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 January 2004 2003 2002 2001

February 28,2005 Crosslinks and crosstalk: Human cancer syndromes and DNA repair defects
  A subset of human cancer syndromes result from inherited defects in genes responsible for DNA repair. During the past few years, discoveries concerning the intersection of certain DNA repair processes have increased our understanding of how the disruption of specific DNA repair mechanisms leads to genomic instability and tumorigenesis. This review focuses on the human genes MUTYH, BRCA2/FANCD1, and BLM.
February 27,2005 Applying a new generation of genetic maps to understand human inflammatory disease
  The sequencing of the human genome and the intense study of its variation in different human populations have improved our understanding of the genome’s architecture. It is now becoming clear that segments of the genome that are unbroken by reshuffling or recombination during meiosis create a mosaic of DNA ‘haplotype blocks’. Here, we discuss the advantages and limitations of this block structure. Haplotype blocks hold the promise of reducing the complexity of analysing the human genome for association with disease. But can they deliver on this promise? First generation maps of these block patterns, such as the admixture and haplotype maps, are now emerging and, it is to be hoped, will accelerate the discovery of alleles that contribute to susceptibility to human inflammatory diseases.
February 26,2005 APPLICATION OF MICROBIAL GENOMIC SCIENCE TO ADVANCED THERAPEUTICS
  Since the publication of the first complete microbial genome sequence of Haemophilus influenzae in 1995, more than 200 additional microbial genome se-quences have become available in the public domain. Approximately 40% of these represent important human pathogens. Comparative in silico methods, along with large-scale approaches such as transcriptomics and proteomics, are beginning to reveal insights into new virulence genes, pathogen-host interactions, and the molecular basis of host specificity. Sequence data are also starting to accumulate from multiple isolates or strains of a single pathogen, and this type of data has proven to be quite valuable in providing new insights into the genetic variability that is present in a particular species as well as in facilitating correlations between genotype and phenotype.
February 25,2005 Genetics of Variation in HDL Cholesterol in Humans and Mice
  Plasma high-density lipoprotein cholesterol (HDL-C) concentrations are genetically determined to a great extent, and quantitative trait locus (QTL) analysis has been used to identify chromosomal regions containing genes regulating HDL-C levels. We discuss new genes found to participate in HDL metabolism. We also summarize 37 mouse and 30 human QTLs for plasma HDL-C levels, finding that all but three of the mouse QTLs have been confirmed by a second cross or a homologous human QTL, that the mouse QTL map is almost saturated because 92% of recently reported QTLs are repeats of those already found, and that 28 of the 30 human QTLs are located in regions homologous to mouse QTLs. This high degree of concordance between mouse and human QTLs suggests that the underlying genes may be the same.
February 24,2005 SIGNALING NETWORKS IN LIVING CELLS
  Recent advances in cell signaling research suggest that multiple sets of signal transducing molecules are preorganized and sequestered in distinct compart-ments within the cell. These compartments are assembled and maintained by specific cellular machinery. The molecular ecology within a compartment creates an environ-ment that favors the efficient and accurate integration of signaling information arriving from humoral, mechanical, and nutritional sources. The functional organization of these compartments suggests they are the location of signaling networks that naturally organize into hierarchical interconnected sets of molecules through their participa-tion in different classes of interacting units.
February 23,2005 RNA POLYMERASES I AND III, GROWTH CONTROL AND CANCER
  Transcription of rRNA and tRNA genes by RNA polymerases I and III is essential for sustained protein synthesis and is therefore a fundamental determinant of the capacity of a cell to grow. When cell growth is not required, this transcription is repressed by retinoblastoma protein, p53 and ARF. However, inactivation of these tumour suppressors in cancers deregulates RNA polymerases I and III, and oncoproteins such as Myc can stimulate these systems further. Such events might have a significant impact on the growth potential of tumours.
February 22,2005 Integrative Genomics:In Silico Coupling of Rat Physiology and Complex Traits With Mouse and Human Data
  Integration of the large variety of genome maps from several organisms provides the mechanism by which physiological knowledge obtained in model systems such as the rat can be projected onto the human genome to further the research on human disease.The release of the rat genome sequence provides new information for studies using the rat model and is a key reference against which existing and new rat physiological results can be aligned. Previously,we described comparative maps of the rat,mouse,and human based on EST sequence comparisons combined with radiation hybrid maps.Here,we use new data and introduce the Integrated Genomics Environment, an extensive database of curated and integrated maps,markers,and physiological results.
February 21,2005 Plant and animal stem cells: conceptually similar, molecularly distinct?
  Animals and plants maintain small pools of stem cells that continuously provide the precursors of more-specialized cells to sustain growth or to replace tissues. A comparison of plant and animal stem cells can highlight core aspects of stem-cell biology. In both types of organism, stem cells are maintained by intercellular signals that are available only in defined regions (niches) in the tissues. Although plants use different signals and are more flexible at establishing stem-cell niches in new locations, recent evidence suggests that the mechanisms restricting cell fate in stem-cell progeny are similar in both kingdoms and might pre-date the evolution of multicellular organisms.
February 20,2005 High-throughput cell-free systems for synthesis of functionally active proteins
  Continuous cell-free translation systems with perpetual supply of consumable substrates and removal of reac-tion products made the process of in vitro synthesis of individual proteins sustainable and productive. Improvements of cell-free reaction mixtures, including new ways for efficient energy generation, had an additional impact on progress in cell-free protein synthesis technology. The requirement for gene-product identification in genomic studies, the development of high-throughput structural proteomics, the need for protein engineering without cell constraints (including the use of unnatural amino acids), and the need to produce cytotoxic, poorly expressed and unstable proteins have caused increased interest in cell-free protein synthesis technologies for molecular biologists, biotechnologists and pharmacologists.
February 19,2005 Karyopherins: from nuclear-transport mediators to nuclear-function regulators
  The karyopherin β (or importin β) family comprises soluble transport factors that mediate the movement of proteins and RNAs between the nucleus and cytoplasm. Recent studies have extended the role of karyopherins to regulating assembly of the nuclear pore complex (NPC), assembly of the nuclear envelope, mitosis and replication. New data also address how karyopherins specifically recognize and transport many distinct cargoes and traverse the NPC. These data raise the possibility that, although there might be a universal mechanism for nuclear transport, specific interactions between karyopherins and components of the NPC might function to regulate differentially the ability of the different karyopherins to cross the NPC.
February 18,2005 Insights into Programmed Cell Death through Structural Biology
  Programmed cell death plays a critical role in controlling the number of cells in development and throughout an organism’s life by the removal of cells at the appropriate time. It is an important biological process for the elimination of unwanted cells such as those with potentially harmful genomic mutations, autoreactive lymphocytes, or virally infected cells. Alterations of this normal process can result in the disruption of the delicate balance between cell proliferation and cell death and can lead to a variety of diseases (Thompson, 1995). For example, in many forms of cancer, key proapoptotic proteins are mutated or antiapoptotic proteins are upregulated, leading to the accumulation of cells and the inability to respond to harmful mutations, DNA damage, or chemotherapeutic agents.
February 17,2005 Is JAK3 a new drug target for immunomodulation-based therapies?
  JAK3, a member of the Janus kinase family, has a crucial role in T-cell development and the homeostasis of the immune system because of its association with the common gamma chain (γc) of cytokine receptors. Disruption of either JAK3 or γc expression results in severe combined immunodeficiency disease. Thus, JAK3 has attracted significant attention in recent years as a target for therapeutic intervention in several immune-related diseases. Inhibitors of JAK3 have been developed that might act as either immunosuppressive agents in human organ transplantation or as immuno-modulators in autoimmune disorders. We propose that targeting JAK3 offers alternative avenues for the development of new immunomodulatory strategies of therapeutic value. Furthermore, we believe that in addition to the tyrosine kinase domain of JAK3, where inhibitor design efforts are currently focused, non-catalytic regions of JAK3 might represent candidate targets for future drugs.
February 16,2005 Interleukin-4 receptor signaling pathways in asthma pathogenesis
  Asthma is a chronic allergic inflammatory disease, the initiation and progression of which is dependent on the cytokines interleukin (IL)-4 and IL-13 acting through related receptor complexes. Disease pathogenesis is effected by intracellular signaling pathways that couple primarily to specific motifs within the intracellular domain of the IL-4 receptor α chain (IL-4Rα), a subunit that is common to the IL-4 and IL-13 receptor complexes. Recent studies using genetic approaches have identified distinct functions for the respective IL-4Rα-coupled signaling pathways in regulating both early and chronic stages of asthma. Polymorphisms in components of the IL-4 and IL-13 cytokine-receptor axes are associated with allergy and asthma, suggesting that variations among individuals in the activity of this pathway contribute to disease susceptibility and manifestations.
February 15,2005 Update on human α1 -adrenoceptor subtype signaling and genomic organization
  α1-Adrenoceptors are G-protein-coupled receptors that bind catecholamines. Sixteen distinct human α1A -adrenoceptor isoforms have been identified from human tissues, including five full-length and 11 trun-cated versions. An updated scheme for the identification of α1A -adrenoceptor splice variants is proposed. Given the established roles of α1 -adrenoceptors in benign prostatic hyperplasia, myocardial hypertrophy and other cardiovascular disorders, elucidation of the bio-logical significance of the signaling diversity and potential pharmacological roles of α1A -adrenoceptor splice variants are important areas of future research.
February 14,2005 Experimental Autoimmune Diabetes: A New Tool to Study Mechanisms and Consequences of Insulin-Specific Autoimmunity
  (Prepro)insulin is considered a central antigenic determinant in diabetic autoimmunity. Insulin has been used to modify diabetes development in NOD mice and prediabetic individuals. We have recently shown that (prepro)insulin can adversely promote diabetes development in murine type 1 diabetes. Based on these findings we have developed experimental autoimmune diabetes (EAD), a new mouse model characterized by (1) CD4+/CD8+ insulitis, induced by (2) (prepro)insulin DNA vaccination, leading to (3) beta cell damage and insulin deficiency in (4) RIP-B7.1 transgenic mice (H-2b). EAD develops rapidly in 60–95% of mice after intramuscular, but not intradermal (“gene gun”), vaccination; and DNA plasmids expressing insulin or the insulin analogues glargine, aspart, and lispro are equally potent to induce EAD.
February 13,2005 Use of Anti-CD3 Monoclonal Antibody to Induce Immune Regulation in Type 1 Diabetes
  Achieving immunologic tolerance to autoimmune diabetes is the goal of therapies for treatment and prevention of the disease. However, whether this can be achieved with an antigen-specific approach is still unproven in humans. Other approaches, including treatment with anti-CD3 monoclonal antibody, have focused on regulation of an active immune response. Preclinical studies with anti-CD3 mAb showed the ability to reverse diabetes and induce tolerance to autoimmunity, even at the time of presentation with hyperglycemia. These studies also suggested that mAb treatment induced an active regulatory process. Based on these and other preclinical data, we have carried out a Phase I/II trial of the humanized FcR non-binding anti-CD3 mAb hOKT3γ1(Ala-Ala) in patients with new-onset type 1 diabetes.
February 12,2005 The Power of an Integrated Informatic and Molecular Approach to Type 1 Diabetes Research
  Recent years have witnessed an explosive growth in available biological data. This includes a tremendous quantity of sequence data (e.g., biological structures, genetic and physical maps, pathways) generated by genome and transcriptome projects focused on humans, mice, and a multitude of other species. Diabetes research stands to greatly benefit from this data, which is distributed across public and private databases and the scientific literature. The increasing quantity and complexity of this biological data necessitates use of novel bioinformatics strategies for its efficient retrieval, analysis, and interpretation. Bioinformatic capability is becoming increasingly indispensable for fast and comprehensive analysis of biological data by diabetes researchers.
February 11,2005 APOPTOSIS AND GENOMIC INSTABILITY
  Genomic instability is intrinsically linked to significant alterations in apoptosis control. Chromosomal and microsatellite instability can cause the inactivation of pro-apoptotic pathways. In addition, the inhibition of apoptosis itself can be permissive for the survival and ongoing division of cells that have failed to repair DNA double-strand breaks, experience telomere dysfunction or are in an abnormal polyploid state. Furthermore, DNA-repair proteins can regulate apoptosis. So, genomic instability and apoptosis are intimately linked phenomena, with important implications for the pathophysiology of cancer.
February 10,2005 Coronary Vessel Development
  Coronary artery disease accounts for 54% of all cardiovascular disease in the United States. Understanding how coronary vessels develop is likely to uncover novel drug targets and therapeutic strategies that will be useful in directing the repair or remodeling of coronary vessels in adults. Recent insights have identified the importance of cells derived from the proepicardium and epicardium in the formation of coronary vessels. This article reviews the basic steps in coronary vessel develop-ment, the molecules implicated in these steps, and the pressing ques-tions awaiting answers.
February 9,2005 CELLULAR LENGTH CONTROL SYSTEMS
  The problem of organelle size control can be addressed most simply by considering cellular structures that are linear, so that their size can be defined by a single parameter: length. We compare existing studies on several linear biological structures including prokaryotic flagella and flagellar hooks, eukaryotic flagella, sarcomere thin filaments, and microvilli. In some cases, existing evidence strongly supports the idea that length control involves a molecular ruler, in which the size of the overall structure is compared with the size of an individual molecule. In other cases, length control is likely to involve a steady-state balance of assembly and disassembly, in which one or the other rate is inherently length dependent.
February 8,2005 Common logic of transcription factor and microRNA action
  Over the past few years, microRNAs (miRNAs) have emerged as abundant regulators of gene expression. Like many transcription factors (TFs), miRNAs are important determinants of cellular fate specification. Here I provide a conceptual framework for miRNA action in the context of creating cellular diversity in a develop-ing organism, and emphasize the conceptual similarity of TF- and miRNA-mediated control of gene expression. Both TFs and miRNAs are trans-acting factors that exert their activity through composite cis-regulatory elements that are ‘hard-wired’ into DNA or RNA. TFs and miRNAs act in a largely combinatorial manner – that is, many different TFs or miRNAs control one gene – and they act cooperatively on their targets – that is, there are several cis-regulatory elements for a single TF or miRNA species in a target gene.
February 7,2005 Regulation of exocytosis in neurons and neuroendocrine cells
  Neurons communicate with one another through the release of molecules from synaptic vesicles and large dense core granules through the process of exocytosis. During exocytosis, molecules are released to the extracellular space through a fusion pore, which can either dilate, resulting in full fusion, or close, resulting in incomplete exocytosis, often referred to as ‘kiss and run’ exocytosis. Recently, there has been much interest in the regulation of this process in both neurons and neuroendocrine cells. There has been much recent work that addresses the existence of incomplete exocytosis in neurons and neuroendocrine cells, as well as recent work probing the molecular components and modulation of the fusion pore.
February 6,2005 Homeostasis and T cell regulation
  Homeostatic regulation of cell numbers is an important principle in biology. Mechanisms that function to maintain or re-establish homeostasis in the immune system include interactions among antigen-presenting cells, regulatory T cells and cytokines. The vital role that homeostatic regulation plays in maintaining a functionally intact immune system is illustrated by the perturbation of the peripheral T cell repertoire that occurs after lymphopenic incidents, which frequently provoke either exacerbated immune or autoimmune responses. Recent studies show that transient states of lymphopenia occur in viral infections and in the neonatal state and might be involved in the development of autoimmune diseases. On the positive side, lymphopenia-provoked T cell expansion might enhance weak immune responses and thereby aid the rejection of tumours or the elimination of parasites.
February 5,2005 Start-up entities in the origin of new genes
  The remarkable diversity in the contents of genomes raises questions about how new genes and new functions originate. Recent evidence indicates that parasitism, particularly the molecular interactions between phage and their bacterial hosts, is a likely mechanism for generating new genes. This invention of such novel functions seems to be founded on a strategy that secures the short-term survival of parasitic elements and thereby contributes to the renovation of gene repertoires in their host.
February 4,2005 The role of the AT1 angiotensin receptor in cardiac hypertrophy
  Activation of the AT1 angiotensin receptor is a clinically important maladaptive response during cardiac hyper-trophy. Autocrine and paracrine effects of locally generated angiotensin II, are believed to be the main mediators of these responses. However, a recent report has suggested that mechanical stress can activate AT1 receptors independently of angiotensin II generation. This finding, as well as recent studies on intracrine effects and the pharmacological consequences of recep-tor hetero-oligomerization, suggest that unexpected mechanisms could contribute to the role of the renin– angiotensin system during cardiac hypertrophy.
February 3,2005 CELL SIGNALLING AND THE CONTROL OF PRE-mRNA SPLICING
  The transcripts of most metazoan protein-coding genes are alternatively spliced, but the mechanisms that are involved in the control of splicing are not well understood. Recent evidence supports the potential of both extra- and intracellular signalling to the splicing machinery as a means of regulating gene expression, and indicates that this form of gene control is widespread and mechanistically complex. However, important questions about these pathways need to be answered before this method of post-transcriptional regulation can be fully appreciated.
February 2,2005 Implications of apoptosis regulators in tumorigenesis
  The process of cell loss and cell gain is homeostatically balanced in order to not only generate and maintain the complex dynamic architecture of tissues,but also to allow adaptation to changing circumstances. Tumor cells survive only by virtue of mutations that allow them to proliferate and to evade death signals.In fact,defects in the programd cell death inducing pathways contribute to neoplastic transformation, progression and metastasis by creating a permissive environment for genetic instability and accumulation of gene mutation.Resistance to apoptosis can also enhance the escape to tumor cells from surveillance by the immune system.Moreover,because chemotherapy and irradiation act mostly by inducing apoptosis, dysregulation in the apoptostic pathway can make cancer cells resistant to therapy.
February 1,2005 Beginnings of a signal-transduction pathway for bioenergetic control of cell survival
  Two integral components of cellular transformation are increased cellular metabolism and apoptotic resistance. Recent progress in understanding the cellular functions of core apoptotic components and of growth factor-induced apoptotic regulatory proteins has indicated that the control of cellular metabolism and apoptosis are intertwined. There is growing evidence for connections between the regulation of both cellular bioenergetics and apoptosis and, thus, it is intriguing to explore the idea that growth factor regulation of cellular metab-olism can directly affect cell survival.

January 2004 2003 2002 2001