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June 30,2005 Specific memory within innate immune systems
  Research into immune defense has been considerably enriched by the increasing focus on innate immunity. This type of immunity is still considered to lack specific memory, largely because there is no evidence of mechanisms that could provide such memory (such as acquired immunity). However, recent experimental data demonstrate specific memory phenomena in invertebrates: these organisms are thought to rely solely on innate defense. Here, I argue that a clear definition of the terms ‘specificity’ and ‘memory’, together with dissection of the evolutionary roots of immune defense, show us that innate immunity should not be, and is probably not, necessarily free of specific memory.
June 29,2005 ADVANCES IN CANCER EPIDEMIOLOGY: Understanding Causal Mechanisms and the Evidence for Implementing Interventions
  In a worldwide population of 6 billion, in the year 2000, approximately 10 million cancers were diagnosed, and there were an estimated 6.2 million cancer deaths. Whereas the universality of cancer incidence and mortality is established, the burden of cancer by type or organ site is distributed unequally between developing and industrialized nations. Populations in developing countries are disproportionately affected by cancers in which infectious agents are causal.
June 28,2005 Circulating cardiovascular markers and mediators in acute illness: an update
  An update is given of the circulating markers and mediators of cardiovascular dysfunction in acute illness. Some of these circulating markers reflect mediator action on the peripheral vasculature, such as endothelium-derived endothelin and nitrite/ nitritate, the stable end products of nitric oxide. Other markers mainly reflect actions on the heart, such as the natriuretic peptide family, released from the heart upon dilatation, serving as a marker of congestive heart failure and potentially having negative inotropic effects. Indeed, some factors may be both markers as well as mediators of cardiovascular dysfunction of the acutely ill and bear prognostic significance.
June 27,2005 B CELL SIGNALING AND TUMORIGENESIS
  The proliferation and differentiation of lymphocytes are regulated by receptors localized on the cell surface. Engagement of these receptors induces the activation of intracellular signaling proteins that transmit the receptor signals to distinct targets and control the cellular responses. The first signaling proteins to be discovered in higher organisms were the products of oncogenes. For example, the kinases Src and Abelson (Abl) were originally identified as oncogenes and were later characterized as important proteins for signal transduction in various cell types, including lymphocytes.
June 26,2005 Systems analysis of RNA trafficking in neural cells
  In neural cells, certain RNAs are targeted to dendrites by a specific RNA trafficking pathway, termed the A2 pathway, mediated by the trans-acting trafficking factor, heterogeneous nuclear ribonucleoprotein (hnRNP) A2, which binds to an 11 nucleotide cis-acting trafficking sequence, termed the hnRNP A2 response element (A2RE). RNAs containing A2RE-like sequences are recognized by hnRNP A2 in the nucleus and exported to the cytoplasm where they assemble into trafficking intermediates, termed granules, which also contain components of the translation machinery and molecular motors (cytoplasmic dynein and conventional kinesin).
June 25,2005 Clinical Applications of Stem Cells for the Heart
  Repair of the heart is an old dream of physicians caring for patients with cardiac disease. Experimental studies suggest that cardiac transfer of stem and progenitor cells can have a favorable impact on tissue perfusion and contractile performance of the injured heart. Some researchers favor stable stem cell engraftment by fusion or transdifferentiation into cardiomyocyte or vascular cell lineages as likely explanations for these beneficial effects. Others have proposed that transient cell retention may be sufficient to promote functional effects, eg, by release of paracrine mediators.
June 24,2005 Type 2 diabetes: principles of pathogenesis and therapy
  Type 2 diabetes mellitus has become an epidemic, and virtually no physician is without patients who have the disease. Whereas insulin insensitivity is an early phenomenon partly related to obesity, pancreas β-cell function declines gradually over time already before the onset of clinical hyperglycaemia. Several mechanisms have been proposed, including increased non-esterified fatty acids, inflammatory cytokines, adipokines, and mitochondrial dysfunction for insulin resistance, and glucotoxicity, lipotoxicity, and amyloid formation for β-cell dysfunction. Moreover, the disease has a strong genetic component, but only a handful of genes have been identified so far: genes for calpain 10, potassium inward-rectifier 6.2, peroxisome proliferator-activated receptor γ, insulin receptor substrate-1, and others.
June 23,2005 Fate and function of lymphoid tissue inducer cells
  The discovery that Peyer’s patch and lymph node development is regulated by the collaboration between fetal hematopoietic cells and mesenchymal cells has thrown new light on our understanding of the mechanisms underlying the formation of lymphoid organs. Lymphoid tissue inducer cells trigger a coordinated series of events leading to cell clustering and changes in gene expression and differentiation. Nevertheless, many questions regarding the origin, recruitment and fate of the inducer cells and cellular crosstalk with neighboring cells remain unanswered.
June 22,2005 Inflammatory mediators in atherosclerotic vascular disease
  An impressive body of work has established the current paradigm of atherosclerosis as an in.ammatory process that promotes lesion development and progression. Early atheroma formation is characterized by leukocyte recruitment and expression of in.ammatory mediators which is confounded in the context of hyperlipidemia. Evidence for an involvement of both innate and adaptive immunity in lesion formation has emerged, supporting a causal relation between the balance of pro- and anti-in.ammatory cytokines and atherogenesis. The function of chemokines in distinct steps during mononuclear cell recruitment to vascular lesions has been studied in genetically deficient mice and other suitable models, and displays a high degree of specialization and cooperation.
June 21,2005 Seamless cloning and gene fusion
  Gene fusion technology is a key tool in facilitating gene function studies. Hybrid molecules in which all the components are joined precisely, without the presence of intervening and unwanted extraneous sequences, enable accurate studies of molecules and the characterization of individual components. This article reviews situations in which seamlessly fused genes and proteins are required or desired and describes molecular approaches that are available for generating these hybrid molecules.
June 20,2005 DNA transposons in vertebrate functional genomics
  Genome sequences of many model organisms of developmental or agricultural importance are becoming available. The tremendous amount of sequence data is fuelling the next phases of challenging research: annotating all genes with functional information, and devising new ways for the experimental manipulation of vertebrate genomes. Transposable elements are known to be efficient carriers of foreign DNA into cells. Notably, members of the Tc1/mariner and the hAT transposon families retain their high transpositional activities in species other than their hosts. Indeed, several of these elements have been successfully used for trans- genesis and insertional mutagenesis, expanding our abilities in genome manipulations in vertebrate model organisms.
June 19,2005 NEW ANTICOAGULANT THERAPY
  The development of new anticoagulants is expanding the list of drugs that can be used to prevent and treat venous and arterial thrombosis. New parenteral anticoagulants have been developed to overcome the limitations of heparin and lowmolecular- weight heparin, whereas novel orally active anticoagulants have been designed to provide more streamlined therapy than vitamin K antagonists. This review identifies the molecular targets of new anticoagulants, describes the results of clinical trials, and provides clinical perspective on the opportunities for new anticoagulants.
June 18,2005 THE MITOCHONDRIAL UNCOUPLING-PROTEIN HOMOLOGUES
  Uncoupling protein (UCP)1 is an integral membrane protein that is located in the mitochondrial inner membrane of brown adipocytes. Its physiological role is to mediate a regulated, thermogenic proton leak. UCP2 and UCP3 are recently identified UCP1 homologues. They also mediate regulated proton leak, and might function to control the production of superoxide and other downstream reactive oxygen species. However, their role in normal physiology remains unknown. Recent studies have shown that UCP2 has an important part in the pathogenesis of type-2 diabetes. The obscure roles of the UCP homologues in normal physiology, together with their emerging role in pathophysiology, provide exciting potential for further investigation.
June 17,2005 COUNTING ON NEURONS: THE NEUROBIOLOGY OF NUMERICAL COMPETENCE
  Numbers are an integral part of our everyday life — we use them to quantify, rank and identify objects. The verbal number concept allows humans to develop superior mathematical and logic skills that define technologically advanced cultures. However, basic numerical competence is rooted in biological primitives that can be explored in animals, infants and human adults alike. We are now beginning to unravel its anatomical basis and neuronal mechanisms on many levels, down to its single neuron correlate. Neural representations of numerical information can engage extensive cerebral networks, but the posterior parietal cortex and the prefrontal cortex are the key structures in primates.
June 16,2005 Site selection for the cleavage furrow at cytokinesis
  The question of how the site for division of the cytoplasm is determined at the end of mitosis has been studied for over a century, and it remains an active, controversial and fascinating problem in cell biology. This problem draws on the use of several model cell types, with the goal of understanding and identifying how the cell cycle regulates signals between the mitotic apparatus and the cell cortex. Studies in different cell types and using a vast array of techniques reveal different answers: these might reflect differences in experimental approaches,multiple and redundantmechanisms and, importantly, diversity in biology.
June 15,2005 Intronic microRNAs
  MicroRNAs (miRNAs), small single-stranded regulatory RNAs capable of interfering with intracellular mRNAs that contain partial complementarity, are useful for the design of new therapies against cancer polymorphism and viral mutation. MiRNA was originally discovered in the intergenic regions of the Caenorhabditis elegans genome as native RNA fragments that modulate a wide range of genetic regulatory pathways during animal development. However, neither RNA promoter nor polymerase responsible for miRNA biogenesis was determined. Recent findings of intron-derived miRNA in C.
June 14,2005 Targeting Ras and Rho GTPases as opportunities for cancer therapeutics
  The Ras and Rho GTPases contribute to the initiation and progression of cancer by subverting the normal regulation of specific intracellular signalling pathways. As a result, Ras and Rho play significant roles in the development of numerous aspects of the malignant phenotype by promoting cell cycle progression, resistance to apoptotic stimuli, neovascularisation and tumour cell motility, invasiveness and metastasis. With these GTPases contributing at so many levels, they are appealing targets for the development of cancer chemotherapeutic agents.
June 13,2005 METABOLIC SYNDROME: A Clinical and Molecular Perspective
  The metabolic syndrome is a cluster of interrelated common clinical disorders, including obesity, insulin resistance, glucose intolerance, hypertension, and dyslipidemia (hypertriglyceridemia and low HDL cholesterol levels). According to recently defined criteria, the metabolic syndrome is prevalent and is associated with a greater risk of atherosclerotic cardiovascular disease than any of its individual components. Primary defects in energy balance that produce obesity (and visceral adiposity in particular) are sufficient to drive all aspects of the syndrome. Increased free fatty acids and lipid accumulation in certain organs are mediators of insulin resistance.
June 12,2005 Clinical anticancer drug development: targeting the cyclin-dependent kinases
  Cell division involves a cyclical biochemical process composed of several step-wise reactions that have to occur once per cell cycle. Dysregulation of cell division is a hallmark of all cancers. Genetic and epigenetic mechanisms frequently result in deranged expression and/or activity of cell-cycle proteins including the cyclins, cyclin-dependent kinases (Cdks), Cdk inhibitors and checkpoint control proteins. The critical nature of these proteins in cell cycling raises hope that targeting them may result in selective cytotoxicity and valuable anticancer activity.
June 11,2005 Gene medicines: The end of the beginning?
  First-generation gene medicines and genetic vaccines represent a promising new class of therapeutics that have the potential to prevent, correct, or modulate genetic or acquired diseases. The rational design of synthetic gene delivery and expression systems continues to be essential to enable the precise temporal and spatial control of transgene expression in vivo. With the tantalizing efficacy results and outstanding safety profile observed with nonviral, plasmid-based product candidates in early clinical trials, a multidisciplinary approach remains critical to further improve the effectiveness, reduce the manufacturing costs, and maintain the safety of gene therapeutics and vaccines for their successful development.
June 10,2005 TIMP-2: an endogenous inhibitor of angiogenesis
  Remodeling of the extracellular matrix – regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors – is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors.
June 9,2005 MsiRNA and miRNA: an insight into RISCs
  Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identi- fied as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation.
June 8,2005 MOLECULAR MOTORS AND MECHANISMS OF DIRECTIONAL TRANSPORT IN NEURONS
  Intracellular transport is fundamental for neuronal morphogenesis, function and survival. Many proteins are selectively transported to either axons or dendrites. In addition, some specific mRNAs are transported to dendrites for local translation. Proteins of the kinesin superfamily participate in selective transport by using adaptor or scaffolding proteins to recognize and bind cargoes. The molecular components of RNA-transporting granules have been identified, and it is becoming clear how cargoes are directed to axons and dendrites by kinesin superfamily proteins. Here we discuss the molecular mechanisms of directional axonal and dendritic transport with specific emphasis on the role of motor proteins and their mechanisms of cargo recognition.
June 7,2005 Stress-induced immune dysfunction: implications for health
  Folk wisdom has long suggested that stressful events take a toll on health. The field of psychoneuroimmunology (PNI) is now providing key mechanistic evidence about the ways in which stressors — and the negative emotions that they generate — can be translated into physiological changes. PNI researchers have used animal and human models to learn how the immune system communicates bidirectionally with the central nervous and endocrine systems and how these interactions impact on health.
June 6,2005 siRNA and miRNA: an insight into RISCs
  Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identi- fied as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation.
June 5,2005 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 sequences 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.
June 4,2005 ATRIAL FIBRILLATION: Modern Concepts and Management
  Atrial fibrillation (AF) is a common cardiac arrhythmia responsible for significant morbidity and mortality. In recent years, progress has been made in determining the genetic abnormalities that may lead to AF. New trials have shown that rate control and anticoagulation are acceptable as a primary treatment strategy in many patients who have a high risk of recurrence. Newer and safer antiarrhythmics are now available. Pacemaker and implantable cardiac defibrillator technology is rapidly evolving and may play a significant role in future treatment and prevention of AF. Direct thrombin inhibitors are likely to add a user-friendly option to the current standard therapy for stroke prevention.
June 3,2005 CANCER NANOTECHNOLOGY: OPPORTUNITIES AND CHALLENGES
  Nanotechnology is a multidisciplinary field, which covers a vast and diverse array of devices derived from engineering, biology, physics and chemistry. These devices include nanovectors for the targeted delivery of anticancer drugs and imaging contrast agents. Nanowires and nanocantilever arrays are among the leading approaches under development for the early detection of precancerous and malignant lesions from biological fluids. These and other nanodevices can provide essential breakthroughs in the fight against cancer.
June 2,2005 The Molecular Requirements for Cytokinesis
  After anaphase onset, animal cells build an actomyosin contractile ring that constricts the plasma membrane to generate two daughter cells connected by a cytoplasmic bridge. The bridge is ultimately severed to complete cytokinesis. Myriad techniques have been used to identify proteins that participate in cytokinesis in vertebrates, insects, and nematodes. A conserved core of about 20 proteins are individually involved with cytokinesis in most animal cells. These components are found in the contractile ring, on the central spindle, within the RhoA pathway, and on vesicles that expand the membrane and sever the bridge. Cytokinesis involves additional proteins, but they, or their requirement in cytokinesis, are not conserved among animal cells.
June 1,2005 Inflammatory mediators in atherosclerotic vascular disease
  An impressive body of work has established the current paradigm of atherosclerosis as an inflammatory process that promotes lesion development and progression. Early atheroma formation is characterized by leukocyte recruitment and expression of inflammatory mediators which is confounded in the context of hyperlipidemia. Evidence for an involvement of both innate and adaptive immunity in lesion formation has emerged, supporting a causal relation between the balance of pro- and anti-inflammatory cytokines and atherogenesis. The function of chemokines in distinct steps during mononuclear cell recruitment to vascular lesions has been studied in genetically deficient mice and other suitable models, and displays a high degree of specialization and cooperation.

May April March February January 2004 2003 2002 2001