每日一文(0312)

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 November October September August July June May April March February January 2002 2001

December 31,2003 Regulation of Transforming Growth Factor-β Signaling
  Members of transforming growth factor β (TGF-β) family are potent regulators of multiple cellular functions, including cell proliferation, differentiation, migration, organization, and death. Yet the signaling pathways underpinning a wide array of biological activities of TGF-β appear to be deceptively simple. At every step from TGF-β secretion to activation of its target genes, the activity of TGF-bis regulated tightly, both positively and negatively. Biologically active TGF-β is cleaved from a precursor protein (latent form) and multiple process factors control the levels of active TGF-β.
December 30,2003 Oxidative DNA damage: mechanisms, mutation, and disease
  Oxidative DNA damage is an inevitable consequence of cellular metabolism, with a propensity for increased levels following toxic insult. Although more than 20 base lesions have been identified, only a fraction of these have received appreciable study, most notably 8-oxo-2'deoxyguanosine. This lesion has been the focus of intense research interest and been ascribed much importance, largely to the detriment of other lesions. The present work reviews the basis for the biological significance of oxidative DNA damage, drawing attention to the multiplicity of proteins with repair activities along with a number of poorly considered effects of damage.
December 29,2003 Microarray analysis of gene expression during the cell cycle
  Microarrays have been applied to the determination of genome-wide expression patterns during the cell cycle of a number of different cells. Both eukaryotic and prokaryotic cells have been studied using whole-culture and selective synchronization methods. The published microarray data on yeast, mammalian, and bacterial cells have been uniformly interpreted as indicating that a large number of genes are expressed in a cell-cycle-dependent manner. These conclusions are reconsidered using explicit criteria for synchronization and precise criteria for identifying gene expression patterns during the cell cycle.
December 28,2003 Cell cycle control,DNA damage checkpoints and cancer
  DNA damage checkpoints are essential control points the cell cycle ensuring effective damage repair. The loss of checkpoint functions leads to loss of genomic integrity and allows accumulation of genetic damage in the daughter cells. Checkpoint deficiency is one of the main causes of DNA aberrations in cancer.
December 27,2003 Bioinformatics and Medical Informatics: Collaborations on the Road to Genomic Medicine?
  Abstract In this report, the authors compare and contrast medical informatics (MI) and bioinformatics (BI) and provide a viewpoint on their complementarities and potential for collaboration in various subfields. The authors compare MI and BI along several dimensions, including......
December 26,2003 Virtual laboratories in the life sciences
  In a few years, the European Union (EU) will have grown from its current 15 member states to 25 nations. At the same time, a truly European convention is being discussed that will give the EU a new legal basis for its business. These political developments will also have important implications for European scientists and researchers. Basically, we are at the crossroads where Europe as a whole has to decide whether it will invest more into scientific research-particularly in the life sciences-because it is no longer feasible to continue research with the modest funds that are now the case for many European states.
December 25,2003 Switched on to RNA
  Shape-shifting RNAs that sense the environment — ‘riboswitches’ — can alter gene activity. Jonathan Knight reports on a discovery that is explaining some of the mysteries of gene regulation.
December 24,2003 Techniques and Pitfalls in the Detection of Pathogenic Mitochondrial DNA Mutations
  Mutations in the mitochondrial DNA (mtDNA) are now recognized as major contributors to human pathologies and possibly to normal aging. A large number of rearrangements and point mutations in protein coding and tRNA genes have been identified in patients with mitochondrial disorders. In this review, we discuss genotype-phenotype correlations in mitochondrial diseases and common techniques used to identify pathogenic mtDNA mutations in human tissues. Although most of these approaches employ standard molecular biology tools, the co-existence of wild-type and mutated mtDNA (mtDNA heteroplasmy) in diseased tissues complicates both the detection and accurate determination of the size of the mutated fractions. To address these problems, novel approaches were developed and are discussed in this review.
December 23,2003 Ubiquitin and the Deconstruction of Synapses
  The remodeling of synapses is a fundamental mechanism for information storage and processing in the brain (1, 2). Much of this remodeling occurs at the postsynaptic density (PSD), a specialized biochemical apparatus containing neurotransmitter receptors and associated scaffolding proteins that organizes signal transduction pathways at the postsynaptic membrane (3-5). Easily visible in the electron microscope, the PSD is a disk-like structure ~30 nm thick and a few hundred nanometers wide, positioned opposite presynaptic terminals (see the figure, below).
December 22,2003 DISSECTING HIV-1 THROUGH RNA INTERFERENCE
  In cells of organisms, ranging from nematodes to primates, there is a process known as RNA interference (RNAi) that effects the degradation of RNA in a highly sequence-specific manner. Scientists have figured out a way to co-opt elements of the RNAi machinery such that almost any RNA can be targeted for degradation. It is now clear that HIV-1 is fair game for RNAi; viral RNA intermediates have been targeted as well as messenger RNAs for cellular co-factors that are required for replication of HIV-1. The hope is that RNAi can be used not only as a research tool, but also as a therapeutic strategy for infection with HIV-1.
December 21,2003 Apoptosis and Autoimmune Disorders
  Apoptosis or programmed cell death plays a central role in regulating not only the development of lymphocytes but also in their homeostasis. A breakdown in apoptosis related signaling mechanisms could result in the development of autoimmune disorders. The past decade has witnessed an explosive increase in knowledge with respect to various apoptotic signaling pathways and their aberrant behavior in autoimmune disorders. Although Fas/FasL mediated signaling appears to be a common paradigm that has emerged from studies in various autoimmune disorders, examples suggesting a role for other cell death pathways have also surfaced. Understanding the definitive role of apoptosis in various autoimmune disorders is likely to define novel targets for future therapeutic intervention.
December 20,2003 A Gene-Coexpression Network for Global Discovery of Conserved Genetic Modules
  To elucidate gene function on a global scale, we identi.ed pairs of genes that are coexpressed over 3182 DNA microarrays from humans, .ies, worms, and yeast.We found 22,163 such coexpression relationships, each of which has been conserved across evolution. This conservation implies that the coexpression of these gene pairs confers a selective advantage and therefore that these genes are functionally related. Manyof these relationships provide strong evidence for the involvement of new genes in core biological functions such as the cell cycle, secretion, and protein expression. We experimentallycon.rmed the predictions implied bysome of these links and identi.ed cell proliferation functions for several genes. By assembling these links into a gene-coexpression network, we found several components that were animal-speci.c as well as interrelationships between newly evolved and ancient modules.
December 19,2003 HUMAN CLONING: CAN IT BE MADE SAFE?
  There are continued claims of attempts to clone humans using nuclear transfer, despite the serious problems that have been encountered in cloning other mammals. It is known that epigenetic and genetic mechanisms are involved in clone failure, but we still do not know exactly how. Human reproductive cloning is unethical, but the production of cells from cloned embryos could offer many potential benefits. So, can human cloning be made safe?
December 18,2003 Molecular and Genetic Mechanisms of Obesity: Implications for Future Management
  Abstract: Obesity has become a worldwide public health problem affecting millions of people. A disruption of the balance between energy intake and energy expenditure is believed to be the major cause of obesity. Substantial progress has been made in deciphering the pathogenesis of energy homeostasis over the past few years. The fact that obesity is under strong genetic control has been well established. Human monogenic obesity is rare in large populations, the most common form of obesity is considered to be a polygenic disorder arising from the interaction of multiple genetic and environmental factors. Here, we attempt to briefly review the most recent understanding of molecular mechanisms involved in energy homeostasis and adipogenesis. We discuss the advantages and disadvantages of various approaches commonly used in search for susceptibility genes for obesity. The main results from these genetic studies are summarized, with comments made on the most striking or representative findings. Finally, the implications of the recent advances in the understanding of molecular genetic mechanisms of body weight regulation on prevention and therapeutic intervention of obesity will be discussed.
December 17,2003 Target discovery
  Target discovery, which involves the identification and early validation of diseasemodifying targets, is an essential first step in the drug discovery pipeline. Indeed, the drive to determine protein function has been stimulated, both in industry and academia, by the completion of the human genome project. In this article, we critically examine the strategies and methodologies used for both the identification and validation of disease-relevant proteins. In particular, we will examine the likely impact of recent technological advances, including genomics, proteomics, small interfering RNA and mouse knockout models, and conclude by speculating on future trends.
December 16,2003 What Is the Role of β-Adrenergic Signaling in Heart Failure?
  Abstract-This review addresses open questions about the role of β-adrenergic receptors in cardiac function and failure. Cardiomyocytes express all three β-adrenergic receptor subtypes-β1, β2, and, at least in some species, β3. The β1 subtype is the most prominent one and is mainly responsible for positive chronotropic and inotropic effects of catecholamines. The β2 subtype also increases cardiac function, but its ability to activate nonclassical signaling pathways suggests a function distinct from the β1 subtype. In heart failure, the sympathetic system is activated, cardiac β-receptor number and function are decreased, and downstream mechanisms are altered. However, in spite of a wealth of data, we still do not know whether and to what extent these alterations are adaptive/protective or detrimental, or both. Clinically, β-adrenergic antagonists represent the most important advance in heart failure therapy, but it is still debated whether they act by blocking or by resensitizing the β-adrenergic receptor system. Newer experimental therapeutic strategies aim at the receptor desensitization machinery and at downstream signaling steps.
December 15,2003 STAT Proteins: From Normal Control of Cellular Events to Tumorigenesis
  Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that participate in normal cellular events, such as differentiation, proliferation, cell survival, apoptosis, and angiogenesis following cytokine, growth factor, and hormone signaling. STATs are activated by tyrosine phosphorylation, which is normally a transient and tightly regulates process. Nevertheless, several constitutively activated STATs have been observed in a wide number of human cancer cell lines and primary tumors, including blood malignancies and solid neoplasias. STATs can be divided into two groups according to their specific functions. One is made up of STAT2, STAT4, and STAT6, which are activated by a small number of cytokines and play a distinct role in the development of T-cells and in IFNg signaling. The other group includes STAT1, STAT3, and STAT5, activated in different tissues by means of a series of ligands and involved in IFN signaling, development of the mammary gland, response to GH, and embriogenesis. This latter group of STATS plays an important role in controlling cell-cycle progression and apoptosis and thus contributes to oncogenesis. Although an increased expression of STAT1 has been observed in many human neoplasias, this molecule can be considered a potential tumor suppressor, since it plays an important role in growth arrest and in promoting apoptosis.Onthe other hand, STAT3 and 5 are considered as oncogenes, since they bring about the activation of cyclin D1, c-Myc, and bcl-xl expression, and are involved in promoting cell-cycle progression, cellular transformation, and in preventing apoptosis.
December 14,2003 New molecular pathways in angiogenesis
  Angiogenesis has developed into a major area of cancer research. Recently, several newly identified signalling pathways have been shown to play a role in both normal and pathological (including tumour) angiogenesis. Several of the molecules involved in these pathways have potential as novel anti-cancer therapeutic targets including members of the ephrin/Eph receptor, Notch/delta, sprouty, hedgehog and roundabout/slit families. These developments are reviewed.
December 13,2003 DNA replication: a complex matter
  In eukaryotic cells, the essential function of DNA replication is carried out by a network of enzymes and proteins, which work together to rapidly and accurately duplicate the genetic information of the cell. Many of the components of this DNA replication apparatus associate with other cellular factors as components of multiprotein complexes, which act cooperatively in networks to regulate cell cycle progression and checkpoint control, but are distinct from the prereplication complexes that associate with the origins and regulate their firing. In this review, we summarize current knowledge about the composition and dynamics of these large multiprotein complexes in mammalian cells and their relationships to the replication factories.
December 12,2003 Basic concepts in medical informatics
  This glossary defines terms used in the comparatively young science of medical informatics. It is hoped that it will be of interest to both novices and professionals in the field.
December 11,2003 Cytokine gene polymorphisms in multifactorial diseases: gateways to novel targets for immunotherapy?
  Recent advances in cytokine biology have led to novel approaches to the treatment of inflammatory diseases. In this article, we review recent data regarding the role of functional polymorphisms in the genes encoding the prototypic Th1 cytokine interferon g and Th2 cytokine interleukin 4 in multifactorial disorders. We have compared genetic data across a heterogeneous assortment of such conditions using a ??haplotype tagging?ˉ approach, and demonstrate that cytokine gene association studies are instrumental in the identification of specific disease states or clinical manifestations that are probably caused by genetically determined aberrant cytokine expression. Some of these new findings suggest cytokine effects that go beyond a classical Th1¨CTh2 dichotomy. Thus, we propose that this information could provide novel targets for immunotherapy and, in particular, might facilitate the identification of clinical subgroups of patients who, by virtue of their genetic constitution at these cytokine gene loci, are more likely to benefit from cytokine agonist or antagonist therapy.
December 10,2003 Cancer, cadmium and genome integrity
  The direct inhibition of DNA mismatch repair by cadmium provides a molecular mechanism for cadmium toxicity with profound implications for human health, risk assessment and biological understanding of environmental mutagens. Alteration of key DNA damage response pathways may prove even more important than direct DNA damage by mutagens.
December 9,2003 New jobs for an old enzyme: the revival of IDO
  Unresponsiveness towards autoantigens or potentially harmful pathogens can be thought of as an active process of developing tolerance. The induction of this activity relies on the interaction of antigen-presenting cells (APCs) and T cells, causing T-cell tolerance. Very recently, a new feature of regulatory APCs was observed. The expression of indoleamine-2,3-dioxygenase (IDO) activity by certain dendritic cells (DCs), monocytes and macrophages has immunomodulatory effects on Tcells that are related to the peri-cellular degradation of the essential amino acid tryptophan [1]. In their recent review, Grohmann and co-authors [2] described the central role of IDO in the control of T-cell activity during infection, pregnancy, autoimmunity, transplantation and neoplasia.
December 8,2003 How to make tubes: signaling by the Met receptor tyrosine kinaseq
  Hepatocyte growth factor/scatter factor (HGF/SF), acting through the receptor tyrosine kinase Met, stimulates cells derived from a variety of different organs to form elongated hollow tubules when grown in threedimensional gels. In vivo data also indicate a role for HGF/SF and Met in tubule formation during liver and kidney regeneration and mammary gland formation. Activation of Met results in the recruitment of a myriad of signal transducers that regulate dissociation of adherens junctions and the stimulation of cellular motility, survival, proliferation and morphogenesis during tubule formation. Among these many signal transducers, the Gab1 adaptor protein and its effector, the SHP2 tyrosine phosphatase, have been found to be crucial for tubulogenesis and for the sustained stimulation of the ERK/MAP kinase pathway. Here, we discuss the contribution of these and other signaling pathways and the role of HGF/SF and Met in the formation of epithelial cell tubules both in vitro in branching-morphogenesis assays and in vivo during organogenesis.
December 7,2003 Evolving views of telomerase and cancer
  The maintenance of telomeres, nucleoprotein structures that constitute the ends of eukaryotic chromosomes, regulates many crucial cellular functions and might, in multicellular organisms, participate in the control of complex phenotypes such as aging and cancer. Stabilization of telomere length is strongly associated with cellular immortalization, and constitutive telomerase activation occurs in most human cancers. Such observations form the basis for the prevailing model that postulates that alterations in telomere biology both suppress and facilitate malignant transformation by regulating genomic stability and cell life span. However, recent findings suggest that telomere maintenance might not be an obligate requirement for initial tumor formation in some settings and that telomerase activation contributes to tumorigenesis independently of its role in maintaining telomere length. These recent developments indicate that our understanding of telomere biology remains incomplete and implicate additional complexity in the relationships among telomeres, telomerase and cancer.
December 6,2003 Influenza
  Although most influenza infections are self-limited, few other diseases exert such a huge toll of suffering and economic loss. Despite the importance of influenza, there had been, until recently, little advance in its control since amantadine was licensed almost 40 years ago. During the past decade, evidence has accrued on the protection afforded by inactivated vaccines and the safety and efficacy in children of live influenza-virus vaccines. There have been many new developments in vaccine technology. Moreover, work on viral neuraminidase has led to the licensing of potent selective antiviral drugs, and economic decision modelling provides further justification for annual vaccination and a framework for the use of neuraminidase inhibitors. Progress has also been made on developing near-patient testing for influenza that may assist individual diagnosis or the recognition of widespread virus circulation, and so optimise clinical management. Despite these advances, the occurrence of avian H5N1, H9N2, and H7N7 influenza in human beings and the rapid global spread of severe acute respiratory syndrome are reminders of our vulnerability to an emerging pandemic. The contrast between recent cases of H5N1 infection, associated with high mortality, and the typically mild, self-limiting nature of human infections with avian H7N7 and H9N2 influenza shows the gaps in our understanding of molecular correlates of pathogenicity and underlines the need for continuing international research into pandemic influenza. Improvements in animal and human surveillance, new approaches to vaccination, and increasing use of vaccines and antiviral drugs to combat annual influenza outbreaks are essential to reduce the global toll of pandemic and interpandemic influenza.
December 5,2003 From biological databases to platforms for biomedical discovery
  The use of high-throughput DNA sequencing and proteomic methods has led to an unprecedented increase in the amount of genomic and proteomic data. Application of computing technologies and development of computational tools to analyze and present these data has not kept pace with the accumulation of information. Here, we discuss the use of different database systems to store biological information and mention some of the key emerging computing technologies that are likely to have a key role in the future of bioinformatics.
December 4,2003 Synthetic gene libraries: in search of the optimal diversity
  Directed evolution has proven to be an effective method for evolving proteins with desired properties. A key step is the creation of suitably diverse gene libraries. Two new methods for creating such libraries make sole use of synthesized oligonucleotides and allow researchers to tailor the diversity of a library with greater precision and create libraries with greater diversity than was previously possible. Such increased diversity appears to accelerate directed evolution.
December 3,2003 Integrating Structure, Bioinformatics, and Enzymology to Discover Function
  Structural proteomics projects are generating threedimensional structures of novel, uncharacterized proteins at an increasing rate. However, structure alone is often insufficient to deduce the specific biochemical function of a protein. Here we determined the function for a protein using a strategy that integrates structural and bioinformatics data with parallel experimental screening for enzymatic activity. BioH is involved in biotin biosynthesis in Escherichia coli and had no previously known biochemical function. The crystal structure of BioH was determined at 1.7 ?resolution. An automated procedure was used to compare the structure of BioH with structural templates from a variety of different enzyme active sites. This screen identified a catalytic triad (Ser82, His235, and Asp207) with a configuration similar to that of the catalytic triad of hydrolases. Analysis of BioH with a panel of hydrolase assays revealed a carboxylesterase activity with a preference for short acyl chain substrates. The combined use of structural bioinformatics with experimental screens for detecting enzyme activity could greatly enhance the rate at which function is determined from structure.
December 2,2003 Genomic insulators: connecting properties to mechanism
  Insulators are regulatory elements that establish independent domains of transcriptional activity within eukaryotic genomes. Insulators possess two properties: an anti-enhancer activity that blocks enhancer–promoter communication, and an anti-silencer activity that prevents the spread of repressive chromatin. Some insulators are composite elements with separable activities, while others employ a single mechanism to confer both properties. Recent studies focus on elucidating the molecular mechanisms of insulator function. Emerging themes support connections between insulators, transcriptional activators and topological chromosomal domains. Understanding these processes will provide insights into prevention of inappropriate regulatory interactions, knowledge that can be applied to gene therapies.
December 1,2003 Chromatin remodeling and human disease
  In the past few years, there has been a nascent convergence of scientific understanding of inherited human diseases with epigenetics. Identified epigenetic processes involved in human disease include covalent DNA modifications, covalent histone modifications, and histone relocation. Each of these processes influences chromatin structure and thereby regulates gene expression and DNA methylation, replication, recombination, and repair. The importance of these processes for nearly all aspects of normal growth and development is illustrated by the array of multi-system disorders and neoplasias caused by their dysregulation.

November October September August July June May April March February January 2002 2001