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Annual Review of Physiology - Volume 69, 2007
Volume 69, 2007
- Introduction
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- Preface
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Life Among the Axons
Vol. 69 (2007), pp. 1–18More LessAbstractA blink in history's eye has brought us an understanding of electricity, and with it a revolution in human life. From the frog leg twitch experiments of Galvani and the batteries of Volta, we have progressed to telegraphs, motors, telephones, computers, and the Internet. In the same period, the ubiquitous role of electricity in animal and plant life has become clear. A great milestone in this journey was the elucidation of electrical signaling by Hodgkin & Huxley in 1952. This chapter gives a personal account of a small part of this story, the transformation of the rather abstract electrical conductances of Hodgkin & Huxley into the more tangible gated ion channel.
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Mitochondrial Ion Channels
Vol. 69 (2007), pp. 19–49More LessAbstractIn work spanning more than a century, mitochondria have been recognized for their multifunctional roles in metabolism, energy transduction, ion transport, inheritance, signaling, and cell death. Foremost among these tasks is the continuous production of ATP through oxidative phosphorylation, which requires a large electrochemical driving force for protons across the mitochondrial inner membrane. This process requires a membrane with relatively low permeability to ions to minimize energy dissipation. However, a wealth of evidence now indicates that both selective and nonselective ion channels are present in the mitochondrial inner membrane, along with several known channels on the outer membrane. Some of these channels are active under physiological conditions, and others may be activated under pathophysiological conditions to act as the major determinants of cell life and death. This review summarizes research on mitochondrial ion channels and efforts to identify their molecular correlates. Except in a few cases, our understanding of the structure of mitochondrial ion channels is limited, indicating the need for focused discovery in this area.
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Preconditioning: The Mitochondrial Connection
Vol. 69 (2007), pp. 51–67More LessAbstractOver the past decade there has been considerable progress in elucidating the signaling pathways involved in cardioprotection. Considerable recent data suggest that many of these signaling pathways converge on the mitochondria, where such pathways alter the activity of key mitochondrial proteins, leading to reduced apoptosis and necrosis. Inhibition of the mitochondrial permeability transition pore is emerging as a central mechanism in cardioprotection. This review focuses on mechanisms by which cardioprotection alters mitochondrial proteins and channels that regulate cell death and survival.
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Iron Homeostasis
Vol. 69 (2007), pp. 69–85More LessAbstractIron is needed by all mammalian cells but is toxic in excess. Specialized transport mechanisms conduct iron across cellular membranes. These are regulated to ensure homeostasis both systemically in living organisms and within individual cells. Over the past decade, major advances have been made in identifying and characterizing the proteins involved in the transport, handling, and homeostatic regulation of iron. Molecular understanding of these processes has provided important insights into the pathophysiology of human iron disorders.
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Transporters as Channels
Vol. 69 (2007), pp. 87–112More LessAbstractThis review investigates some key aspects of transport mechanisms and recent advances in our understanding of this ubiquitous cellular process. The prevailing model of cotransport is the alternating access model, which suggests that large conformational changes in the transporter protein accompany cotransport. This model rests on decades of research and has received substantial support because many transporter characteristics are explained using its premises. New experiments, however, have revealed the existence of channels in transporters, an idea that is in conflict with traditional models. The alternating access model is the subject of previous detailed reviews. Here we concentrate on the relatively recent data that document primarily the channel properties of transporters. In some cases, namely, the observation of single-transporter currents, the evidence is direct. In other cases the evidence—for example, from fluctuation analysis or transporter currents too large to be described as anything other than channel-like—is indirect. Although the existence of channels in transporters is not in doubt, we are far from understanding the significance of this property. In the online Supplemental Material, we review some pertinent aspects of ion channel theory and cotransport physiology to provide background for the channels and transporters presented here. We discuss the existence of channels in transporters, and we speculate on the biological significance of this newly unveiled property of transport proteins.
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Hypoxia Tolerance in Mammals and Birds: From the Wilderness to the Clinic
Vol. 69 (2007), pp. 113–143More LessAbstractAll mammals and birds must develop effective strategies to cope with reduced oxygen availability. These animals achieve tolerance to acute and chronic hypoxia by (a) reductions in metabolism, (b) the prevention of cellular injury, and (c) the maintenance of functional integrity. Failure to meet any one of these tasks is detrimental. Birds and mammals accomplish this triple task through a highly coordinated, systems-level reconfiguration involving the partial shutdown of some but not all organs. This reconfiguration is achieved through a similarly complex reconfiguration at the cellular and molecular levels. Reconfiguration at these various levels depends on numerous factors that include the environment, the degree of hypoxic stress, and developmental, behavioral, and ecological conditions. Although common molecular strategies exist, the cellular and molecular changes in any given cell are very diverse. Some cells remain metabolically active, whereas others shut down or rely on anaerobic metabolism. This cellular shutdown is temporarily regulated, and during hypoxic exposure, active cellular networks must continue to control vital functions. The challenge for future research is to explore the cellular mechanisms and conditions that transform an organ or a cellular network into a hypometabolic state, without loss of functional integrity. Much can be learned in this respect from nature: Diving, burrowing, and hibernating animals living in diverse environments are masters of adaptation and can teach us how to deal with hypoxia, an issue of great clinical significance.
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Hypoxia Tolerance in Reptiles, Amphibians, and Fishes: Life with Variable Oxygen Availability
Vol. 69 (2007), pp. 145–170More LessAbstractThe ability of fishes, amphibians, and reptiles to survive extremes of oxygen availability derives from a core triad of adaptations: profound metabolic suppression, tolerance of ionic and pH disturbances, and mechanisms for avoiding free-radical injury during reoxygenation. For long-term anoxic survival, enhanced storage of glycogen in critical tissues is also necessary. The diversity of body morphologies and habitats and the utilization of dormancy have resulted in a broad array of adaptations to hypoxia in lower vertebrates. For example, the most anoxia-tolerant vertebrates, painted turtles and crucian carp, meet the challenge of variable oxygen in fundamentally different ways: Turtles undergo near-suspended animation, whereas carp remain active and responsive in the absence of oxygen. Although the mechanisms of survival in both of these cases include large stores of glycogen and drastically decreased metabolism, other mechanisms, such as regulation of ion channels in excitable membranes, are apparently divergent. Common themes in the regulatory adjustments to hypoxia involve control of metabolism and ion channel conductance by protein phosphorylation. Tolerance of decreased energy charge and accumulating anaerobic end products as well as enhanced antioxidant defenses and regenerative capacities are also key to hypoxia survival in lower vertebrates.
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Integration of Rapid Signaling Events with Steroid Hormone Receptor Action in Breast and Prostate Cancer
Vol. 69 (2007), pp. 171–199More LessAbstractSteroid hormone receptors (SRs) are ligand-activated transcription factors and sensors for growth factor–initiated signaling pathways in hormonally regulated tissues, such as the breast or prostate. Recent discoveries suggest that several protein kinases are rapidly activated in response to steroid hormone binding to cytoplasmic SRs. Induction of rapid signaling upon SR ligand binding ensures that receptors and coregulators are appropriately phosphorylated as part of optimal transcription complexes. Alternatively, SR-activated kinase cascades provide additional avenues for SR-regulated gene expression independent of SR nuclear action. We provide an overview of SR and signaling cross talk in breast and prostate cancers, using the human progesterone receptor (PR) and androgen receptor (AR) as models. Kinases are emerging as key mediators of SR action. Cross talk between SR and membrane-initiated signaling events suggests a mechanism for coordinate regulation of gene subsets by mitogenic stimuli in hormonally responsive normal tissues; such cross talk is suspected to contribute to cancer biology.
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Nuclear Receptor Structure: Implications for Function
Vol. 69 (2007), pp. 201–220More LessAbstractSmall lipophilic molecules such as steroidal hormones, retinoids, and free fatty acids control many of the reproductive, developmental, and metabolic processes in eukaryotes. The mediators of these effects are nuclear receptor proteins, ligand-activated transcription factors capable of regulating the expression of complex gene networks. This review addresses the structure and structural properties of nuclear receptors, focusing on the well-studied ligand-binding and DNA-binding domains as well as our still-emerging understanding of the largely unstructured N-terminal regions. To emphasize the allosteric interdependence among these subunits, a more detailed inspection of the structural properties of the human progesterone receptor is presented. Finally, this work is placed in the context of developing a quantitative and mechanistic understanding of nuclear receptor function.
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Regulation of Intestinal Cholesterol Absorption
Vol. 69 (2007), pp. 221–248More LessAbstractThe identification of defective structures in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in patients with sitosterolemia suggests that these two proteins are an apical sterol export pump promoting active efflux of cholesterol and plant sterols from enterocytes back into the intestinal lumen for excretion. The newly identified Niemann-Pick C1–like 1 (NPC1L1) protein is also expressed at the apical membrane of enterocytes and plays a crucial role in the ezetimibe-sensitive cholesterol absorption pathway. These findings indicate that cholesterol absorption is a multistep process that is regulated by multiple genes at the enterocyte level and that the efficiency of cholesterol absorption may be determined by the net effect between influx and efflux of intraluminal cholesterol molecules crossing the brush border membrane of the enterocyte. Combination therapy using cholesterol absorption (NPC1L1) inhibitor (ezetimibe) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) provides a powerful novel strategy for the prevention and treatment of hypercholesterolemia.
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Why Does Pancreatic Overstimulation Cause Pancreatitis?
Vol. 69 (2007), pp. 249–269More LessAbstractMany animal models are available to investigate the pathogenesis of pancreatitis, an inflammatory disorder of the pancreas. However, the secretagogue hyperstimulation model of pancreatitis is the most commonly used. Animals infused with high doses of cholecystokinin (CCK) exhibit hyperamylasemia, pancreatic edema, and acinar cell injury, which closely mimic pancreatitis in humans. Intra-acinar zymogen activation is an essential early event in the pathogenesis of secretagogue-induced pancreatitis. Early in the course of pancreatitis, lysosomal hydrolases colocalize with digestive zymogens and activate them. These activated zymogens then cause acinar cell injury and necrosis, a characteristic of pancreatitis. Besides being the site of initiation of injury in pancreatitis, acinar cells also synthesize and release cytokines and chemokines very early in the course of pancreatitis, which then attract and activate inflammatory cells and initiate the disease's systemic phase.
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Timing and Computation in Inner Retinal Circuitry
Vol. 69 (2007), pp. 271–290More LessAbstractIn the vertebrate inner retina, the second stage of the visual system, different components of the visual scene are transformed, discarded, or selected before visual information is transmitted through the optic nerve. This review discusses the connections between higher-level functions of visual processing, mathematical descriptions of the neural code, inner retinal circuitry, and visual computations. In the inner plexiform layer, bipolar cells deliver spatially and temporally filtered input to approximately ten anatomical strata. These layers receive a unique combination of excitation and inhibition, causing cells in different layers to respond with different kinetics to visual input. These distinct temporal channels interact through amacrine cells, a diverse class of inhibitory interneurons, which transmit signals within and between layers. In particular, wide-field amacrine cells transmit transient inhibition over long distances within a layer. These mechanisms and properties are combined into computations to detect the presence of differential motion and suppress the visual effects of eye movements.
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Understanding Circuit Dynamics Using the Stomatogastric Nervous System of Lobsters and Crabs
Eve Marder, and Dirk BucherVol. 69 (2007), pp. 291–316More LessAbstractStudies of the stomatogastric nervous systems of lobsters and crabs have led to numerous insights into the cellular and circuit mechanisms that generate rhythmic motor patterns. The small number of easily identifiable neurons allowed the establishment of connectivity diagrams among the neurons of the stomatogastric ganglion. We now know that (a) neuromodulatory substances reconfigure circuit dynamics by altering synaptic strength and voltage-dependent conductances and (b) individual neurons can switch among different functional circuits. Computational and experimental studies of single-neuron and network homeostatic regulation have provided insight into compensatory mechanisms that can underlie stable network performance. Many of the observations first made using the stomatogastric nervous system can be generalized to other invertebrate and vertebrate circuits.
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Molecular Mechanisms of Renal Ammonia Transport
Vol. 69 (2007), pp. 317–340More LessAbstractAcid-base homeostasis to a great extent relies on renal ammonia metabolism. In the past several years, seminal studies have generated important new insights into the mechanisms of renal ammonia transport. In particular, the theory that ammonia transport occurs almost exclusively through nonionic NH3 diffusion and NH4+ trapping has given way to a model postulating that a variety of proteins specifically transport NH3 and NH4+ and that this transport is critical for normal ammonia metabolism. Many of these proteins transport primarily H+ or K+ but also transport NH4+. Nonerythroid Rh glycoproteins transport ammonia and may represent critical facilitators of ammonia transport in the kidney. This review discusses the underlying aspects of renal ammonia transport as well as specific proteins with important roles in renal ammonia transport.
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Phosphatonins and the Regulation of Phosphate Homeostasis
Vol. 69 (2007), pp. 341–359More LessAbstractInorganic phosphate (Pi) is required for energy metabolism, nucleic acid synthesis, bone mineralization, and cell signaling. The activity of cell-surface sodium-phosphate (Na+-Pi) cotransporters mediates the uptake of Pi from the extracellular environment. Na+-Pi cotransporters and organ-specific Pi absorptive processes are regulated by peptide and sterol hormones, such as parathyroid hormone (PTH) and 1α,25-dihydroxyvitamin D (1α,25(OH)2D3), which interact in a coordinated fashion to regulate Pi homeostasis. Recently, several phosphaturic peptides such as fibroblast growth factor-23 (FGF-23), secreted frizzled related protein-4 (sFRP-4), matrix extracellular phosphoglycoprotein, and fibroblast growth factor-7 have been demonstrated to play a pathogenic role in several hypophosphatemic disorders. By inhibiting Na+-Pi transporters in renal epithelial cells, these proteins increase renal Pi excretion, resulting in hypophosphatemia. FGF-23 and sFRP-4 inhibit 25-hydroxyvitamin D 1α-hydroxylase activity, reducing 1α,25(OH)2D3 synthesis and thus intestinal Pi absorption. This review examines the role of these factors in Pi homeostasis in health and disease.
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Specificity and Regulation of Renal Sulfate Transporters
Vol. 69 (2007), pp. 361–375More LessAbstractSulfate is essential for normal cellular function. The kidney plays a major role in sulfate homeostasis. Sulfate is freely filtered and then undergoes net reabsorption in the proximal tubule. The apical membrane Na+/sulfate cotransporter NaS1 (SLC13A1) has a major role in mediating proximal tubule sulfate reabsorption, as demonstrated by the findings of hyposulfatemia and hypersulfaturia in Nas1-null mice. The anion exchanger SAT1 (SLC26A1), the founding member of the SLC26 sulfate transporter family, mediates sulfate exit across the basolateral membrane to complete the process of transtubular sulfate reabsorption. Another member of this family, CFEX (SLC26A6), is present at the apical membrane of proximal tubular cells. It also can transport sulfate by anion exchange, which probably mediates backflux of sulfate into the lumen. Knockout mouse studies have demonstrated a major role of CFEX as an apical membrane Cl−/oxalate exchanger that contributes to NaCl reabsorption in the proximal tubule. Several additional SLC26 family members mediate sulfate transport and show some level of renal expression (e.g., SLC26A2, SLC26A7, SLC26A11). Their roles in mediating renal tubular sulfate transport are presently unknown. This paper reviews current data available on the function and regulation of three sulfate transporters (NaS1, SAT1, and CFEX) and their physiological roles in the kidney.
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Overview of Structure and Function of Mammalian Cilia
Vol. 69 (2007), pp. 377–400More LessAbstractCilia are membrane-bounded, centriole-derived projections from the cell surface that contain a microtubule cytoskeleton, the ciliary axoneme, surrounded by a ciliary membrane. Axonemes in multiciliated cells of mammalian epithelia are 9 + 2, possess dynein arms, and are motile. In contrast, single nonmotile 9 + 0 primary cilia are found on epithelial cells, such as those of the kidney tubule, but also on nonepithelial cells, such as chondrocytes, fibroblasts, and neurons. The ciliary membranes of all cilia contain specific receptors and ion channel proteins that initiate signaling pathways controlling motility and/or linking mechanical or chemical stimuli, including sonic hedgehog and growth factors, to intracellular transduction cascades regulating differentiation, migration, and cell growth during development and in adulthood. Unique motile 9 + 0 cilia, found during development at the embryonic node, determine left-right asymmetry of the body.
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Previous Volumes
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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)