsequent discovery of neurons with endogenous bursting properties within the preBötzinger Complex have led to the hypothesis that rhythmogenesis results from synchronized activity of pacemaker or group-pacemaker neurons.
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SEXUAL DIFFERENTIATION OF AVIAN BRAIN AND BEHAVIOR: Current Views on Gonadal Hormone-Dependent and Independent Mechanisms
Vol. 60 (1998), pp. 407–429More Less▪ AbstractGonadal hormones are known to act during development to establish permanent sex differences in the anatomy and function of the vertebrate brain. They also act on the adult brain to activate reproductive behaviors. However, there are wide gaps in our understanding of how sexually dimorphic neural circuits translate into sex differences in behavior and other CNS functions. Moreover, not all sexually dimorphic properties of the adult brain can be attributed to known effects of gonadal hormones during development or adulthood, and factors other than gonadal steroids may contribute to these sex differences. This paper reviews sexual differentiation and the role of gonadal steroids and non-gonadal factors on sexually dimorphic development of the avian brain.
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THE PHYSIOLOGY OF PARATHYROID HORMONE-RELATED PROTEIN: An Emerging Role as a Developmental Factor
Vol. 60 (1998), pp. 431–460More Less▪ AbstractParathyroid hormone-related protein (PTHrP) is the agent responsible for humoral hypercalcemia of malignancy. Its pathogenic role in this syndrome is well established, and attention has focused in recent years on the elucidation of the roles played by PTHrP in normal developmental and adult physiology. This review focuses on studies of the past two years: (a) elucidation of the posttranslational processing pattern of PTHrP, the mechanisms of action of the various secretory forms of PTHrP, the role of PTHrP as an intracrine regulator of cell growth and cell death; (b) the emergence of PTHrP as a critical developmental factor in the mammary gland, epidermis, and the skeleton; and (c) the advances in understanding of the roles of PTHrP in the regulation of pancreatic islet mass, vascular smooth muscle tone and proliferation, and materno-fetal calcium transfer across the placenta.
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THE LUTEINIZING HORMONE RECEPTOR1
Vol. 60 (1998), pp. 461–496More Less▪ AbstractThe luteinizing hormone receptor (LHR) is a member of the subfamily of glycoprotein hormone receptors within the superfamily of G protein–coupled receptor (GPCR)/seven-transmembrane domain receptors. Over the past eight years, major advances have been made in determining the structure and function of the LHR and its gene. The hormone-binding domain has been localized to exons 1–7 in the extracellular (EC) domain/region of the receptor, which contains several leucine-rich repeats. High-affinity binding of LH and human chorionic gonadotropin (hCG) causes secondary hormone or receptor contacts to be established with regions of the EC loop/transmembrane module that initiate signal transduction.
Models of hormone-receptor interaction have been derived from the crystal structures of hCG and of the ribonuclease inhibitor, which also contains leucine-rich repeats. Such models provide a framework for the interpretation of mutational studies and for further experiments. The extracellular domain of the receptor has been overexpressed in vitro, which will facilitate crystallographic resolution of the structure of the receptor-binding site. The transmembrane domain/loop/cytoplasmic module transduces the signal for couplingto G proteins.
Several constitutive, activating mutations that cause human disease have been found in helix VI and adjacent structures. These mutations have provided valuable information about mechanisms of signal transfer and G protein coupling. The structure of the LHR gene has been elucidated, and the regulation of its transcription is beginning to be understood. Valuable insights into receptor evolution have been derived from analysis of sequence homologies, the gene structure of glycoprotein hormone receptors and other members of the GPCR family, and the glycoprotein hormone receptor–like precursors identified in several invertebrate species.
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SEX IN THE 90s: SRY and the Switch to the Male Pathway
Vol. 60 (1998), pp. 497–523More Less▪ AbstractIn mammals the male sex determination switch is controlled by a single gene on the Y chromosome, SRY. SRY encodes a protein with an HMG-like DNA-binding domain, which probably acts as a local organizer of chromatin structure. It is believed to regulate downstream genes in the sex determination cascade, although no direct targets of SRY are clearly known. More genes in the pathway have been isolated through mutation approaches in mouse and human. At least three genes, SRY itself, SOX9, and DAX1, are dosage sensitive, providing molecular evidence that the sex determination step operates at a critical threshold. SRY initiates development of a testis from the bipotential cells of the early gonad. The dimorphic male and female pathways present a rare opportunity to link a pivotal gene in development with morphogenetic mechanisms that operate to pattern an organ and the differentiation of its cells. Mechanisms of testis organogenesis triggered downstream of SRY include pathways of cell signaling controlling cell reorganization, cell proliferation, cell migration, and vascularization.
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PROTEOLYTIC ACTIVITIES THAT MEDIATE APOPTOSIS
Vol. 60 (1998), pp. 533–573More Less▪ AbstractSince the discovery that cells can activate their own suicide program, investigators have attempted to determine whether the events that are associated with this form of cell death are genetically determined. The discovery that the ced-3 gene of Caenorhabditis elegans encodes a cysteine protease essential for developmentally regulated apoptosis ignited interest in this area of research. As a result, we now know that cell death is specified by a number of genes and that this biologic process contributes significantly to development, tumorigenesis, and autoimmune disease. In this review I summarize what is currently known about signaling pathways involved in apoptosis, with particular emphasis on the function of the cysteine proteases known as caspases. However, there is also evidence that protease-independent cell death pathways exist. Is there a relationship between these two distinct mechanisms? If so, how do they communicate? Finally, even though the involvement of tumor necrosis factor/nerve growth factor family of receptors and cysteine proteases has been elegantly established as a component of many apoptotic signaling pathways, what happens downstream of these initial events? Why are only a selected group of cellular proteins—many nuclear—the targets of these proteases? Are nuclear events essential for apoptosis in vivo? Are the cellular genes that encode products involved in apoptotic signaling frequent targets of mutation/alteration during tumorigenesis? These are only a few questions that may be answered in the next ten years.
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THE MANY ROLES OF c-Myc IN APOPTOSIS
Vol. 60 (1998), pp. 575–600More Less▪ AbstractThe proto-oncogene c-myc encodes a transcription factor c-Myc, which is of great importance in controlling cell growth and vitality. The quantity of c-Myc is carefully controlled by many mechanisms, and its actions to induce and repress genes are modulated by interactions with other regulatory proteins. Understanding the kinetic and quantitative relationships that determine how and what genes c-Myc regulates is essential to understanding how Myc is involved in apoptosis. Reduction of c-myc expression and its inappropriate expression can be associated with cellular apoptosis. This review outlines the nature and regulation of the c-myc gene and of c-Myc and presents the systems and conditions in which Myc-related apoptotic events occur. Hypotheses of the mechanisms by which expression and repression of c-myc lead to apoptosis are discussed.
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CELL CYCLE REGULATION AND APOPTOSIS1
Vol. 60 (1998), pp. 601–617More Less▪ AbstractTissue homeostasis requires a balance between cell proliferation and death. Apoptosis and proliferation are linked by cell cycle regulators, and apoptotic stimuli affect both cell proliferation and death. Glucocorticoids induce G1 arrest and apoptosis in transformed lymphoid cells. Decreased expression of the cell cycle components c-myc and cyclin D3 is essential for glucocorticoid-induced growth arrest and death in dividing cells. Other G1 regulators, such as p53, pRb, and E2F, have also been implicated in apoptosis. Mice lacking either p53 or E2F display aberrant cell proliferation and tumor formation, suggesting that these proteins are involved in the elimination of abnormal cells through apoptosis. In contrast, pRb induces G1 arrest and suppresses apoptosis in cultured cells. Mice that lack pRb are nonviable and show ectopic mitosis and massive cell death, suggesting that pRb is an apoptotic suppressor. Further analysis of common components of apoptotic and cell cycle machinery may provide insight into the coordinated regulation of these antagonistic processes.
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THE MITOCHONDRIAL DEATH/LIFE REGULATOR IN APOPTOSIS AND NECROSIS
Vol. 60 (1998), pp. 619–642More Less▪ AbstractBoth physiological cell death (apoptosis) and, in some cases, accidental cell death (necrosis) involve a two-step process. At a first level, numerous physiological and some pathological stimuli trigger an increase in mitochondrial membrane permeability. The mitochondria release apoptogenic factors through the outer membrane and dissipate the electrochemical gradient of the inner membrane. Mitochondrial permeability transition (PT) involves a dynamic multiprotein complex formed in the contact site between the inner and outer mitochondrial membranes. The PT complex can function as a sensor for stress and damage, as well as for certain signals connected to receptors. Inhibition of PT by pharmacological intervention on mitochondrial structures or mitochondrial expression of the apoptosis-inhibitory oncoprotein Bcl-2 prevents cell death, suggesting that PT is a rate-limiting event of the death process. At a second level, the consequences of mitochondrial dysfunction (collapse of the mitochondrial inner transmembrane potential, uncoupling of the respiratory chain, hyperproduction of superoxide anions, disruption of mitochondrial biogenesis, outflow of matrix calcium and glutathione, and release of soluble intermembrane proteins) entails a bioenergetic catastrophe culminating in the disruption of plasma membrane integrity (necrosis) and/or the activation of specific apoptogenic proteases (caspases) by mitochondrial proteins that leak into the cytosol (cytochrome c, apoptosis-inducing factor) with secondary endonuclease activation (apoptosis). The relative rate of these two processes (bioenergetic catastrophe versus protease and endonuclease activation) determines whether a cell will undergo primary necrosis or apoptosis. The acquisition of the biochemical and ultrastructural features of apoptosis critically relies on the liberation of apoptogenic proteases or protease activators from mitochondria. The fact that mitochondrial events control cell death has major implications for the development of cytoprotective and cytotoxic drugs.
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REGULATION OF CERAMIDE PRODUCTION AND APOPTOSIS
Vol. 60 (1998), pp. 643–665More Less▪ AbstractCeramide is a sphingosine-based lipid signaling molecule that regulates cellular differentiation, proliferation, and apoptosis. The emerging picture suggests that coupling of ceramide to specific signaling cascades is both stimulus and cell-type specific. Ceramide action is determined within the context of other stimuli and by the subcellular topology of its production. Here, we discuss the pathways of ceramide generation and the interaction of ceramide with caspases and other apoptotic signaling cascades.
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A VIEW OF SUR/KIR6.X, KATP CHANNELS
Vol. 60 (1998), pp. 667–687More Less▪ AbstractATP-sensitive potassium channels, termed KATP channels, link the electrical activity of cell membranes to cellular metabolism. These channels are heteromultimers of sulfonylurea receptor (SUR) and KIR6.x subunits associated with a 1:1 stoichiometry as a tetramer (SUR/KIR6.x)4. KIR6.x forms the pores, whereas SUR regulates their activity. Changes in [ATP]i and [ADP]i gate the channel. The diversity of KATP channels results from the assembly of SUR and KIR6.x subtypes. KIR6.1-based channels differ from KIR6.2 channels mainly by their smaller unitary conductance. SUR1- and SUR2-based channels are distinguished by their differential sensitivity to sulfonylureas, whereas SUR2A-based channels are distinguished from SUR2B channels by their differential sensitivity to diazoxide. Mutations that result in the loss of KATP channels in pancreatic β-cells have been identified in SUR1 and KIR6.2. These mutations lead to familial hyperinsulinism. Understanding the mutations in SUR and KIR6.x is allowing insight into how these channels respond to nucleotides, sulfonylureas, and potassium channel openers, KCOs.
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ClC AND CFTR CHLORIDE CHANNEL GATING
Vol. 60 (1998), pp. 689–717More Less▪ AbstractChloride channels are widely expressed and play important roles in cell volume regulation, transepithelial transport, intracellular pH regulation, and membrane excitability. Most chloride channels have yet to be identified at a molecular level. The ClC gene family and the cystic fibrosis transmembrane conductance regulator (CFTR) are distinct chloride channels expressed in many cell types, and mutations in their genes are the cause of several diseases including myotonias, cystic fibrosis, and kidney stones. Because of their molecular definition and roles in disease, these channels have been studied intensively over the past several years. The focus of this review is on recent studies that have provided new insights into the mechanisms governing the opening and closing, i.e. gating, of the ClC and CFTR chloride channels.
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FUNCTIONAL PROPERTIES AND PHYSIOLOGICAL ROLES OF ORGANIC SOLUTE CHANNELS
Kiaran Kirk, and Kevin StrangeVol. 60 (1998), pp. 719–739More Less▪ AbstractMembrane channels provide routes for the rapid, passive movement of solutes across plasma and intracellular membranes. It is generally assumed that the major physiological role of membrane channels is to transport inorganic ions for processes such as transepithelial salt absorption and secretion, cell volume regulation, signal transduction, and control of membrane electrical properties. Increasing evidence indicates, however, that channels play an important role in organic solute transport in a wide variety of cell types and organisms. Some of the major physiological roles of organic solute channels include uptake of nutrients, excretion of metabolic waste products, volume-regulatory organic osmolyte transport, and control of mitochondrial metabolism. This article reviews the functions and characteristics of channels that participate in the transport and regulation of both charged and electroneutral organic solutes.
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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)