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August 31,2004 Positive and negative regulators of Ras in T cells
  T cell antigen receptor (TCR) engagement by cognate peptide antigen presented by MHC leads to the activation of a number of signaling pathways whose crosstalk is responsible for T cell commitment to growth, differentiation or apoptosis. A crucial event in this decision is the activation of the small GTPase Ras. Post-translational addition of a farnesyl moiety results in Ras localization at the inner leaflet of the membrane, where it switches between the “on”, GTPbound state, and the “off”, GDP-bound state [1]. When bound to GTP, Ras binds to and activates effector proteins, of which the best characterized is the serine/threonine kinase Raf-1.
August 30,2004 Vascular Calcification:Mechanisms and Clinical Ramifications
  Vascular calcification, long thought to result from passive degeneration, involves a complex, regulated process of biomineralization resembling osteogenesis. Evidence indicates that proteins controlling bone mineralization are also involved in the regulation of vascular calcification. Artery wall cells grown in culture are induced to become osteogenic by inflammatory and atherogenic stimuli. Furthermore, osteoclast-like cells are found in calcified atherosclerotic plaques, and active resorption of ectopic vascular calcification has been demonstrated. In general, soft tissue calcification arises in areas of chronic inflammation, possibly functioning as a barrier limiting the spread of the inflammatory stimulus.
August 29,2004 Intracellular Cholesterol Transport
  Intracellular cholesterol transport is essential for the maintenance of cholesterol homeostasis. Many aspects of cholesterol metabolism are well-known, including its synthesis in the endoplasmic reticulum, its extracellular transport in plasma lipoproteins, its uptake by the low-density lipoprotein receptor, and its regulation of SREBP and LXR transcription factors. These fundamental pathways in cholesterol metabolism all rely on its proper intracellular distribution among subcellular organelles and the plasma membrane. Transport involving the ER and endosomes is essential for cholesterol synthesis, uptake, and esterification, whereas cholesterol catabolism by enzymes in mitochondria and ER generates steroids, bile acids, and oxysterols.
August 28,2004 Telomere epigenetics: a higher-order control of telomere length in mammalian cells
  Telomeres are capping structures at the ends of eukaryotic chromosomes composed of TTAGGG repeats bound to an array of specialized proteins. Telomeres, together with centromeres, have been classically considered heterochromatic regions. Constitutive heterochromatin domains typically consist of repetitive DNA and have a very low gene content. In addition, constitutive heterochromatin is characterized by a number of hallmark histone modifications, as well as DNA modifications. In the case of pericentric heterochromatin, several activities responsible for these epigenetic modifications have been recently identified and characterized.
August 27,2004 The role of Zic genes in neural development
  The Zic family of zinc-finger proteins plays a crucial role in neural development. Zic genes are vertebrate homologs of odd-paired, the Drosophila pair-rule gene. Their gene products have zinc-finger domains similar to those of Gli proteins, which act as transcriptional regulators in hedgehog signaling. Recent studies of human, mouse, frog, fish and ascidian Zic homologs have provided evidence that Zic genes are involved in a variety of developmental processes, including neurogenesis, myogenesis, skeletal patterning, and left– right axis establishment. Zic genes appear to have multiple roles in neural development.
August 26,2004 Prospects for an AIDS vaccine
  The unremitting devastation created by the AIDS pandemic will probably only be controlled when a vaccine is developed that is safe, effective, affordable, and simple enough to permit implementation in developing countries where the impact of AIDS is most severe. Although formidable practical, political, economic, social, and ethical challenges face the AIDS vaccine development effort, the most fundamental challenges now reside at the level of the basic biology of HIV-1 infection and pathogenesis. Of these biological considerations, three questions loom especially large.
August 25,2004 Medical Technology Development and Approval
  Alvin Toffler, a 20th century philosopher and author of the novel Future Shock once said, “As we move into the 21st century, not only will technology advance, but the rate at which technology advances will increase exponentially.”1 Perhaps those technological advances with greatest relevance to the health and welfare of society involve science and healthcare. Indeed, societal demands for new drug and device design and development have never been greater. Because of advances in medical care, the mortality from cardiovascular diseases has progressively declined over the past 2 decades. We currently stand on the threshold of “cures” for several of mankind’s greatest afflictions, including cancer, atherosclerotic cardiovascular disease, and human immunodeficiency disease.2
August 24,2004 LKB1 tumor suppressor protein
  The LKB1 (also called serine/threonine kinase 11) tumor suppressor gene was cloned in 1998 by linkage analysis of Peutz-Jeghers cancer syndrome patients. Mammalian LKB1 has been implicated as a regulator of multiple biological processes and signaling pathways, including the control of cell-cycle arrest, p53-mediated apoptosis, Wnt signaling, transforming growth factor (TGF)-β signaling, ras-induced cell transformation, and energy metabolism. The Caenorhabditis elegans and Drosophila melanogaster LKB1 homologs, termed PAR4 and dLKB1, respectively, regulate cell polarity.
August 23,2004 Apoptosis and Dependence Receptors
  Classical signal transduction is initiated by ligand-receptor interactions. We have described an alternative form of signal transduction that is initiated by the withdrawal of ligands from specific receptors referred to as dependence receptors. This process is widespread, featuring in developmental cell death, carcinogenesis (especially metastasis), neurodegeneration, and possibly subapoptotic events such as neurite retraction and somal atrophy. Initial mechanistic studies of dependence receptors suggest that these receptors form complexes that include specific caspases. Complex formation appears to be a function of ligand-receptor interaction, and dependence receptors appear to exist in at least two conformational states.
August 22,2004 T Cell Receptor Signaling
  The adaptive phase of the immune response begins with engagement on CD4+ helper T cells of the T cell antigen receptor (TCR)1 by its ligand, a small foreign peptide bound to a cell surface protein of the class II major histocompatibility complex (peptide-MHC) expressed on an antigen-presenting cell. This engagement initiates a series of biochemical events that can differentially signal the naive T cell to: 1) enter into a pathway leading to generation of effector T cells with the onset of rapid proliferation and production of effector cytokines; 2) enter into a state of antigenic non-responsiveness known as anergy; or 3) die by apoptosis.
August 21,2004 The HIV vaccine saga
  The development of a vaccine that can prevent infection by the Human immunodeficiency virus or prevent the Acquired Immunodeficiency Syndrome has remained elusive despite 20 years of scientific effort. This "Commentary" analyzes the reasons that the development of a vaccine has been so difficult, and proposes a plan to work towards an immunological approach to investigate the best vaccine candidates in the first world in individuals who are already infected, before taking the most promising vaccines to the developing world to attempt to prevent infection and disease.
August 20,2004 Practical Markers Used in the Diagnosis of Endocrine Tumors
  Endocrine tumors constitute a large group of neoplasms that are widely dispersed throughout the body. They are made up mostly of neuroendocrine tumors (NE), which are characterized by the presence of secretory granules and production of peptide hormones, and non-NE tumors such as those derived from thyroid follicular cells and adrenal cortical cells. Immunohistochemical markers have been used to characterize these lesions and distinguish them from other histologically similar tumors. Chromogranin and synaptophysin are the most widely used broad-spectrum neuroendocrine tumor markers. The use of antibodies to transcription factors, keratins, and specific peptides is quite valuable in the diagnosis of endocrine tumors.
August 19,2004 RAS oncogenes: the first 30 years
  From the pioneering work with acute transforming retroviruses to the current post-genomic era, RAS genes have always been at the leading edge of signal transduction and molecular oncology. Yet, a complete understanding of RAS function and dysfunction - mainly in human cancer - is still to come. The knowledge that has accumulated since their discovery 30 years ago has, however, been remarkable, and should pave the way for not only solving the outstanding issues regarding RAS biology, but also for developing efficacious drugs that could have a significant impact on cancer treatment.
August 18,2004 Hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy is a common genetically transmitted disease, defined clinically by the presence of unexplained left ventricular hypertrophy. The disease has a varied clinical course and outcome; many patients have little or no discernible cardiovascular symptoms, whereas others have profound exercise limitation and recurrent arrhythmias. The overall risk of disease-related complications such as sudden death, endstage heart failure, and fatal stroke is roughly 1–2% per year, but the absolute risk in individuals varies as a function of underlying genetic abnormality, age, myocardial pathology, and other pathophysiological abnormalities such as impaired peripheral vascular responses.
August 17,2004 Regulation of local mRNA translation
  Regulated local mRNA translation is one mechanism cells employ to concentrate proteins in particular locations. However, cells use many different strategies to accomplish this task; for example, some mRNAs are destroyed in regions where they are not wanted, other mRNAs are repressed in areas where their translation would be deleterious, and yet other mRNAs are transported, in a quiescent state, to the sites where their translation is activated. The importance of local translation cannot be overstated, for, depending on the species or cell type, it is required for cell division, establishment of mating type, development and memory formation.
August 16,2004 Microarray analysis in clinical oncology
  DNA microarray profiling performed on clinical tissue specimens can potentially provide significant information regarding human cancer biology. Biopsy cores, the typical source of human tumor tissue, however, generally provide very small amounts of RNA (0.3-15 μg). RNA amplification is a common method used to increase the amount of material available for hybridization experiments. Using human xenograft tissue, we sought to address the following three questions: 1) is amplified RNA representative of the original RNA profile? 2) what is the minimum amount of total RNA required to perform a representative amplification? 3) are the direct and indirect methods of labeling the hybridization probe equivalent?
August 15,2004 Structure and regulation of MAPK phosphatases
  MAP kinases (MAPKs), which control mitogenic signal transduction in all eukaryotic organisms, are inactivated by dual specificity MAPK phosphatases (DS-MKPs). Recent studies reveal that substrate specificity and enzymatic activity of MKPs are tightly controlled not only by the conserved C-terminal phosphatase domain but also by an N-terminal (NT) kinase-binding domain. Notably, MKPs that consist of a kinase-binding domain and a phosphatase domain exhibit little phosphatase activity in the absence of their physiological substrates. MKP binding to a specific MAPK results in enzymatic activation of the phosphatase in a substrate-induced activation mechanism.
August 14,2004 T LYMPHOCYTE–ENDOTHELIAL CELL INTERACTIONS
  Human vascular endothelial cells (EC) basally display class I and II MHC-peptide complexes on their surface and come in regular contact with circulating T cells. We propose that EC present microbial antigens to memory T cells as a mechanism of immune surveillance. Activated T cells, in turn, provide both soluble and contact-dependant signals to modulate normal EC functions, including formation and remodeling of blood vessels, regulation of blood flow, regulation of blood fluidity, maintenance of permselectivity, recruitment of inflammatory leukocytes, and antigen presentation leading to activation of T cells.
August 13,2004 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.
August 12,2004 Inflammatory Cytokines and Postmyocardial Infarction Remodeling
  Inflammatory response and cytokine elaboration are particularly active after myocardial infarction and contribute to cardiac remodeling and eventual host outcome. The triggers of cytokine release in the acute postinfarction period include mechanical deformation, ischemic stimulus, reactive oxygen species (ROS), and cytokine selfamplification pathways. Acutely, the elaboration of tumor necrosis factor, IL-1 and IL-6, transforming growth factor families of cytokines, contribute to survival or deaths of myocytes, modulation of cardiac contractility, alterations of vascular endothelium, and recruitment of additional circulating cells of inflammation to the injured myocardium.
August 11,2004 NUTRITION AND CANCER PREVENTION
  More than one million Americans were expected to be diagnosed with cancer in 2003 (7a). Compelling experimental, epidemiological, and clinical evidence indicates that many cancers are preventable, especially because diet and nutrition are key factors in the modulation of cancer risk. The road to nutritional intervention in cancer prevention has led to successful trials as well as trials that did not reach their intended endpoints. This chapter reviews four case studies of trials, with two ending in success and two ending in null findings or adverse effects.
August 10,2004 Recent advances in gene structure prediction
  De novo gene predictors are programs that predict the exonintron structures of genes using the sequences of one or more genomes as their only input. In the past two years, dual-genome de novo predictors, which exploit local rates and patterns of mutation inferred from alignments between two genomes, have led to significant improvements in accuracy. Systems that exploit more than two genomes simultaneously have only recently begun to appear and are not yet competitive on practical tasks, but offer the greatest hope for near-term improvements. Dual-genome de novo prediction for compact eukaryotic genomes such as those of Arabidopsis thaliana and Caenorhabditis elegans is already quite accurate.
August 9,2004 New views of the immunological synapse
  The interaction of T cells with antigen-presenting cells results in the formation of a contact face, termed the immunological synapse. The prototypical dynamics of this process are well established and involve cessation of crawling, a highly fluid 'immature' synapse phase during which signaling is initiated, and ultimately the formation of a 'mature' synapse characterized by centralized and peripheral supramolecular activating complexes. Ongoing research is directed towards defining how these supramolecular assemblies are formed and, more importantly, to what end.
August 8,2004 Extra-cellular matrix in vascular networks
  The vascular network is a series of linked conduits of blood vessels composed of the endothelium, a monolayer of cells that adorn the vessel lumen and surrounding layer(s) of mesenchymal cells . In addition to providing structural support, the mesenchymal cells are essential for vessel contractility. The extracellular matrix is a major constituent of blood vessels and provides a framework in which these various cell types are attached and embedded. The composition and organization of vascular extracellular matrix is primarily controlled by the mesenchymal cells, and is also responsible for the mechanical properties of the vessel wall, forming complex networks of structural proteins which are highly regulated.
August 7,2004 Stem cell origin of cancer and differentiation therapy
  Our forefathers in pathology, on observing cancer tissue under the microscope in the mid-19th century, noticed the similarity between embryonic tissue and cancer, and suggested that tumors arise from embryo-like cells [1,2]. The concept that adult tissues contain embryonic remnants that generally lie dormant, but that could be activated to become cancer was later formalized by Cohnheim [3,4] and Durante [5] , as the "embryonal rest" theory of cancer. An updated version of the embryonal rest theory of cancer is that cancers arise from tissue stem cells in adults. Analysis of the cellular origin of carcinomas of different organs indicates that there is, in each instance, a determined stem cell required for normal tissue renewal that is the most likely cell of origin of carcinomas [6] .
August 6,2004 EUKARYOTIC mRNA DECAPPING
  Eukaryotic mRNAs are primarily degraded by removal of the 3' poly(A) tail, followed either by cleavage of the 5' cap structure (decapping) and 5'->3' exonucleolytic digestion, or by 3' to 5' degradation. mRNA decapping represents a critical step in turnover because this permits the degradation of the mRNA and is a site of numerous control inputs. Recent analyses suggest decapping of an mRNA consists of four central and related events. These include removal, or inactivation, of the poly(A) tail as an inhibitor of decapping, exit from active translation, assembly of a decapping complex on the mRNA, and sequestration of the mRNA into discrete cytoplasmic foci where decapping can occur.
August 5,2004 The tight junction: a multifunctional complex
  Multicellular organisms are separated from the external environment by a layer of epithelial cells whose integrity is maintained by intercellular junctional complexes composed of tight junctions, adherens junctions, and desmosomes, whereas gap junctions provide for intercellular communication. The aim of this review is to present an updated overview of recent developments in the area of tight junction biology. In a relatively short time, our knowledge of the tight junction has evolved from a relatively simple view of it being a permeability barrier in the paracellular space and a fence in the plane of the plasma membrane to one of it acting as a multicomponent, multifunctional complex that is involved in regulating numerous and diverse cell functions.
August 4,2004 STARTING AT THE BEGINNING
  The gastrointestinal tract is the central organ for uptake of fluids and nutrients, and at the same time it forms the main protective barrier between the sterile environment of the body and the outside world. In mammals, the intestine has further evolved to harbor a vast load of commensal bacteria that have important functions for the host. Discrimination by the host defense system of nonself from self can prevent invasion of pathogens, but equivalent responses to dietary or colonizing bacteria can lead to devastating consequences for the organism.
August 3,2004 Prevention of Type 2 diabetes mellitus. A review of the evidence and its application in a UK setting
  Type 2 Diabetes mellitus (T2DM) is a complex metabolic, multifactorial disease, which affects the quality, quantity and style of life. People with T2DM have a life expectancy that can be shortened by as much as 15 years, with up to 75% dying of macrovascular complications. To reduce the impact of T2DM in the 21st century, we need an approach that not only optimally treats the person with established diabetes but also prevents diabetes from occurring in the first place. The best evidence for prevention of diabetes is for interventions that target individuals at highest risk.
August 2,2004 Structure and function of poly(A) binding proteins
  Poly (A) tails are found at the 3' ends of almost all eukaryotic mRNAs. They are bound by two different poly (A) binding proteins, PABPC in the cytoplasm and PABPN1 in the nucleus. PABPC functions in the initiation of translation and in the regulation of mRNA decay. In both functions, an interaction with the m7G cap at the 5' end of the message plays an important role. PABPN1 is involved in the synthesis of poly (A) tails, increasing the processivity of poly (A) polymerase and contributing to defining the length of a newly synthesized poly (A) tail.
August 1,2004 p63: molecular complexity in development and cancer
  Discovery of the p53 homologs p63 and p73 has brought new excitement to the p53 field. Identification of homologous genes coding for several proteins with similar and antagonistic properties towards p53 has been both intriguing and perplexing. A multitude of properties have been attributed to these new homologs and this review will focus on the biochemical and biological aspects of one family member, p63. Although the most ancient member of the p53 family, p63 is the most recently discovered and the least is known about this family member. Unlike p53, whose protein expression is not readily detectable in epithelial cells unless they are exposed to various stress conditions, p63 is expressed in select epithelial cells at high levels under normal conditions.

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