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 August July June May April March February January 2003 2002 2001

September 30,2004 RAGs AND REGULATION OF AUTOANTIBODIES
  Autoreactive antibodies are etiologic agents in a number of autoimmune diseases. Like all other antibodies these antibodies are produced in developing B cells by V(D)J recombination in the bone marrow. Three mechanisms regulate autoreactive B cells: deletion, receptor editing, and anergy. Here we review the prevalence of autoantibodies in the initial antibody repertoire, their regulation by receptor editing, and the role of the recombinase proteins (RAG1 and RAG2) in this process.
September 29,2004 Pancreatic β-cell growth and survival in the onset of type 2 diabetes
  The control of pancreatic β-cell growth and survival in the adult plays a pivotal role in the pathogenesis of type 2 diabetes. In certain insulin-resistant states, such as obesity, the increased insulin-secretory demand can often be compensated for by an increase in β-cell mass, so that the onset of type 2 diabetes is avoided. This is why approximately two-thirds of obese individuals do not progress to type 2 diabetes. However, the remaining one-third of obese subjects that do acquire type 2 diabetes do so because they have inadequate compensatory β-cell mass and function. As such, type 2 diabetes is a disease of insulin insufficiency.
September 28,2004 The PARP superfamily
  Poly(ADP-ribosyl)ation is an immediate DNA-damagedependent post-translational modification of histones and other nuclear proteins that contributes to the survival of injured proliferating cells. Poly(ADP-ribose) polymerases (PARPs) now constitute a large family of 18 proteins, encoded by different genes and displaying a conserved catalytic domain in which PARP-1 (113 kDa), the founding member, and PARP-2 (62 kDa) are so far the sole enzymes whose catalytic activity has been shown to be immediately stimulated by DNA strand breaks. A large repertoire of sequences encoding novel PARPs now extends considerably the field of poly(ADP-ribosyl)ation reactions to various aspects of the cell biology including cell proliferation and cell death.
September 27,2004 Stem Cells and Cancer: The Polycomb Connection
  Proteins from the Polycomb group (PcG) are epigenetic chromatin modifiers involved in cancer develop- ment and also in the maintenance of embryonic and adult stem cells. The therapeutic potential of stem cells and the growing conviction that tumors contain stem cells highlights the importance of understanding the extrinsic and intrinsic circuitry controlling stem cell fate and their connections to cancer.
September 26,2004 PROTEIN MODIFICATION BY SUMO
  Small ubiquitin-related modifier (SUMO) family proteins function by becoming covalently attached to other proteins as post-translational modifications. SUMO modifies many proteins that participate in diverse cellular processes, including transcriptional regulation, nuclear transport, maintenance of genome integrity, and signal transduction. Reversible attachment of SUMO is controlled by an enzyme pathway that is analogous to the ubiquitin pathway. The functional consequences of SUMO attachment vary greatly from substrate to substrate, and in many cases are not understood at the molecular level.
September 25,2004 International policy failures
  In late 2003, two international bodies were unable to resolve disagreements that involved bioethical issues. First, the United Nations General Assembly failed to pass a treaty on reproductive cloning because of insistence by some countries that the treaty include a ban on cloning for research. In view of the importance of enacting prohibition of reproductive cloning, the two issues should be separated and each argued on its own merits. Relevant objections to separation of the two issues can be refuted. Second, the European Union (EU) failed to agree on conditions for funding stem-cell research because of the diversity of views and policies of the countries of the EU.
September 24,2004 Scaffolding and docking proteins of the heart, an introduction
  The force of cardiac contraction is subject to moment by moment regulation—as a result of changes in preload and afterload, and as a result of neuroendocrine regulation, e.g. by the actions of norepinephrine, angiotensin, cytokines and other circulating factors. These fluctuating changes in the environment of the cardiac myocytes need to be faithfully transduced to cause altered function of a set of proteins within the cell. In order to minimize delays due to diffusion, efficient signaling requires a mechanism of rapid on-and-off switching of the signal within a defined subcellular microdomain. This requirement has been most clearly illustrated for regulation of ion channel function which occurs on a millisecond time scale.
September 23,2004 THE CO-WORKERS OF ACTIN FILAMENTS
  Cells have various surface architectures, which allow them to carry out different specialized functions. Actin microfilaments that are associated with the plasma membrane are important for generating these cell-surface specializations, and also provide the driving force for remodelling cell morphology and triggering new cell behaviour when the environment is modified. This phenomenon is achieved through a tight coupling between cell structure and signal transduction, a process that is modulated by the regulation of actin-binding proteins.
September 22,2004 THE THREE ES OF CANCER IMMUNOEDITING
  After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models—together with compelling data from human patients— indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed “cancer immunoediting.”
September 21,2004 BioPD: a web-based information center for bioactive peptides
  Bioactive peptide database (BioPD) is a web-based knowledge base that contains more than 1100 protein sequences from human, mouse and rat, which are putative or are known to be bioactive peptides. In addition to peptide sequences and the annotation, the database also contains gene sequences with annotation, protein interaction and disease data related to the peptides. Each entry has as many references as possible to support the information represented. BioPD consists of six parts: PROTEIN, GENE, DISEASE, LINKS, INTERACTION, and REFERENCE. The database is searchable through keyword, gene and protein name, receptor name, etc. The links to PDB, InterPro, Pfam, OMIM, etc. are provided in each entry.
September 20,2004 Protein kinase C and beyond
  Protein kinase C molecules regulate both positive and negative signal transduction pathways essential for the initiation and homeostasis of immune responses. There are multiple isoforms of protein kinase C that are activated differently by calcium and diacylglycerol, and these are activated mainly by antigen receptors in T cells, B cells and mast cells. Additionally, mammals express several other diacylglycerol binding proteins that are linked to a network of key signal transduction pathways that control lymphocyte biology. Diacylglycerol and protein kinase C regulate a broad range of gene transcription programs but also modulate integrins, chemokine responses and antigen receptors, thereby regulating lymphocyte adhesion, migration, differentiation and proliferation.
September 19,2004 Redox signaling
  Except for the role of NO in the activation of guanylate cyclase, which is well established, the involvement of reactive oxygen species (ROS) and reactive nitrogen species (RNS) in signal transduction remains controversial, despite a large body of evidence suggestive of their participation in a variety of signaling pathways. Several problems have limited their acceptance as signaling molecules, with the major one being the difficulty in identifying the specific targets for each pathway and the chemical reactions supporting reversible oxidation of these signaling components, consistent with a second messenger role for ROS and RNS.
September 18,2004 CYTOSKELETAL REGULATION
  Phosphorylated derivatives of the phospholipid phosphatidylinositol, or phosphoinositides, are implicated in many aspects of cell function. Binding of phosphoinositides that are localized within cell membranes to soluble protein ligands allows spatially selective regulation at the cytoplasm–membrane interface. Recently, studies that relate phosphoinositide production to membrane domains are converging with those that show effects of these lipids on the assembly of cellular actin, and are therefore linking membrane and cytoskeletal structures in new ways.
September 17,2004 BIOMATERIALS
  Since its inception just over a half century ago, the field of biomaterials has seen a consistent growth with a steady introduction of new ideas and productive branches. This review describes where we have been, the state of the art today, and where we might be in 10 or 20 years. Herein, we highlight some of the latest advancements in biomaterials that aim to control biological responses and ultimately heal. This new generation of biomaterials includes surface modification of materials to overcome nonspecific protein adsorption in vivo, precision immobilization of signaling groups on surfaces, development of synthetic materials with controlled properties for drug and cell carriers, biologically inspired materials that mimic natural processes, and design of sophisticated three-dimensional (3-D) architectures to produce well-defined patterns for diagnostics, e.g., biological microelectromechanical systems (bioMEMs), and tissue engineering.
September 16,2004 THE BCR-ABL STORY: Bench to Bedside and Back
  The twenty-first century is beginning with a sharp turn in the field of cancer therapy. Molecular targeted therapies against specific oncogenic events are now possible. The BCR-ABL story represents a notable example of how research from the fields of cytogenetics, retroviral oncology, protein phosphorylation, and small molecule chemical inhibitors can lead to the development of a successful molecular targeted therapy. Imatinib mesylate (Gleevec, STI571, or CP57148B) is a direct inhibitor of ABL (ABL1), ARG (ABL2), KIT, and PDGFR tyrosine kinases. This drug has had a major impact on the treatment of chronic myelogenous leukemia (CML) as well as other blood neoplasias and solid tumors with etiologies based on activation of these tyrosine kinases.
September 15,2004 TETHERING: Fragment-Based Drug Discovery
  The genomics revolution has provided a deluge of new targets for drug discovery. To facilitate the drug discovery process, many researchers are turning to fragment-based approaches to find lead molecules more efficiently. One such method, Tethering1, allows for the identification of small-molecule fragments that bind to specific regions of a protein target. These fragments can then be elaborated, combined with other molecules, or combined with one another to provide high-affinity drug leads. In this review we describe the background and theory behind Tethering and discuss its use in identifying novel inhibitors for protein targets including interleukin-2 (IL-2), thymidylate synthase (TS), protein tyrosine phosphatase 1B (PTP-1B), and caspases.
September 14,2004 Network integration of the adrenergic system in cardiac hypertrophy
  Adrenergic receptors play a pivotal role in regulating cardiac function in response to a constantly changing environment. Altered a and h adrenergic receptor signaling in vivo is associated with cardiac hypertrophy and failure. This review focuses on the different roles of adrenergic receptors in regulating cardiac function under normal and pathological conditions. Understanding the signaling mechanisms of these receptors in the context of the heart is likely to provide a better therapeutic approach towards treatment of heart failure.
September 13,2004 The ins and outs of lysophosphatidic acid signaling
  Lysophosphatidic acid (LPA) is a lipid mediator with a wide variety of biological actions, particularly as an inducer of cell proliferation, migration and survival. LPA binds to specific G-protein-coupled receptors and thereby activates multiple signal transduction pathways, including those initiated by the small GTPases Ras, Rho, and Rac. LPA signaling has been implicated in such diverse processes as wound healing, brain development, vascular remodeling and tumor progression. Knowledge of precisely how and where LPA is produced has long proved elusive. Excitingly, it has recently been discovered thatLPAis generated from precursors by ‘autotaxin’, a once enigmatic exo-phosphodiesterase implicated in tumor cell motility. Exogenous phospholipases D can also produce LPA, which may contribute to their toxicity.
September 12,2004 Junctions on the road to cancer
  Mus81-Eme1 is a structure-specific DNA endonuclease complex that processes DNA junctions during the recombinational repair of DNA damage. The recent observation that mice containing disruptions in one or both copies of the MUS81 gene are profoundly cancer prone demonstrates that efficient processing of recombination intermediates is necessary to guard against tumorigenesis.
September 11,2004 Stem cells and repair of the heart
  Stem-cell therapy provides the prospect of an exciting and powerful treatment to repair the heart. Although research has been undertaken in animals to analyse the safety and ef.cacy of this new approach, results have been inconclusive. The mechanism by which stem cells could improve cardiac function remains unclear. We describe the background to the concept of natural repair and the work that has been done to establish the role of stem cells in cardiac repair. Controversies have arisen in interpretation of experimental data. The important issues surrounding the application of stem-cell therapy to man are discussed critically.
September 10,2004 Nonsense-mediated decay approaches the clinic
  Nonsense-mediated decay (NMD) eliminates mRNAs containing premature termination codons and thus helps limit the synthesis of abnormal proteins. New results uncover a broader role of NMD as a pathway that also affects the expression of wild-type genes and alternative-splice products. Because the mechanisms by which NMD operates have received much attention, we discuss here the emerging awareness of the impact of NMD on the manifestation of human genetic diseases. We explore how an understanding of NMD accounts for phenotypic differences in diseases caused by premature termination codons.
September 9,2004 Myocyte hypertrophy and apoptosis
  In response to a variety of extrinsic and intrinsic stimuli that impose increased biomechanical stress the heart responds by enlarging the individual myofibers. Even though myocardial hypertrophy can normalize wall tension, it instigates an unfavorable outcome and threatens affected patients with sudden death or progression to overt heart failure, suggesting that in most instances hypertrophy is a maladaptive process. Increasing evidence suggests that several of the signaling cascades controling myocyte growth in the adult heart also function to enhance survival of the myocyte population in response to pleiotropic death stimuli. In this review, we summarize recent insights into hypertrophic signaling pathways and their ability to control the balance between myocyte life and death.
September 8,2004 CYTOCHROME C-MEDIATED APOPTOSIS
  Apoptosis, or programmed cell death, is involved in development, elimination of damaged cells, and maintenance of cell homeostasis. Deregulation of apoptosis may cause diseases, such as cancers, immune diseases, and neurodegenerative disorders. Apoptosis is executed by a subfamily of cysteine proteases known as caspases. In mammalian cells, a major caspase activation pathway is the cytochrome c-initiated pathway. In this pathway, a variety of apoptotic stimuli cause cytochrome c release from mitochondria, which in turn induces a series of biochemical reactions that result in caspase activation and subsequent cell death.
September 7,2004 Cancer genes and the pathways they control
  The revolution in cancer research can be summed up in a single sentence: cancer is, in essence, a genetic disease. In the last decade, many important genes responsible for the genesis of various cancers have been discovered, their mutations precisely identified, and the pathways through which they act characterized. The purposes of this review are to highlight examples of progress in these areas, indicate where knowledge is scarce and point out fertile grounds for future investigation.
September 6,2004 Human genetic variation and health
  Human genetic variation is often biologically relevant, particularly when it influences (or is influenced by) health outcomes. For example, human genetic variation can modulate disease aetiology as in the case of homozygous beta sickle gene (βS/βS or sickle cell) pathology. Conversely, health outcomes, such as the frequency and duration of homozygous sickle cell pathology, can change affected group gene frequencies by selectively targeting and culling specific genotypes in a group, such as clinically more severe βSBantu/βSBantu versions of the βS gene, thereby changing future patterns of genetic variation in this gene.
September 5,2004 Dysregulation of HSG triggers vascular proliferative disorders
  Vascular proliferative disorders, such as atherosclerosis and restenosis, are the most common causes of severe cardiovascular diseases, but a common molecular mechanism remains elusive. Here, we identify and characterize a novel hyperplasia suppressor gene, named HSG (later re-named rat mitofusin-2). HSG expression was markedly reduced in hyper-proliferative vascular smooth muscle cells (VSMCs) from spontaneously hypertensive rat arteries, balloon-injured Wistar Kyoto rat arteries, or ApoE-knockout mouse atherosclerotic arteries. Overexpression of HSG overtly suppressed serum-evoked VSMC proliferation in culture, and blocked balloon injury induced neointimal VSMC proliferation and restenosis in rat carotid arteries.
September 4,2004 OPIOID RECEPTORS
  Opioid receptors belong to the large superfamily of seven transmembrane- spanning (7TM) G protein-coupled receptors (GPCRs). As a class, GPCRs are of fundamental physiological importance mediating the actions of the majority of known neurotransmitters and hormones. Opioid receptors are particularly intriguing members of this receptor family. They are activated both by endogenously produced opioid peptides and by exogenously administered opiate compounds, some of which are not only among the most effective analgesics known but also highly addictive drugs of abuse.
September 3,2004 Secretory trafficking in neuronal dendrites
  The neuronal secretory pathway represents the intracellular route for proteins involved in synaptic transmission and plasticity, as well as lipids required for outgrowth and remodelling of dendrites and axons. Although neurons use the same secretory compartments as other eukaryotic cells, the enormous distances involved, as well as the unique morphology of the neuron and its signalling requirements, challenge canonical models of secretory pathway organization. Here, we review evidence for a distributed secretory pathway in neurons, suggest mechanisms that may regulate secretory compartment distribution, and discuss the implications of a distributed secretory pathway for neuronal morphogenesis and neural-circuit plasticity.
September 2,2004 Controlled Release Systems for DNA Delivery
  Adapting controlled release technologies to the delivery of DNA has the potential to overcome extracellular barriers that limit gene therapy. Controlled release systems can enhance gene delivery and increase the extent and duration of transgene expression relative to more traditional delivery methods (e.g., injection). These sysstems typically deliver vectors locally, which can avoid distribution to distant tissues, decrease toxicity to nontarget cells, and reduce the immune response to the vector. Delivery vehicles for controlled release are fabricated from natural and synthetic polymers, which function either by releasing the vector into the local tissue environment or by maintaining the vector at the polymer surface.
September 1,2004 A role for chemistry in stem cell biology
  Although stem cells hold considerable promise for the treatment of numerous diseases including cardiovascular disease, neurodegenerative disease,musculoskeleral disease,diabetes and cancer,obstacles such as the control of stem cell fate, allogenic rejection and limited cell availability must be overcome before their therapeutic potential can be realized.This requires an improved understanding of the signaling pathways that affect cell fate.Cell-based phenotypic and pathwayspecific screens of natural products and synthetic compounds have recenthy provided a number of small molecules that can be used to selectively control stem cell proliferation and differentiation.

August July June May April March February January 2003 2002 2001