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 2004 2003 2002 2001

January 31,2005 Control of smooth muscle development by the myocardin family of transcriptional coactivators
  Differentiation of smooth muscle cells (SMCs) is accompanied by the transcriptional activation of an array of muscle-specific genes that confer the unique contractile and physiologic properties of this muscle cell type. The majority of smooth muscle genes are controlled by serum response factor (SRF), a widely expressed transcription factor that also regulates genes involved in cell proliferation. Myocardin and myocardin-related transcription factors (MRTFs) interact with SRF and potently stimulate SRF-dependent transcription. Gain- and loss-of-function experiments have shown myocardin to be sufficient and necessary for SMC differentiation. SMCs are highly plastic and can switch between differentiated and proliferative states in response to extracellular cues. Suppression of SMC differentiation by growth factor signaling is mediated, at least in part, by the displacement of myocardin from SRF by growth factor-dependent ternary complex factors.
January 30,2005 A prehistory of cell adhesion
  Cell adhesion is a basic property of animal cells, but is also present in many other eukaryotes. Did cell adhesion systems arise independently in different eukaryotic groups, or do they share common origins? Recent results show that cell adhesion proteins related to cadherin, IgG-like CAM and C-type lectin are present both in sponges, the most distant animal branch, and in eukaryote groups outside the metazoan lineage, indicating that these forms of adhesion arose prior to animal evolution. Furthermore, proteins containing features of animal adhesion systems, such as Fas-1 and thrombospondin domains, are distributed throughout the eukaryotes and function in cell adhesion.
January 29,2005 Oncolytic viruses for the treatment of cancer: current strategies and clinical trials
  Tumor-selective replicating viruses offer appealing advantages over conventional cancer therapy and are a promising new approach for the treatment of human cancer. The development of virotherapeutics is based on several strategies that each provides a different foundation for tumor-selective targeting and replication. Results emerging from clinical trials with oncolytic viruses demonstrate the safety and feasibility of a virotherapeutic approach and provide early indications of efficacy. Strategies to overcome potential obstacles and challenges to virotherapy are currently being explored and are discussed here. Importantly, the successful development of systemic administration of oncolytic viruses will extend the range of tumors that can be treated using this novel treatment modality.
January 28,2005 Mathematical and computational techniques to deduce complex biochemical reaction mechanisms
  Time series data can now be routinely collected for biochemical reaction pathways,and recently,several methods have been proposed to infer reaction mechanisms for metabolic pathways and networks.In this paper we provide a survey of mathematical techniques for determining reaction mechanisms for time series data on the concentration or abundance of different reacting components,with little prior information about the pathways involved.
January 27,2005 GENE THERAPY FOR AUTOIMMUNE DISEASES: QUO VADIS?
  Biological therapies using antibodies and cytokines are becoming widespread for the treatment of chronic inflammatory autoimmune diseases. However, these treatments have several limitations — such as expense, the need for repeated injections and unwanted side-effects — that can be overcome by genetic delivery. This review summarizes the ingenuity, sophistication and variety of gene-therapy approaches that have been taken in the design of therapeutic molecules and vectors, the engineering of cells and the regulation of gene expression for the targeting of disease outcome. We focus our attention on multiple sclerosis, type 1 diabetes and rheumatoid arthritis.
January 26,2005 Genome-wide high-throughput screens in functional genomics
  The availability of complete genome sequences from many organisms has yielded the ability to perform high-throughput, genome-wide screens of gene function. Within the past year, rapid advances have been made towards this goal in many major model systems, including yeast, worms, flies, and mammals. Yeast genome-wide screens have taken advantage of libraries of deletion strains, but RNA-interference has been used in other organisms to knockdown gene function. Examples of recent large-scale functional genetic screens include drug-target identification in yeast, regulators of fat accumulation in worms, growth and viability in flies, and proteasome-mediated degradation in mammalian cells. Within the next five years, such screens are likely to lead to annotation of function of most genes across multiple organisms. Integration of such data with other genomic approaches will extend our understanding of cellular networks.
January 25,2005 Target discovery in metabolic disease
  The prevalence of metabolic diseases is taking on epidemic proportions and poses a serious threat to human health. Current treatment options have proven insufficient to cope with obesity and diabetes because they rarely restore normal metabolism and thus leave patients exposed to life-threatening complications. Successful management of these diseases depends on novel, improved therapeutic strategies targeting early intervention in disease progression. Discovery of novel metabolic disease targets has been hampered by the complexity of contributing environmental and genetic factors, as well as the need for potent but safe treatments suitable for chronic diseases. Genomic approaches are excellent tools to manage genetic complexity and have been applied successfully to identify candidate target genes that will lead to the development of novel therapies for metabolic diseases.
January 24,2005 THE RAF PROTEINS TAKE CENTRE STAGE
  Since their discovery over 20 years ago, the RAF proteins have been intensely studied. For most of that time, the focus of the field has been the C-RAF isoform and its role as an effector of the RAS proteins. However, a report that implicates B-RAF in human cancer has highlighted the importance of all members of this protein kinase family and recent studies have uncovered intriguing new data relating to their complex regulation and biological functions.
January 23,2005 Proteomic patterns for early cancer detection
  The advent of proteomics has brought with it the hope of discovering novel biomarkers that can be used to diagnose diseases, predict susceptibility, and monitor progression. Much of this effort has focused on the mass spectral identification of the thousands of proteins that populate complex biosystems such as serum and tissues. A revolutionary approach in proteomic pattern analysis has emerged as an effective method for the early diagnosis of diseases such as ovarian, breast, and prostate cancer. This technology is capable of analyzing hundreds of clinical samples per day and has the potential to be a novel, highly sensitive diagnostic tool for the early detection of diseases, or as a predictor of response to therapy.
January 22,2005 Protein folding in the cell: reshaping the folding funnel
  Models of protein folding have historically focused on a subset of ‘well-behaved’ proteins that can be success-fully refolded from denaturants in vitro. Energy land-scapes, including folding funnel ‘cartoons’, describe the largely uncomplicated folding of these isolated chains at infinite dilution. However, the frequent failure of many polypeptides to fold to their native state requires more comprehensive models of folding to accommodate the crucial role of interactions between partially folded intermediates. By incorporating additional deep minima, which reflect off-pathway interchain inter-actions, the folding funnel concept can be extended to describe the behavior of a more diverse set of proteins under more physiologically relevant conditions. In particular, the effects of ribosomes (translation), mol-ecular chaperones and other aspects of the cellular environment on early chain conformations can be included to account for the folding behavior of poly-peptide chains in cells.
January 21,2005 Progress and challenges in profiling the dynamics of chromatin and transcription factor binding with DNA microarrays
  ChIP-chip, or chromatin immunoprecipitation followed by DNA microarray analysis, has proven to be an efficient means of mapping protein-genome interactions. Recent experiments using this tool are beginning to reveal the complex dynamics of transcription factor binding and chromatin organization, and how these processes interact with each other to generate a cellular response to environmental and developmental cues. Data derived from this approach, particularly data involving chromatin components and histone modifications, might be affected by assumptions underlying the procedure, and the data might be made more useful by adoption of standardized whole-genome microarray platforms.
January 20,2005 Pharmaceutical approaches to the treatment of obesity
  The recent increase in pharmaceutical companies’ efforts toward the treatment of obesity reflects recognition of the related health risks, the growth of knowledge about mechanisms that control energy balance, and the potential market for new compounds. The current patent literature gives a picture of the targets that are available for pharmaceutical intervention; these include signals of satiety and signals related to fat storage that act in the hypothalamus. The regulation of energy use and storage in adipocytes and the reduction of intestinal absorption of energy are also pharmaceutical focus areas. The multiplicity of targets illustrates not only the many potential approaches to the treatment of obesity but also the complexity and redundancy of the processes that regulate energy storage in the body.
January 19,2005 Chymase as a novel target for the prevention of vascular diseases
  In vascular tissues, chymase catalyzes the production of angiotensin II, which plays a crucial role in vascular diseases. Recent clinical studies and animal models of vascular proliferation and atherosclerosis have provided evidence that angiotensin II formed by chymase is involved in these processes. These observations suggest that chymase might promote the development of vascular proliferation and atherosclerosis. Chymase also activates matrix metalloproteinase 9, which pro-motes aortic aneurysm and angiogenesis, and thus chymase inhibitors might also prevent the progression of abdominal aortic aneurysm and angiogenesis. We propose that chymase is a novel target for preventing vascular diseases.
January 18,2005 RNA-interference-based functional genomics in mammalian cells
  Sequencing of complete genomes has provided researchers with wealth of information to study genome organiza- tion,genetic instability,and polymorphisms,s well as knowledge of all potentially expressed genes.The identi cation of all genes encoded in the human genome opens the door for large-scale systematic gene silencing using small interfering RNAs (siRNAs)and short hairpin RNAs (shRNAs).With the recent development of siRNA and shRNA expression libraries,the application of RNAi technology to assign function to cancer genes and to delineate molecular pathways in which these genes affect in normal and transformed cells,will contribute signi - cantly to the knowledge necessary to develop new and also improve existing cancer therapy.
January 17,2005 14-3-3 Proteins—a focus on cancer and human disease
  14-3-3 Proteins are a ubiquitous family of molecules that participate in protein kinase signaling pathways within all eukaryotic cells. Functioning as phosphoserine/phosphothreonine-binding modules, 14-3-3 proteins participate in phosphorylation-dependent protein–protein interactions that control progression through the cell cycle, initiation and maintenance of DNA damage checkpoints, activation of MAP kinases, prevention of apoptosis, and coordination of integrin signaling and cytoskeletal dynamics. In this review, we discuss the regulation of 14-3-3 structure and ligand binding, with a focus on the role of 14-3-3 proteins in human disease, particularly cancer.
January 16,2005 Labeling neurons in vivo for morphological and functional studies
  Increasingly sophisticated strategies for labeling cells in vivo are providing unprecedented opportunities to study neurons in living animals. Transgenic expression of genetically encoded reporters enables us to monitor changes in neuronal activity in response to sensory stimuli, and the labeling of single neurons with fluorescent proteins allows the dynamics of neuronal connectivity to be observed in transgenic animals over periods ranging from minutes to months. Advances in transient labeling techniques such as viral infection and electroporation provide a rapid means by which to analyze neuronal gene function in vivo. These new approaches to labeling, manipulating and imaging neurons in intact organisms are transforming the way in which the nervous system is studied.
January 15,2005 Therapeutic Antibody Gene Transfer
  Advances in gene transfer approaches are enabling the possibility of applying therapeutic antibodies using DNA. In particular gene transfer in combination with electroporation is promising and can result in generating in vivo antibody concentrations in the low therapeutic range. However, several important problems need to be dealt with before antibody gene transfer can become a valuable supplement to the current therapies. As antibody production following gene transfer is difficult to control, the danger of inducing autoimmune conditions or uncontrollable side effects occurs in cases in which autologous antigens are targeted. It is suggested that the most promising area of application therefore appears to be infectious disease in which heterologous antigens are targeted and concerns for long-term antibody exposure are minimal.
January 14,2005 EPIGENETICS AND HUMAN DISEASE
  Epigenetics is comprised of the stable and heritable (or potentially heritable) changes in gene expression that do not entail a change in DNA sequence. The role of epigenetics in the etiology of human disease is increasingly recognized with the most obvious evidence found for genes subject to genomic imprinting. Mu-tations and epimutations in imprinted genes can give rise to genetic and epigenetic phenotypes, respectively; uniparental disomy and imprinting defects represent epi-genetic disease phenotypes. There are also genetic disorders that affect chromatin structure and remodeling. These disorders can affect chromatin in trans or in cis,as well as expression of both imprinted and nonimprinted genes.
January 13,2005 Biology of LPA in health and disease
  The functions of lysophosphatidic acid (LPA) can be broadly divided into two classes: (1) physiological and (2) pathological roles. The role of LPA in embryonic development can be seen as early as oocyte formation. It continues in postnatal homeostasis, through its ability to impart a level of protection from both stress and local injury, by regulating cellular proliferation, apoptosis, and the reorganization of cytoskeletal fibers. LPA may function as a double-edged sword. While it helps maintain homeostasis against stress and insult, it may also augment the development and spread of pathological processes, including cancers.
January 12,2005 CONNEXINS AND CELL SIGNALING IN DEVELOPMENT AND DISEASE
  Gap junctions contain hydrophilic membrane channels that allow di-rect communication between neighboring cells through the diffusion of ions, metabo-lites, and small cell signaling molecules. They are made up of a hexameric array of polypeptides encoded by the connexin multi-gene family. Cell-cell communication me-diated by connexins is crucial to various cellular functions, including the regulation of cell growth, differentiation, and development. Mutations in connexin genes have been linked to a variety of human diseases, including cardiovascular anomalies, peripheral neuropathy, deafness, skin disorders, and cataracts. In addition to their coupling func-tion, recent studies suggest that connexin proteins may also mediate signaling.
January 11,2005 Sindbis virus – an effective targeted cancer therapeutic
  Viral therapies for cancer therapy have many potential positive attributes. These include the ability to specifi-cally infect targeted cells, specifically express toxic or immune-enhancing genes, and the ability to specifically replicate within a tumor cell. Despite these biological advantages, efficacy to date has been limited. A recent report demonstrates that the Sindbis virus has remark-able properties in three challenging areas of gene therapy – specificity, efficacy and delivery, suggesting that Sindbis has the potential to become an important gene therapy vector for cancer therapy.
January 10,2005 Platelets: signaling cells in the immune continuum
  Platelets have intricate signaling mechanisms and participate in a breadth of cellular interactions. This diversity is frequently unrecognized. In addition to being the chief cellular effectors of haemostasis, platelets are innate inflammatory cells that have previously unrecog-nized molecular pathways and synthetic capacities, which can link innate and adaptive responses in the immune continuum. Characterization of these features and parallel in vivo observations identify new sentinel, surveillance and information-transfer functions. Recent observations indicate that platelets have key roles in adaptive responses to microbial and antigen challenge, in addition to their well known acute defensive activities in tissue injury, and suggest that these mechanisms can be dysregulated in disease. Ongoing characterization of the platelet transcriptome, secretome and proteome also suggest that additional functions of platelets relevant to innate and adaptive immunity remain to be discovered.
January 9,2005 MAMMALIAN CIRCADIAN BIOLOGY: Elucidating Genome-Wide Levels of Temporal Organization
  During the past decade, the molecular mechanisms underlying the mammalian circadian clock have been defined. A core set of circadian clock genes common to most cells throughout the body code for proteins that feed back to regulate not only their own expression, but also that of clock output genes and pathways throughout the genome. The circadian system represents a complex multioscillatory temporal network in which an ensemble of coupled neurons comprising the principal circadian pacemaker in the suprachiasmatic nucleus of the hypothalamus is entrained to the daily light/dark cycle and subsequently transmits synchronizing signals to local circadian oscillators in peripheral tissues.
January 8,2005 Oncology studies using siRNA libraries
  High-throughput,human cell-based applications of RNA- mediated interference (RNAi)have emerged in recent years as perhaps the most powerful of a ‘second wave ’of functional genomics technologies.The available reagents and methodologies for RNAi screening studies now enable a wide range of different scopes and scales of investiga- tion,from single-parameter assays applied to focused subsets of genes,to comprehensive genome-wide surveys based on rich,multiparameter readouts.As such,RNAi- based screens are offering important new avenues for the discovery and validation of novel therapeutic targets for several disease areas,including oncology.By enabling a ‘clean ’determination of gene function,that is the creation of direct causal links between gene and phenotype in human cells,RNAi investigations promise levels of pathophysiological relevance,ef ciency,and range of applicability never befor possible on this scale.
January 7,2005 Hierarchical thinking in network biology
  As reconstructed biochemical reaction networks con-tinue to grow in size and scope, there is a growing need to describe the functional modules within them. Such modules facilitate the study of biological processes by deconstructing complex biological networks into con-ceptually simple entities. The definition of network modules is often based on intuitive reasoning. As an alternative, methods are being developed for defining biochemical network modules in an unbiased fashion. These unbiased network modules are mathematically derived from the structure of the whole network under consideration.
January 6,2005 Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs
  RNA interference (RNAi) holds considerable promise as a therapeutic approach to silence disease-causing genes, particularly those that encode so-called ‘non-druggable’ targets that are not amenable to conventional therapeutics such as small molecules, proteins, or monoclonal antibodies. The main obstacle to achieving in vivo gene silencing by RNAi technologies is delivery. Here we show that chemically modified short interfering RNAs (siRNAs) can silence an endogenous gene encoding apolipoprotein B (apoB) after intravenous injection in mice. Administration of chemically modified siRNAs resulted in silencing of the apoB messenger RNA in liver and jejunum, decreased plasma levels of apoB protein, and reduced total cholesterol. We also show that these siRNAs can silence human apoB in a transgenic mouse model.
January 5,2005 Exploring the post-transcriptional RNA world with DNA microarrays
  Genomic approaches are valuable for understanding the complex layer of gene regulation that involves the control of RNA processing, localization and stability. Recent work provides a prime example of the power of unbiased microarray-based methods to discover unexpected func-tions for proteins in the RNA world. The challenges ahead relate to extending such approaches to larger genomes and to integrating this type of information with that generated by standard expression profiling.
January 4,2005 Initiation of autoimmunity
  It has recently become clear that several factors must coincide for the initiation of autoimmunity. At minimum, these involve a genetic predisposition, nave lymphocytes that can react with autoantigens and a precipitating event that leads to T and/or B cell activation. Inter-individual variations in these factors probably explain the significant complexity associated with autoimmune diseases; however, quantitative issues are also important because clinical disease will manifest only if a sufficient amount of cellular material has been destroyed. Therefore, the presence of autoreactive lymphocytes does not always signify disease; rather, the kinetics of their generation, their resulting numbers and the regulation of their activation and effector functions (destructive versus regulatory) will determine the ultimate outcome and make the difference between subclinical autoimmunity and disease.
January 3,2005 Bringing the role of mRNA decay in the control of gene expression into focus
  The process of mRNA decay is integral to the post-transcriptional control of gene expression. The enzymes of the pathway have been identified, and now several laboratories have found that the mRNA decay machin-ery is localized to discrete cytoplasmic foci whose existence had not been suspected previously. In addition, we can now see that mRNA turnover is a means to coordinate gene expression, first through integration with control of transcription, export and translation of mRNAs, and second through enabling mRNAs involved in similar processes to decay at similar rates. These and other aspects of the field are discussed.
January 2,2005 Blood and endothelium in immune complex-mediated tissue injury
  Antigen–antibody complexes can be formed both intra-vascularly and perivascularly and damage tissues by inducing inflammatory mechanisms. Recent studies have characterized a definite sequence of steps involved in these inflammatory mechanisms, and identified the predominance of particular chemical mediator(s) in each step. The lesions associated with this type of inflam-mation are characterized by the early development of plasma leakage, followed by the recruitment of poly-morphonuclear leukocytes mediated by chemokines generated by FcgR-dependent mechanisms. The deve-lopment of these lesions is modulated by endothelial cell-derived paracrine mediators, and activation of the coagulation system can ensue. The activation of plate-lets and coagulation, if not properly counterbalanced by fibrinolysis, might be a major factor for the late development of fibrotic changes and organ remodeling.
January 1,2005 NUCLEAR RECEPTORS IN MACROPHAGE BIOLOGY
  Macrophages are essential modulators of lipid metabolism and the in-nate immune system. Lipid and inflammatory pathways induced in activated macro-phages are central to the pathogenesis of human diseases including atherosclerosis. Recent work has shown that expression of genes involved in lipid uptake and choles-terol efflux in macrophages is controlled by peroxisome proliferator-activated receptors (PPARs) and liver Xreceptors (LXRs). Other studies have implicated these same recep-tors in the modulation of macrophage inflammatory gene expression. Together, these observations position PPARs and LXRs at the crossroads of lipid metabolism and in-flammation and suggest that these receptors may serve to integrate these pathways in the control of macrophage gene expression.

2004 2003 2002 2001