bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic Imprinting and Kinship: How Good is the Evidence?
Authors: Haig David
Published: November 2004

▪ Abstract  The kinship theory of genomic imprinting proposes that parent-specific gene expression evolves at a locus because a gene's level of expression in one individual has fitness effects on other individuals who have different probabilities of carrying the maternal and paternal alleles of the individual in which the gene is expressed. Therefore, natural selection favors different levels of expression depending on an allele's sex-of-origin in the previous generation. This review considers the strength of evidence in support of this hypothesis for imprinted genes in four “clusters,” associated with the imprinted loci Igf2, Igf2r, callipyge, and Gnas. The clusters associated with Igf2 and Igf2r both contain paternally expressed transcripts that act as enhancers of prenatal growth and maternally expressed transcripts that act as inhibitors of prenatal growth. This is consistent with predictions of the kinship theory. However, the clusters also contain imprinted genes whose phenotypes as yet remain unexplained by the theory. The principal effects of imprinted genes in the callipyge and Gnas clusters appear to involve lipid and energy metabolism. The kinship theory predicts that maternally expressed transcripts will favor higher levels of nonshivering thermogenesis (NST) in brown adipose tissue (BAT) of animals that huddle for warmth as offspring. The phenotypes of reciprocal heterozygotes for Gnas knockouts provide provisional support for this hypothesis, as does some evidence from other imprinted genes (albeit more tentatively). The diverse effects of imprinted genes on the development of white adipose tissue (WAT) have so far defied a unifying hypothesis in terms of the kinship theory.
Integration of Adeno-Associated Virus (AAV) and Recombinant AAV Vectors
Authors: McCarty Douglas M. , Young Samuel M. , Samulski R. Jude
Published: November 2004

▪ Abstract  The driving interest in adeno-associated virus (AAV) has been its potential as a gene delivery vector. The early observation that AAV can establish a latent infection by integrating into the host chromosome has been central to this interest. However, chromosomal integration is a two-edged sword, imparting on one hand the ability to maintain the therapeutic gene in progeny cells, and on the other hand, the risk of mutations that are deleterious to the host. A clearer understanding of the mechanism and efficiency of AAV integration, in terms of contributing viral and host-cell factors and circumstances, will provide a context in which to evaluate these potential benefits and risks. Research to date suggests that AAV integration in any context is inefficient, and that the persistence of AAV gene delivery vectors in tissues is largely attributable to episomal genomes.
The Genetics of Geochemistry
Authors: Croal Laura R. , Gralnick Jeffrey A. , Malasarn Davin , Newman Dianne K.
Published: November 2004

▪ Abstract  Bacteria are remarkable in their metabolic diversity due to their ability to harvest energy from myriad oxidation and reduction reactions. In some cases, their metabolisms involve redox transformations of metal(loid)s, which lead to the precipitation, transformation, or dissolution of minerals. Microorganism/mineral interactions not only affect the geochemistry of modern environments, but may also have contributed to shaping the near-surface environment of the early Earth. For example, bacterial anaerobic respiration of ferric iron or the toxic metalloid arsenic is well known to affect water quality in many parts of the world today, whereas the utilization of ferrous iron as an electron donor in anoxygenic photosynthesis may help explain the origin of Banded Iron Formations, a class of ancient sedimentary deposits. Bacterial genetics holds the key to understanding how these metabolisms work. Once the genes and gene products that catalyze geochemically relevant reactions are understood, as well as the conditions that trigger their expression, we may begin to predict when and to what extent these metabolisms influence modern geochemical cycles, as well as develop a basis for deciphering their origins and how organisms that utilized them may have altered the chemical and physical features of our planet.
Recombination Proteins in Yeast
Authors: Krogh Berit Olsen , Symington Lorraine S.
Published: November 2004

▪ Abstract  The process of homologous recombination promotes error-free repair of double-strand breaks and is essential for meiosis. Central to the process of homologous recombination are the RAD52 group genes (RAD50, RAD51, RAD52, RAD54, RDH54/TID1, RAD55, RAD57, RAD59, MRE11, and XRS2), most of which were identified by their requirement for the repair of ionizing radiation-induced DNA damage in Saccharomyces cerevisiae. The Rad52 group proteins are highly conserved among eukaryotes. Recent studies showing defects in homologous recombination and double-strand break repair in several human cancer-prone syndromes have emphasized the importance of this repair pathway in maintaining genome integrity. Herein, we review recent genetic, biochemical, and structural analyses of the genes and proteins involved in recombination.
Epigenetic Regulation of Cellular Memory by the Polycomb and Trithorax Group Proteins
Authors: Ringrose Leonie , Paro Renato
Published: November 2004

▪ Abstract  During the development of multicellular organisms, cells become different from one another by changing their genetic program in response to transient stimuli. Long after the stimulus is gone, “cellular memory” mechanisms enable cells to remember their chosen fate over many cell divisions. The Polycomb and Trithorax groups of proteins, respectively, work to maintain repressed or active transcription states of developmentally important genes through many rounds of cell division. Here we review current ideas on the protein and DNA components of this transcriptional memory system and how they interact dynamically with each other to orchestrate cellular memory for several hundred genes.
Species Specificity in Pollen-Pistil Interactions
Authors: Swanson Robert , Edlund Anna F. , Preuss Daphne
Published: November 2004

▪ Abstract  For pollination to succeed, pollen must carry sperm through a variety of different floral tissues to access the ovules within the pistil. The pistil provides everything the pollen requires for success in this endeavor including distinct guidance cues and essential nutrients that allow the pollen tube to traverse enormous distances along a complex path to the unfertilized ovule. Although the pistil is a great facilitator of pollen function, it can also be viewed as an elaborate barrier that shields ovules from access from inappropriate pollen, such as pollen from other species. Each discrete step taken by pollen tubes en route to the ovules is a potential barrier point to ovule access and waste by inappropriate mates. In this review, we survey the current molecular understanding of how pollination proceeds, and ask to what extent is each step important for mate discrimination. As this field progresses, this synthesis of functional biology and evolutionary studies will provide insight into the molecular basis of the species barriers that maintain the enormous diversity seen in flowering plants.
The Genetics of Maize Evolution
Authors: Doebley John
Published: November 2004

▪ Abstract  Maize and its closest wild relatives, the teosintes, differ strikingly in the morphology of their female inflorescences or ears. Despite their divergent morphologies, several studies indicate that some varieties of teosinte are cytologically indistinguishable from maize and capable of forming fully fertile hybrids with maize. Molecular analyses identified one form of teosinte (Zea mays ssp. parviglumis) as the progenitor of maize. Analyses of the inheritance of the morphological traits that distinguish maize and teosinte indicates that they are under the control of multiple genes and exhibit quantitative inheritance. Nevertheless, these analyses have also identified a few loci of large effect that appear to represent key innovations during maize domestication. Remaining challenges are to identify additional major and minor effect genes, the polymorphisms within these genes that control the phenotypes, and how the combination of the individual and epistatic effects of these genes transformed teosinte into maize.
Genetic Models in Pathogenesis
Authors: Pradel Elizabeth , Ewbank Jonathan J.
Published: November 2004

▪ Abstract  To decipher the complexity of host-pathogen interactions the widest possible range of model hosts and of analytical methods is required. As some virulence mechanisms and certain host responses have been conserved throughout evolution, even simple organisms can be used as model hosts to help our understanding of infectious diseases. The availability of molecular genetic tools and a cooperative community of researchers are pivotal to the emergence of model systems. In this review, we first summarize the genetic screens that can be used to identify pathogen virulence factors, then we present a comparative overview of existing or emerging genetically tractable host models.
Melanocytes and theMicrophthalmiaTranscription Factor Network
Authors: Steingrímsson Eiríkur , Copeland Neal G. , Jenkins Nancy A.
Published: November 2004

▪ Abstract  The first mouse microphthalmia transcription factor (Mitf ) mutation was discovered over 60 years ago, and since then over 24 spontaneous and induced mutations have been identified at the locus. Mitf encodes a member of the Myc supergene family of basic helix-loop-helix zipper (bHLH-Zip) transcription factors. Like Myc, Mitf regulates gene expression by binding to DNA as a homodimer or as a heterodimer with another related family member, in the case of Mitf the Tfe3, Tfeb, and Tfec proteins. The study of Mitf has provided many insights into the biology of melanocytes and helped to explain how melanocyte-specific gene expression and signaling is regulated. The human homologue of MITF is mutated in patients with the pigmentary and deafness disorder Waardenburg Syndrome Type 2A (WS2A). The mouse Mitf mutations therefore serve as a model for the study of this human disease. Mutations and/or aberrant expression of several MITF family member genes have also been reported in human cancer, including melanoma (MITF), papillary renal cell carcinoma (TFE3, TFEB), and alveolar soft part sarcoma (TFE3). Genes in the MITF/TFE pathway may therefore also represent valuable therapeutic targets for the treatment of human cancer. Here we review recent developments in the analysis of Mitf function in vivo and in vitro and show how traditional genetics, modern forward genetics and in vitro biochemical analyses have combined to produce an intriguing story on the role and actions of a gene family in a living organism.
Duplication and Divergence: The Evolution of New Genes and Old Ideas
Authors: Taylor John S. , Raes Jeroen
Published: November 2004

▪ Abstract  Over 35 years ago, Susumu Ohno stated that gene duplication was the single most important factor in evolution ( 97 ). He reiterated this point a few years later in proposing that without duplicated genes the creation of metazoans, vertebrates, and mammals from unicellular organisms would have been impossible. Such big leaps in evolution, he argued, required the creation of new gene loci with previously nonexistent functions ( 98 ). Bold statements such as these, combined with his proposal that at least one whole-genome duplication event facilitated the evolution of vertebrates, have made Ohno an icon in the literature on genome evolution. However, discussion on the occurrence and consequences of gene and genome duplication events has a much longer, and often neglected, history. Here we review literature dealing with the occurence and consequences of gene duplication, begining in 1911. We document conceptual and technological advances in gene duplication research from this early research in comparative cytology up to recent research on whole genomes, “transcriptomes,” and “interactomes.”

We have formerly seen that parts many times repeated are eminently liable to vary in number and structure; consequently it is quite probable that natural selection, during the long-continued course of modification, should have seized on a certain number of the primordially similar elements, many times repeated, and have adapted them to the most diverse purposes.

     Charles Darwin, 1859 ( 23 )
Proteolysis as a Regulatory Mechanism
Authors: Ehrmann Michael , Clausen Tim
Published: November 2004

▪ Abstract  Proteases can play key roles in regulation by controlling the levels of critical components of, for example, signal transduction pathways. Proteolytic processing can remove regulatory proteins when they are not needed, while transforming others from the dormant into the biologically active state. The latter mechanism often involves a subsequent change of cellular localization such as the movement from the membrane to the nucleus. The investigation of these processes has revealed a new type of proteolytic activity, regulated intramembrane proteolysis, and a reversible switch in activity occurring in the HtrA family of serine proteases. The bacterial RseA and the human amyloid precursor processing pathways are used as models to review these novel principles that are evolutionarily conserved and have wide biological implications.
Genetic Control of Retrovirus Susceptibility in Mammalian Cells
Authors: Goff Stephen P.
Published: November 2004

▪ Abstract  Host cellular genes can have profound effects on retrovirus replication. Many of these genes encode restriction factors that block virus infection; others encode positive factors that are exploited by the viruses. Recently, a number of such genes have been cloned and characterized, bringing into sharper focus the mechanisms and pathways exploited by these viruses. The major host factors involved in the early phase of the viral life cycle are discussed.
Comparative Genomic Structure of Prokaryotes
Authors: Bentley Stephen D. , Parkhill Julian
Published: November 2004

▪ Abstract  Recent advances in DNA-sequencing technologies have made available an enormous resource of data for the study of bacterial genomes. The broad sample of complete genomes currently available allows us to look at variation in the gross features and characteristics of genomes while the detail of the sequences reveal some of the mechanisms by which these genomes evolve. This review aims to describe bacterial genome structures according to current knowledge and proposed hypotheses. We also describe examples where mechanisms of genome evolution have acted in the adaptation of bacterial species to particular niches.
THE T CELL RECEPTOR: Critical Role of the Membrane Environment in Receptor Assembly and Function
Authors: Call Matthew E. , Wucherpfennig Kai W.
Published: November 2004

▪ Abstract  Recent studies have demonstrated that cell membranes provide a unique environment for protein-protein and protein-lipid interactions that are critical for the assembly and function of the T cell receptor (TCR)-CD3 complex. Highly specific polar interactions among transmembrane (TM) domains that are uniquely favorable in the lipid environment organize the association of the three signaling dimers with the TCR. Each of these three assembly steps depends on the formation of a three-helix interface between one basic and two acidic residues in the membrane environment. The same polar TM residues that drive assembly also play a central role in quality control and export by directing the retention and degradation of free subunits and partial complexes, while membrane proximal cytoplasmic signals control recycling and degradation of surface receptors. Recent studies also suggest that interactions between the membrane and the cytoplasmic domains of CD3 proteins may be important for receptor triggering.
INTERLEUKIN-6: From Basic Science to Medicine—40 Years in Immunology
Authors: Kishimoto Tadamitsu
Published: November 2004

▪ Abstract  This essay summarizes my 40 years of research in immunology. As a young physician, I encountered a patient with Waldenström's macroglobulinemia, and this inspired me to study the structure of IgM. I began to ask how antibody responses are regulated. In the late 1960s, the essential role of T cells in antibody production had been reported. In search of molecules mediating T cell helper function, I discovered activities in the culture supernatant of T cells that induced proliferation and differentiation of B cells. This led to my life's work: studying one of those factors, interleukin-6 (IL-6). To my surprise, IL-6 turned out to play additional roles, including myeloma growth factor and hepatocyte-stimulating factor activities. More importantly, it was involved in a number of diseases, such as rheumatoid arthritis and Castleman's disease. I feel exceptionally fortunate that my work not only revealed the framework of cytokine signaling, including identification of the IL-6 receptor, gp130, NF-IL6, STAT3, and SOCS-1, but also led to the development of a new therapy for chronic inflammatory diseases.
TNF/TNFR FAMILY MEMBERS IN COSTIMULATION OF T CELL RESPONSES
Authors: Watts Tania H.
Published: November 2004

▪ Abstract  Several members of the tumor necrosis factor receptor (TNFR) family function after initial T cell activation to sustain T cell responses. This review focuses on CD27, 4-1BB (CD137), OX40 (CD134), HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells. The effects of these costimulatory TNFR family members can often be functionally, temporally, or spatially segregated from those of CD28 and from each other. The sequential and transient regulation of T cell activation/survival signals by different costimulators may function to allow longevity of the response while maintaining tight control of T cell survival. Depending on the disease condition, stimulation via costimulatory TNF family members can exacerbate or ameliorate disease. Despite these complexities, stimulation or blockade of TNFR family costimulators shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.
Approaches to Therapy of Prion Diseases
Authors: Weissmann Charles , Aguzzi Adriano
Published: November 2004

Devising approaches to the therapy of transmissible spongiform encephalopathies, or prion diseases, is beset by many difficulties. For one, the nature of the infectious agent, the prion, is understood only in outline, and its composition, structure, and mode of replication are still shrouded in mystery. In addition, the mechanism of pathogenesis is not well understood. Because clinical disease affects mainly the brain parenchyme, therapeutic agents must be able to traverse the brain-blood barrier (BBB) or have to be introduced directly into the cerebrospinal fluid or brain tissue. And finally, because the disease is usually recognized only after onset of severe clinical symptoms, the question arises as to whether the neurodegenerative processes can be reversed to any extent after a successful eradication of the agent.
Andropause: Is Androgen Replacement Therapy Indicated for the Aging Male?
Authors: Hijazi Rabih A. , Cunningham Glenn R.
Published: November 2004

The number of men in the United States ≥65 years of age is projected to increase from 14,452,000 in 2000 to 31,343,000 in 2030. Approximately 30% of men 60–70 years of age and 70% of men 70–80 years of age have low bioavailable or free testosterone levels. Symptoms and findings of testosterone deficiency are similar to those associated with aging. They include loss of energy, depressed mood, decreased libido, erectile dysfunction, decreased muscle mass and strength, increased fat mass, frailty, osteopenia, and osteoporosis. Several small clinical trials indicate that testosterone replacement therapy can improve many of these findings; however, the studies have not been powered to assess potential risks, such as the need for invasive treatment of benign prostatic hyperplasia, development of a clinical prostate cancer, or cardiovascular events. Thus, the benefit/risk ratio of testosterone replacement therapy in aging men is not known.
New Concepts in Von Willebrand Disease
Authors: Sadler J. Evan
Published: November 2004

Von Willebrand factor (VWF) behaves as an extracellular adapter molecule, linking platelets to the extracellular matrix at sites of vascular injury. These interactions are crucial for hemostasis. Too little platelet adhesion causes bleeding that is typical of von Willebrand disease, whereas too much platelet adhesion may cause thrombotic thrombocytopenic purpura. Mutations in VWF or platelet glycoprotein Ib can either reduce or increase the affinity of platelet binding. Paradoxically, affinity changes in either direction cause bleeding. Crystallographic studies now suggest molecular explanations for all of these phenotypes. Clinical investigations of von Willebrand disease type 1 are defining the relationship between plasma VWF level and the risk of bleeding or thrombosis. Emerging data suggest that VWF level is a useful biomarker for the risk of either bleeding or thrombosis and could be incorporated into a comprehensive approach to treat or prevent these adverse events.
New Strategies in the Treatment of the Thalassemias
Authors: Schrier Stanley L. , Angelucci Emanuele
Published: November 2004

In addition to the severe beta thalassemias, hematologists have begun to recognize the more severe forms of alpha thalassemia, namely hemoglobin (Hb) H disease and Hb H/Hb Constant Spring, as well as the beta compound heterozygote, beta thalassemia/HbE. Clinically, variably severe anemia becomes apparent in the first year accompanied by occasionally massive expansion of erythropoiesis. The most anemic patients require regular red blood cell transfusions to avoid death from cardiac failure. However, the inevitable iron accumulation leads to dysfunction, primarily involving the heart, liver, and endocrine system; thus, regularly transfused patients require iron chelation. A major discovery was that allogeneic bone marrow (stem cell) transplantation in severely affected subjects with both alpha and beta thalassemia could result in cure. Current work deals with specific complications, such as iron overload and endocrine, cardiopulmonary, thrombophilic, and osteopenic problems. The thalassemias are likely to benefit in the future from specific gene therapy. There are also important advances in genetic counseling based on results of early fetal diagnosis.
Post-Transplant Lymphoproliferative Disorders
Authors: Gottschalk Stephen , Rooney Cliona M. , Heslop Helen E.
Published: November 2004

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after hematopoietic stem cell or solid organ transplantation. The majority of PTLD is of B-cell origin and associated with Epstein-Barr virus (EBV). During the past decade progress has been made in better understanding the pathogenesis of PTLD, and early detection strategies, such as serial measurement of EBV-DNA load in peripheral blood samples, have assisted in the identification of high-risk patients. In addition, novel immunotherapies have been developed, including the use of monoclonal antibodies and adoptive transfer of EBV-specific T cells. Despite these advances, it remains a major challenge to define indications for preemptive therapies for PTLD and to integrate novel therapeutic approaches with conventional therapies.
Role of Magnetic Resonance Imaging and Immunotherapy in Treating Multiple Sclerosis
Authors: Zhang Jingwu , Hutton George
Published: November 2004

Significant advances in magnetic resonance imaging (MRI) technology and treatment of multiple sclerosis (MS) have been made during the past decade. These advances have revealed evidence of profound heterogeneity in MS. There is a clear need to revisit the key issues in MS pathogenesis and treatment strategies, taking new data into consideration. This paper provides an overview of recent progress in MS research, including (a) a review of clinical, pathologic, and immunologic aspects of MS, (b) a discussion of the mechanism of action of currently available disease-modifying drugs for MS, (c) an account of the role of MRI in clinical management and clinical trials in MS, and (d) an overview of some emerging treatments for MS.
Metabolic Syndrome: A Clinical and Molecular Perspective
Authors: Moller David E. , Kaufman Keith D.
Published: November 2004

The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance. Obesity also leads to a proinflammatory and prothrombotic state that potentiates atherosclerosis. Pathways leading directly from adiposity to the genesis of dyslipidemia and hypertension have been elucidated. Recent knowledge implies a role for fat-derived “adipokines,” including TNFα and adiponectin, as pathogenic contributors or protective factors. Current therapies include diet and exercise as well as agents indicated for the treatment of individual components of the syndrome. Future therapies may accrue from the aggressive pursuit of newer molecular drug targets that have the potential to prevent or treat multiple aspects of the metabolic syndrome.
Endothelial Progenitor Cells
Authors: Khakoo Aarif Y. , Finkel Toren
Published: November 2004

Endothelial progenitor cells are a circulating, bone marrow–derived cell population that appears to participate in both vasculogenesis and vascular homeostasis. Questions persist regarding their functional characteristics, as well as the precise panel of cell surface markers that uniquely define this newly described progenitor cell population. We review experimental results obtained from both animal studies and recent clinical trials that suggest this cell type may have tremendous therapeutic potential for a wide range of human diseases.
GLYCERALDEHYDE-3-PHOSPHATE DEHYDROGENASE, APOPTOSIS, AND NEURODEGENERATIVE DISEASES
Authors: Chuang De-Maw , Hough Christopher , Senatorov Vladimir V.
Published: November 2004

▪ Abstract  Increasing evidence supports the notion that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a protein with multiple functions, including its surprising role in apoptosis. GAPDH is overexpressed and accumulates in the nucleus during apoptosis induced by a variety of insults in diverse cell types. Knockdown of GAPDH using an antisense strategy demonstrates its involvement in the apoptotic cascade in which GAPDH nuclear translocation appears essential. Knowledge concerning the mechanisms underlying GAPDH nuclear translocation and subsequent cell death is growing. Additional evidence suggests that GAPDH may be an intracellular sensor of oxidative stress during early apoptosis. Abnormal expression, nuclear accumulation, changes in physical properties, and loss of glycolytic activity of GAPDH have been found in cellular and transgenic models as well as postmortem tissues of several neurodegenerative diseases. The interaction of GAPDH with disease-related proteins as well as drugs used to treat these diseases suggests that it is a potential molecular target for drug development.
DUAL SPECIFICITY PROTEIN PHOSPHATASES: Therapeutic Targets for Cancer and Alzheimer's Disease
Authors: Ducruet Alexander P. , Vogt Andreas , Wipf Peter , Lazo John S.
Published: November 2004

▪ Abstract  The complete sequencing of the human genome is generating many novel targets for drug discovery. Understanding the pathophysiological roles of these putative targets and assessing their suitability for therapeutic intervention has become the major hurdle for drug discovery efforts. The dual-specificity phosphatases (DSPases), which dephosphorylate serine, threonine, and tyrosine residues in the same protein substrate, have important roles in multiple signaling pathways and appear to be deregulated in cancer and Alzheimer's disease. We examine the potential of DSPases as new molecular therapeutic targets for the treatment of human disease.
REGULATION AND INHIBITION OF ARACHIDONIC ACID ω-HYDROXYLASES AND 20-HETE FORMATION
Authors: Kroetz Deanna L. , Xu Fengyun
Published: November 2004

▪ Abstract  Cytochrome P450–catalyzed metabolism of arachidonic acid is an important pathway for the formation of paracrine and autocrine mediators of numerous biological effects. The ω-hydroxylation of arachidonic acid generates significant levels of 20-hydroxyeicosatetraenoic acid (20-HETE) in numerous tissues, particularly the vasculature and kidney tubules. Members of the cytochrome P450 4A and 4F families are the major ω-hydroxylases, and the substrate selectivity and regulation of these enzymes has been the subject of numerous studies. Altered expression and function of arachidonic acid ω-hydroxylases in models of hypertension, diabetes, inflammation, and pregnancy suggest that 20-HETE may be involved in the pathogenesis of these diseases. Our understanding of the biological significance of 20-HETE has been greatly aided by the development and characterization of selective and potent inhibitors of the arachidonic acid ω-hydroxylases. This review discusses the substrate selectivity and expression of arachidonic acid ω-hydroxylases, regulation of these enzymes during disease, and the application of enzyme inhibitors to study 20-HETE function.
THE ROLE OF METABOLIC ACTIVATION IN DRUG-INDUCED HEPATOTOXICITY
Authors: Park B. Kevin , Kitteringham Neil R. , Maggs James L. , Pirmohamed Munir , Williams Dominic P.
Published: November 2004

▪ Abstract  The importance of reactive metabolites in the pathogenesis of drug-induced toxicity has been a focus of research interest since pioneering investigations in the 1950s revealed the link between toxic metabolites and chemical carcinogenesis. There is now a great deal of evidence that shows that reactive metabolites are formed from drugs known to cause hepatotoxicity, but how these toxic species initiate and propagate tissue damage is still poorly understood. This review summarizes the evidence for reactive metabolite formation from hepatotoxic drugs, such as acetaminophen, tamoxifen, diclofenac, and troglitazone, and the current hypotheses of how this leads to liver injury. Several hepatic proteins can be modified by reactive metabolites, but this in general equates poorly with the extent of toxicity. Much more important may be the identification of the critical proteins modified by these toxic species and how this alters their function. It is also important to note that the toxicity of reactive metabolites may be mediated by noncovalent binding mechanisms, which may also have profound effects on normal liver physiology. Technological developments in the wake of the genomic revolution now provide unprecedented power to characterize and quantify covalent modification of individual target proteins and their functional consequences; such information should dramatically improve our understanding of drug-induced hepatotoxic reactions.
THE MAGIC BULLETS AND TUBERCULOSIS DRUG TARGETS
Authors: Zhang Ying
Published: November 2004

▪ Abstract  Modern chemotherapy has played a major role in our control of tuberculosis. Yet tuberculosis still remains a leading infectious disease worldwide, largely owing to persistence of tubercle bacillus and inadequacy of the current chemotherapy. The increasing emergence of drug-resistant tuberculosis along with the HIV pandemic threatens disease control and highlights both the need to understand how our current drugs work and the need to develop new and more effective drugs. This review provides a brief historical account of tuberculosis drugs, examines the problem of current chemotherapy, discusses the targets of current tuberculosis drugs, focuses on some promising new drug candidates, and proposes a range of novel drug targets for intervention. Finally, this review addresses the problem of conventional drug screens based on inhibition of replicating bacilli and the challenge to develop drugs that target nonreplicating persistent bacilli. A new generation of drugs that target persistent bacilli is needed for more effective treatment of tuberculosis.
CYTOCHROME P450 UBIQUITINATION: Branding for the Proteolytic Slaughter?
Authors: Correia Maria Almira , Sadeghi Sheila , Mundo-Paredes Eduardo
Published: November 2004

▪ Abstract  The hepatic cytochromes P450 (P450s) are monotopic endoplasmic reticulum (ER)-anchored hemoproteins engaged in the enzymatic oxidation of a wide variety of endo- and xenobiotics. In the course of these reactions, the enzymes generate reactive O2 species and/or reactive metabolic products that can attack the P450 heme and/or protein moiety and structurally and functionally damage the enzyme. The in vivo conformational unraveling of such a structurally damaged P450 signals its rapid removal via the cellular sanitation system responsible for the proteolytic disposal of structurally aberrant, abnormal, and/or otherwise malformed proteins. A key player in this process is the ubiquitin (Ub)-dependent 26S proteasome system. Accordingly, the structurally deformed P450 protein is first branded for recognition and proteolytic removal by the 26S proteasome with an enzymatically incorporated polyUb tag. P450s of the 3A subfamily such as the major human liver enzyme CYP3A4 are notorious targets for this process, and they represent excellent prototypes for the understanding of integral ER protein ubiquitination. Not all the participants in hepatic CYP3A ubiquitination and subsequent proteolytic degradation have been identified. The following discussion thus addresses the various known and plausible events and/or cellular participants involved in this multienzymatic P450 ubiquitination cascade, on the basis of our current knowledge of other eukaryotic models. In addition, because the detection of ubiquitinated P450s is technically challenging, the critical importance of appropriate methodology is also discussed.
MOLECULAR PHYSIOLOGY OF INTESTINAL N+/H+ EXCHANGE
Authors: Zachos Nicholas C. , Tse Ming , Donowitz Mark
Published: November 2004

▪ Abstract  The sodium/hydrogen exchange (NHE) gene family plays an integral role in neutral sodium absorption in the mammalian intestine. The NHE gene family is comprised of nine members that are categorized by cellular localization (i.e., plasma membrane or intracellular). In the gastrointestinal (GI) tract of multiple species, there are resident plasma membrane isoforms including NHE1 (basolateral) and NHE2 (apical), recycling isoforms (NHE3), as well as intracellular isoforms (NHE6, 7, 9). NHE3 recycles between the endosomal compartment and the apical plasma membrane and functions in both locations. NHE3 regulation occurs during normal digestive processes and is often inhibited in diarrheal diseases. The C terminus of NHE3 binds multiple regulatory proteins to form large protein complexes that are involved in regulation of NHE3 trafficking to and from the plasma membrane, turnover number, and protein phosphorylation. NHE1 and NHE2 are not regulated by trafficking. NHE1 interacts with multiple regulatory proteins that affect phosphorylation; however, whether NHE1 exists in large multi-protein complexes is unknown. Although intestinal and colonic sodium absorption appear to involve at least NHE2 and NHE3, future studies are necessary to more accurately define their relative contributions to sodium absorption during human digestion and in pathophysiological conditions.
NOVEL RENAL AMINO ACID TRANSPORTERS
Authors: Verrey François , Ristic Zorica , Romeo Elisa , Ramadan Tamara , Makrides Victoria , Dave Mital H. , Wagner Carsten A. , Camargo Simone M.R.
Published: November 2004

▪ Abstract  Reabsorption of amino acids, similar to that of glucose, is a major task of the proximal kidney tubule. Various amino acids are actively transported across the luminal brush border membrane into proximal tubule epithelial cells, most of which by cotransport. An important player is the newly identified cotransporter (symporter) B0AT1 (SLC6A19), which imports a broad range of neutral amino acids together with Na+ across the luminal membrane and which is defective in Hartnup disorder. In contrast, cationic amino acids and cystine are taken up in exchange for recycled neutral amino acids by the heterodimeric cystinuria transporter. The basolateral release of some neutral amino acids into the extracellular space is mediated by unidirectional efflux transporters, analogous to GLUT2, that have not yet been definitively identified. Additionally, cationic amino acids and some other neutral amino acids leave the cell basolaterally via heterodimeric obligatory exchangers.
CELL SURVIVAL IN THE HOSTILE ENVIRONMENT OF THE RENAL MEDULLA
Authors: Neuhofer Wolfgang , Beck Franz-X.
Published: November 2004

▪ Abstract  The countercurrent system in the medulla of the mammalian kidney provides the basis for the production of urine of widely varying osmolalities, but necessarily entails extreme conditions for medullary cells, i.e., high concentrations of solutes (mainly NaCl and urea) in antidiuresis, massive changes in extracellular solute concentrations during the transitions from antidiuresis to diuresis and vice versa, and low oxygen tension. The strategies used by medullary cells to survive in this hostile milieu include accumulation of organic osmolytes and heat shock proteins, the extensive use of the glycolysis for energy production, and a well-orchestrated network of signaling pathways coordinating medullary circulation and tubular work.
RENAL TUBULE ALBUMIN TRANSPORT
Authors: Gekle Michael
Published: November 2004

▪ Abstract  Albumin is the most abundant protein in serum and contributes to the maintenance of oncotic pressure as well as to transport of hydrophobic molecules. Although albumin is a large anionic protein, it is not completely retained by the glomerular filtration barrier. In order to prevent proteinuria, albumin is reabsorbed along the proximal tubules by receptor-mediated endocytosis, which involves the binding proteins megalin and cubilin. Endocytosis depends on proper vesicle acidification. Disturbance of endosomal acidification or loss of the binding proteins leads to tubular proteinuria. Furthermore, endocytosis is subject to modulation by different signaling systems, such as protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K) and transforming growth factor beta (TGF-β). In addition to being reabsorbed in the proximal tubule, albumin can also act as a profibrotic and proinflammatory stimulus, thereby initiating or promoting tubulo-interstitial diseases.
A PHYSIOLOGICAL VIEW OF THE PRIMARY CILIUM
Authors: Praetorius Helle A. , Spring Kenneth R.
Published: November 2004

▪ Abstract  The primary cilium, an organelle largely ignored by physiologists, functions both as a mechano-sensor and a chemo-sensor in renal tubular epithelia. This forgotten structure is critically involved in the determination of left-right sidedness during development and is a key factor in the development of polycystic kidney disease, as well as a number of other abnormalities. This review provides an update of our current understanding about the function of primary cilia. Much new information obtained in the past five years has been stimulated, in part, by discoveries of the primary cilium's key role in the genesis of polycystic kidney disease as well as its involvement in determination of left-right axis asymmetry. Here we focus on the various functions of the primary cilium rather than on its role in pathology.
LUNG VASCULAR DEVELOPMENT: Implications for the Pathogenesis of Bronchopulmonary Dysplasia
Authors: Stenmark Kurt R. , Abman Steven H.
Published: November 2004

▪ Abstract  Past studies have primarily focused on how altered lung vascular growth and development contribute to pulmonary hypertension. Recently, basic studies of vascular growth have led to novel insights into mechanisms underlying development of the normal pulmonary circulation and the essential relationship of vascular growth to lung alveolar development. These observations have led to new concepts underlying the pathobiology of developmental lung disease, especially the inhibition of lung growth that characterizes bronchopulmonary dysplasia (BPD). We speculate that understanding basic mechanisms that regulate and determine vascular growth will lead to new clinical strategies to improve the long-term outcome of premature babies with BPD.
LESSONS IN ESTROGEN BIOLOGY FROM KNOCKOUT AND TRANSGENIC ANIMALS
Authors: Hewitt Sylvia C. , Harrell Joshua C. , Korach Kenneth S.
Published: November 2004

▪ Abstract  Tremendous progress has been made in elucidating numerous critical aspects of estrogen signaling. New tools and techniques have enabled detailed molecular analysis of components that direct estrogen responses. At the other end of the spectrum, generation of a multiplicity of transgenic animals has allowed analysis of the physiological roles of the estrogen-signaling components in biologically relevant models. Here, we review the ever-increasing body of knowledge in the field of estrogen biology, especially as applied to the female reproductive processes.
RNAI AS AN EXPERIMENTAL AND THERAPEUTIC TOOL TO STUDY AND REGULATE PHYSIOLOGICAL AND DISEASE PROCESSES
Authors: Dillon Christopher P. , Sandy Peter , Nencioni Alessio , Kissler Stephan , Rubinson Douglas A. , Van Parijs Luk
Published: November 2004

▪ Abstract  Over the past four years RNA interference (RNAi) has exploded onto the research scene as a new approach to manipulate gene expression in mammalian systems. More recently, RNAi has garnered much interest as a potential therapeutic strategy. In this review, we briefly summarize the current understanding of RNAi biology and examine how RNAi has been used to study the genetic basis of physiological and disease processes in mammalian systems. We also explore some of the new developments in the use of RNAi for disease therapy and highlight the key challenges that currently limit its application in the laboratory, as well as in the clinical setting.
The Social Psychology of Stigma
Authors: Major Brenda , O'Brien Laurie T.
Published: November 2004

This chapter addresses the psychological effects of social stigma. Stigma directly affects the stigmatized via mechanisms of discrimination, expectancy confirmation, and automatic stereotype activation, and indirectly via threats to personal and social identity. We review and organize recent theory and empirical research within an identity threat model of stigma. This model posits that situational cues, collective representations of one's stigma status, and personal beliefs and motives shape appraisals of the significance of stigma-relevant situations for well-being. Identity threat results when stigma-relevant stressors are appraised as potentially harmful to one's social identity and as exceeding one's coping resources. Identity threat creates involuntary stress responses and motivates attempts at threat reduction through coping strategies. Stress responses and coping efforts affect important outcomes such as self-esteem, academic achievement, and health. Identity threat perspectives help to explain the tremendous variability across people, groups, and situations in responses to stigma.
Prosocial Behavior: Multilevel Perspectives
Authors: Penner. Louis A. , Dovidio. John F. , Piliavin. Jane A. , Schroeder. David A.
Published: November 2004

Current research on prosocial behavior covers a broad and diverse range of phenomena. We argue that this large research literature can be best organized and understood from a multilevel perspective. We identify three levels of analysis of prosocial behavior: (a) the “meso” level—the study of helper-recipient dyads in the context of a specific situation; (b) the micro level—the study of the origins of prosocial tendencies and the sources of variation in these tendencies; and (c) the macro level—the study of prosocial actions that occur within the context of groups and large organizations. We present research at each level and discuss similarities and differences across levels. Finally, we consider ways in which theory and research at these three levels of analysis might be combined in future intra- and interdisciplinary research on prosocial behavior.
The Neuroscience of Mammalian Associative Learning
Authors: Fanselow Michael S. , Poulos Andrew M
Published: November 2004

Mammalian associative learning is organized into separate anatomically defined functional systems. We illustrate the organization of two of these systems, Pavlovian fear conditioning and Pavlovian eyeblink conditioning, by describing studies using mutant mice, brain stimulation and recording, brain lesions and direct pharmacological manipulations of specific brain regions. The amygdala serves as the neuroanatomical hub of the former, whereas the cerebellum is the hub of the latter. Pathways that carry information about signals for biologically important events arrive at these hubs by circuitry that depends on stimulus modality and complexity. Within the amygdala and cerebellum, neural plasticity occurs because of convergence of these stimuli and the biologically important information they predict. This neural plasticity is the physical basis of associative memory formation, and although the intracellular mechanisms of plasticity within these structures share some similarities, they differ significantly. The last Annual Review of Psychology article to specifically tackle the question of mammalian associative learning ( Lavond et al. 1993 ) persuasively argued that identifiable “essential” circuits encode memories formed during associative learning. The next dozen years saw breathtaking progress not only in detailing those essential circuits but also in identifying the essential processes occurring at the synapses (e.g., Bi & Poo 2001 , Martinez & Derrick 1996 ) and within the neurons (e.g., Malinow & Malenka 2002 , Murthy & De Camilli 2003 ) that make up those circuits. In this chapter, we describe the orientation that the neuroscience of learning has taken and review some of the progress made within that orientation.
In Search of Memory Traces
Authors: Thompson Richard F.
Published: November 2004

The key issue in analyzing brain substrates of memory is the nature of memory traces, how memories are formed, stored, and retrieved in the brain. In order to analyze mechanisms of memory formation it is first necessary to find the loci of memory storage, the classic problem of localization. Various approaches to this issue are reviewed. A particular strategy is proposed that involves a number of different techniques (electrophysiological recording, lesions, electrical stimulation, pathway tracing) to identify the essential memory trace circuit for a given form of learning and memory. The methods of reversible inactivation can be used to localize the memory traces within this circuit. Using classical conditioning of eye blink and other discrete responses as a model system, the essential memory trace circuit is identified, the basic memory trace is localized (to the cerebellum), and putative higher-order memory traces are characterized in the hippocampus.