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- Volume 73, 2004
Annual Review of Biochemistry - Volume 73, 2004
Volume 73, 2004
- Review Articles
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Emerging Principles of Conformation-Based Prion Inheritance
Vol. 73 (2004), pp. 617–656More Less▪ AbstractThe prion hypothesis proposes that proteins can act as infectious agents. Originally formulated to explain transmissible spongiform encephalopathies (TSEs), the prion hypothesis has been extended with the finding that several non-Mendelian traits in fungi are due to heritable changes in protein conformation, which may in some cases be beneficial. Although much remains to be learned about the specific role of cellular cofactors, mechanistic parallels between the mammalian and yeast prion phenomena point to universal features of conformation-based infection and inheritance involving propagation of ordered β-sheet-rich protein aggregates commonly referred to as amyloid. Here we focus on two such features and discuss recent efforts to explain them in terms of the physical properties of amyloid-like aggregates. The first is prion strains, wherein chemically identical infectious particles cause distinct phenotypes. The second is barriers that often prohibit prion transmission between different species. There is increasing evidence suggesting that both of these can be manifestations of the same phenomenon: the ability of a protein to misfold into multiple self-propagating conformations. Even single mutations can change the spectrum of favored misfolded conformations. In turn, changes in amyloid conformation can shift the specificity of propagation and alter strain phenotypes. This model helps explain many common and otherwise puzzling features of prion inheritance as well as aspects of noninfectious diseases involving toxic misfolded proteins.
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The Molecular Mechanics of Eukaryotic Translation
Lee D. Kapp, and Jon R. LorschVol. 73 (2004), pp. 657–704More Less▪ AbstractGreat advances have been made in the past three decades in understanding the molecular mechanics underlying protein synthesis in bacteria, but our understanding of the corresponding events in eukaryotic organisms is only beginning to catch up. In this review we describe the current state of our knowledge and ignorance of the molecular mechanics underlying eukaryotic translation. We discuss the mechanisms conserved across the three kingdoms of life as well as the important divergences that have taken place in the pathway.
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Mechanical Processes in Biochemistry
Vol. 73 (2004), pp. 705–748More Less▪ AbstractMechanical processes are involved in nearly every facet of the cell cycle. Mechanical forces are generated in the cell during processes as diverse as chromosomal segregation, replication, transcription, translation, translocation of proteins across membranes, cell locomotion, and catalyzed protein and nucleic acid folding and unfolding, among others. Because force is a product of all these reactions, biochemists are beginning to directly apply external forces to these processes to alter the extent or even the fate of these reactions hoping to reveal their underlying molecular mechanisms. This review provides the conceptual framework to understand the role of mechanical force in biochemistry.
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Intermediate Filaments: Molecular Structure, Assembly Mechanism, and Integration Into Functionally Distinct Intracellular Scaffolds
Harald Herrmann, and Ueli AebiVol. 73 (2004), pp. 749–789More Less▪ AbstractThe superfamily of intermediate filament (IF) proteins contains at least 65 distinct proteins in man, which all assemble into ∼10 nm wide filaments and are principal structural elements both in the nucleus and the cytoplasm with essential scaffolding functions in metazoan cells. At present, we have only circumstantial evidence of how the highly divergent primary sequences of IF proteins lead to the formation of seemingly similar polymers and how this correlates with their function in individual cells and tissues. Point mutations in IF proteins, particularly in lamins, have been demonstrated to lead to severe, inheritable multi-systemic diseases, thus underlining their importance at several functional levels. Recent structural work has now begun to shed some light onto the complex fine tuning of structure and function in these fibrous, coiled coil forming multidomain proteins and their contribution to cellular physiology and gene regulation.
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Directed Evolution of Nucleic Acid Enzymes
Vol. 73 (2004), pp. 791–836More Less▪ AbstractJust as Darwinian evolution in nature has led to the development of many sophisticated enzymes, Darwinian evolution in vitro has proven to be a powerful approach for obtaining similar results in the laboratory. This review focuses on the development of nucleic acid enzymes starting from a population of random-sequence RNA or DNA molecules. In order to illustrate the principles and practice of in vitro evolution, two especially well-studied categories of catalytic nucleic acid are considered: RNA enzymes that catalyze the template-directed ligation of RNA and DNA enzymes that catalyze the cleavage of RNA. The former reaction, which involves attack of a 2′- or 3′-hydroxyl on the α-phosphate of a 5′-triphosphate, is more difficult. It requires a comparatively larger catalytic motif, containing more nucleotides than can be sampled exhaustively within a starting population of random-sequence RNAs. The latter reaction involves deprotonation of the 2′-hydroxyl adjacent to the cleavage site, resulting in cleaved products that bear a 2′,3′-cyclic phosphate and 5′-hydroxyl. The difficulty of this reaction, and therefore the complexity of the corresponding DNA enzyme, depends on whether a catalytic cofactor, such as a divalent metal cation or small molecule, is present in the reaction mixture.
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Using Protein Folding Rates to Test Protein Folding Theories
Vol. 73 (2004), pp. 837–859More Less▪ AbstractThe fastest simple, kinetically two-state protein folds a million times more rapidly than the slowest. Here we review many recent theories of protein folding kinetics in terms of their ability to qualitatively rationalize, if not quantitatively predict, this fundamental experimental observation.
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Eukaryotic mRNA Decapping
Jeff Coller, and Roy ParkerVol. 73 (2004), pp. 861–890More Less▪ AbstractEukaryotic mRNAs are primarily degraded by removal of the 3′ poly(A) tail, followed either by cleavage of the 5′ cap structure (decapping) and 5′->3′ exonucleolytic digestion, or by 3′ to 5′ degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur. Each of these steps is a demonstrated, or potential, site for the regulation of mRNA decay. We discuss the decapping process in the light of these central properties, which also suggest fundamental aspects of cytoplasmic mRNA physiology that connect decapping, translation, and storage of mRNA.
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Novel Lipid Modifications of Secreted Protein Signals
Vol. 73 (2004), pp. 891–923More Less▪ AbstractSecreted signaling proteins function in a diverse array of essential patterning events during metazoan development, ranging from embryonic segmentation in insects to neural tube differentiation in vertebrates. These proteins generally are expressed in a localized manner, and they may elicit distinct concentration-dependent responses in the cells of surrounding tissues and structures, thus functioning as morphogens that specify the pattern of cellular responses by their tissue distribution. Given the importance of signal distribution, it is notable that the Hedgehog (Hh) and Wnt proteins, two of the most important families of such signals, are known to be covalently modified by lipid moieties, the membrane-anchoring properties of which are not consistent with passive models of protein mobilization within tissues. This review focuses on the mechanisms underlying biogenesis of the mature Hh proteins, which are dually modified by cholesteryl and palmitoyl adducts, as well as on the relationship between Hh proteins and the self-splicing proteins (i.e., proteins containing inteins) and the Hh-like proteins of nematodes. We further discuss the cellular mechanisms that have evolved to handle lipidated Hh proteins in the spatial deployment of the signal in developing tissues and the more recent findings that implicate palmitate modification as an important feature of Wnt signaling proteins.
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Return of the GDI: The GoLoco Motif in Cell Division
Vol. 73 (2004), pp. 925–951More Less▪ AbstractThe GoLoco motif is a 19-amino-acid sequence with guanine nucleotide dissociation inhibitor activity against G-alpha subunits of the adenylyl-cyclase-inhibitory subclass. The GoLoco motif is present as an independent element within multidomain signaling regulators, such as Loco, RGS12, RGS14, and Rap1GAP, as well as in tandem arrays in proteins, such as AGS3, G18, LGN, Pcp-2/L7, and Partner of Inscuteable (Pins/Rapsynoid). Here we discuss the biochemical mechanisms of GoLoco motif action on G-alpha subunits in light of the recent crystal structure of G-alpha-i1 bound to the RGS14 GoLoco motif. Currently, there is sparse evidence for GoLoco motif regulation of canonical G-protein–coupled receptor signaling. Rather, studies of asymmetric cell division in Drosophila and Caenorhabditis elegans, as well as mammalian mitosis, implicate GoLoco proteins, such as Pins, GPR-1/GPR-2, LGN, and RGS14, in mitotic spindle organization and force generation. We discuss potential mechanisms by which GoLoco/Gα complexes might modulate spindle dynamics.
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Opioid Receptors
Vol. 73 (2004), pp. 953–990More Less▪ AbstractOpioid receptors belong to the large superfamily of seven transmembrane-spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse. A fundamental question in addiction biology is why exogenous opioid drugs, such as morphine and heroin, have a high liability for inducing tolerance, dependence, and addiction. This review focuses on many aspects of opioid receptors with the aim of gaining a greater insight into mechanisms of opioid tolerance and dependence.
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Structural Aspects of Ligand Binding to and Electron Transfer in Bacterial and Fungal P450s
Vol. 73 (2004), pp. 991–1018More Less▪ AbstractCytochrome P450 enzymes are heme-containing monooxygenases that are named after an absorption band at 450 nm when complexed with carbon monoxide. They catalyze a wide variety of reactions and are unique in their ability to hydroxylate nonactivated hydrocarbons. P450 enzymes are involved in numerous biological processes, which include the biosynthesis of lipids, steroids, antibiotics, and the degradation of xenobiotics. In line with the variety of reactions catalyzed, the size of their substrates varies significantly. Some P450s have open active sites (e.g., BM3), and some have shielded active sites that open only transiently (e.g., P450cam), whereas others bind the substrate only when attached to carrier proteins (e.g., Oxy proteins). Structural aspects of both organic and gaseous ligand binding and electron transfer are described.
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Roles of N-Linked Glycans in the Endoplasmic Reticulum
Ari Helenius, and Markus AebiVol. 73 (2004), pp. 1019–1049More Less▪ AbstractFrom a process involved in cell wall synthesis in archaea and some bacteria, N-linked glycosylation has evolved into the most common covalent protein modification in eukaryotic cells. The sugars are added to nascent proteins as a core oligosaccharide unit, which is then extensively modified by removal and addition of sugar residues in the endoplasmic reticulum (ER) and the Golgi complex. It has become evident that the modifications that take place in the ER reflect a spectrum of functions related to glycoprotein folding, quality control, sorting, degradation, and secretion. The glycans not only promote folding directly by stabilizing polypeptide structures but also indirectly by serving as recognition “tags” that allow glycoproteins to interact with a variety of lectins, glycosidases, and glycosyltranferases. Some of these (such as glucosidases I and II, calnexin, and calreticulin) have a central role in folding and retention, while others (such as α-mannosidases and EDEM) target unsalvageable glycoproteins for ER-associated degradation. Each residue in the core oligosaccharide and each step in the modification program have significance for the fate of newly synthesized glycoproteins.
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Analyzing Cellular Biochemistry in Terms of Molecular Networks
Vol. 73 (2004), pp. 1051–1087More Less▪ AbstractOne way to understand cells and circumscribe the function of proteins is through molecular networks. These networks take a variety of forms including webs of protein-protein interactions, regulatory circuits linking transcription factors and targets, and complex pathways of metabolic reactions. We first survey experimental techniques for mapping networks (e.g., the yeast two-hybrid screens). We then turn our attention to computational approaches for predicting networks from individual protein features, such as correlating gene expression levels or analyzing sequence coevolution. All the experimental techniques and individual predictions suffer from noise and systematic biases. These problems can be overcome to some degree through statistical integration of different experimental datasets and predictive features (e.g., within a Bayesian formalism). Next, we discuss approaches for characterizing the topology of networks, such as finding hubs and analyzing subnetworks in terms of common motifs. Finally, we close with perspectives on how network analysis represents a preliminary step toward a systems approach for modeling cells.
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Previous Volumes
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Volume 93 (2024)
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Volume 92 (2023)
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Volume 91 (2022)
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Volume 90 (2021)
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Volume 89 (2020)
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Volume 88 (2019)
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Volume 87 (2018)
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Volume 86 (2017)
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Volume 85 (2016)
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Volume 84 (2015)
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Volume 83 (2014)
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Volume 82 (2013)
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Volume 81 (2012)
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Volume 80 (2011)
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Volume 79 (2010)
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Volume 78 (2009)
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Volume 77 (2008)
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Volume 76 (2007)
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Volume 75 (2006)
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Volume 74 (2005)
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Volume 73 (2004)
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Volume 72 (2003)
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Volume 71 (2002)
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Volume 70 (2001)
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Volume 69 (2000)
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Volume 68 (1999)
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Volume 67 (1998)
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Volume 66 (1997)
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Volume 65 (1996)
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Volume 64 (1995)
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Volume 63 (1994)
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Volume 62 (1993)
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Volume 61 (1992)
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Volume 60 (1991)
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Volume 59 (1990)
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Volume 58 (1989)
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Volume 57 (1988)
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Volume 56 (1987)
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Volume 55 (1986)
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Volume 54 (1985)
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Volume 53 (1984)
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Volume 52 (1983)
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Volume 51 (1982)
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Volume 50 (1981)
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Volume 49 (1980)
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Volume 48 (1979)
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Volume 47 (1978)
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Volume 46 (1977)
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Volume 45 (1976)
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Volume 44 (1975)
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Volume 43 (1974)
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Volume 42 (1973)
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Volume 41 (1972)
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Volume 40 (1971)
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Volume 39 (1970)
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Volume 38 (1969)
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Volume 37 (1968)
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Volume 36 (1967)
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Volume 35 (1966)
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Volume 34 (1965)
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Volume 33 (1964)
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Volume 32 (1963)
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Volume 31 (1962)
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Volume 30 (1961)
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Volume 29 (1960)
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Volume 28 (1959)
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Volume 27 (1958)
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Volume 26 (1957)
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Volume 25 (1956)
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Volume 24 (1955)
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Volume 23 (1954)
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Volume 22 (1953)
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Volume 21 (1952)
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Volume 20 (1951)
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Volume 19 (1950)
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Volume 18 (1949)
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Volume 17 (1948)
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Volume 16 (1947)
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Volume 15 (1946)
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Volume 14 (1945)
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Volume 13 (1944)
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Volume 12 (1943)
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Volume 11 (1942)
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Volume 10 (1941)
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Volume 9 (1940)
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Volume 8 (1939)
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Volume 7 (1938)
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Volume 6 (1937)
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Volume 5 (1936)
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Volume 4 (1935)
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Volume 3 (1934)
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Volume 2 (1933)
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Volume 1 (1932)
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Volume 0 (1932)