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July 31,2005 Mechanisms underlying differential responses to FGF signaling
  Fibroblast growth factors (FGFs) are key regulators of several developmental processes in which cell fate and differentiation to various tissue lineages are determined. The importance of the proper spatial and temporal regulation of FGF signals is evident from human and mouse genetic studies which show that mutations leading to the dysregulation of FGF signals cause a variety of developmental disorders including dominant skeletal diseases and cancer. The FGF ligands signal via a family of receptor tyrosine kinases and, depending on the cell type or stage of maturation, produce diverse biological responses that include proliferation, growth arrest, differentiation or apoptosis.
July 30,2005 Beneficial autoimmunity in Type 1 diabetes mellitus
  The trigger that leads to the pathogenesis of type 1 diabetes is currently unknown. It is well established that the pathophysiology of the disease is biphasic. In the first stage, leukocytes infiltrate the pancreatic islets in a response that does not cause damage. In the second phase, which occurs only in diabetes-prone individuals and strains, autoreactive T cells acquire aggressive potential and destroy the majority of the pancreatic islets. Rodents and humans exhibit a physiological ripple of apoptotic β-cell death shortly after birth, which induces an adaptive autoimmune response towards islet-antigens, both in diabetes-prone nonobese diabetic (NOD) mice and in mice that do not develop diabetes.
July 29,2005 Fusion oncogenes in tumor development
  Currently, all identified fusion oncogenes are found in rare tumor forms, and most of them only in specific tumor types. Some fusion oncogenes are frequent in healthy individuals suggesting that they rarely induce tumor growth. Multiple double-strand breaks that cluster in time and space increases the risk for formation of fusion oncogenes genes. The normal cell type specific spatial distribution of chromatin and genes in interphase nuclei may affect the risk for fusion of specific genes. Transcriptional orientation, splicing of reading frames, size and sequences of breakpoint introns are other risk factors. The biological activity of fusion oncoproteins is the most important factor for penetrance.
July 28,2005 Genetic therapies for cardiovascular diseases
  Recent advances in understanding the molecular and cellular basis of cardiovascular diseases, together with the availability of tools for genetic manipulation of the cardiovascular system, offer possibilities for new treatments. Gene therapies have demonstrated potential usefulness for treating complex cardiovascular diseases, such as hypertension, atherosclerosis and myocardial ischemia, in various animal models. Some of these experimental therapies are now undergoing clinical evaluation in patients with cardiovascular disease. However, the successful transition of these therapies into mainstream clinical practice awaits further improvements to vector platforms and delivery tools and the documentation of clinical feasibility, safety and efficacy through multi-center randomized trials.
July 27,2005 Cardiac tumours: diagnosis and management
  Primary cardiac tumours are rare, with an autopsy incidence ranging from 0·001% to 0·030%. Three-quarters of these tumours are benign and nearly half of the benign tumours are myxomas. Metastases to the heart are far more common than primary cardiac tumours. Primary cardiac tumours present with one or more of the symptoms of the classic triad of: cardiac symptoms and signs resulting from intracardiac obstruction; signs of systemic embolisation; and systemic or constitutional symptoms. They are diagnosed by use of transthoracic and transoesophageal echocardiograms, MRI, and CT scan. Whereas surgery is indicated in patients with benign tumours, systemic chemotherapy is indicated in those who have widespread or unresectable malignant disease, and chemotherapy and radiotherapy are usually combined in treatment of patients with primary cardiac lymphomas.
July 26,2005 Severe acute respiratory syndrome (SARS): epidemiology and clinical features
  Severe acute respiratory syndrome (SARS) is a newly emerged infectious disease with a significant morbidity and mortality. The major clinical features include persistent fever, chills/rigor, myalgia, malaise, dry cough, headache, and dyspnoea. Older subjects may present without the typical febrile response. Common laboratory features include lymphopenia, thrombocytopenia, raised alanine transaminases, lactate dehydrogenase, and creatine kinase. The constellation of compatible clinical and laboratory findings, together with certain characteristic radiological features and lack of clinical response to broad spectrum antibiotics, should arouse suspicion of SARS.
July 25,2005 The metabolic syndrome
  The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.
July 24,2005 Platelets and Chemokines in Atherosclerosis
  It becomes increasingly evident that blood platelets do not only exert important functions in hemostasis and thrombus formation but are also involved in atherosclerotic vascular disease. A major portion of the underlying mechanisms is related to an intricate functional interaction of platelets with chemokines, which have also been implicated in atherogenesis and neointima formation: (1) Platelets can induce the secretion of chemokines in different cells of the vascular wall; (2) In combination with primary agonists, certain chemokines can potentiate platelet aggregation and adhesion; (3) Activated platelets can release and deposit chemokines and precursors on vascular cell surfaces, which trigger atherogenic recruitment of vascular cells or modulate crucial processes such as angiogenesis and lipoprotein metabolism; (4) Surface-adherent platelets can bind and present vascular cell-derived chemokines to trigger arrest of circulating mononuclear cells.
July 23,2005 Epigenetic control of B cell differentiation
  Gene expression, differentiation and the specialized function of various cell types are controlled epigenetically by post-translational histone modifications. These modifications establish a “histone code” that is recognized by various regulatory proteins, thereby creating a stable pattern of gene expression. The focus of this review is to discuss how the chromatin modifications regulate immunoglobulin gene rearrangement and B cell differentiation.
July 22,2005 CHEMICAL APPROACHES TO THE DISCOVERY AND DEVELOPMENT OF CANCER THERAPIES
  The chemical sciences are essential for the process of anticancer-drug discovery, and a range of chemical research techniques is needed to develop clinically effective drugs. Improved understanding of the cellular, molecular and genetic basis of cancer has increased the number of drug targets available. What chemical approaches are used to develop agents that target specific features of cancer cells and make these therapeutics more effective? We outline the roles that chemical synthesis and understanding of drug uptake have had in drug discovery over the past 100 years, as well as the chemical insights derived from knowledge of the threedimensional structure of targets.
July 21,2005 Multi-Tasking RGS Proteins in the Heart
  Regulator of G-protein–signaling (RGS) proteins play a key role in the regulation of G-protein– coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved ≈120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for Gα proteins. Most RGS proteins can serve as GAPs for multiple isoforms of Gα and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners.
July 20,2005 The role of membranes and membrane trafficking in RNA localization
  Eukaryotic cells possess highly sophisticated membrane trafficking pathways that define specific membrane domains and provide a means for moving vesicles between them (Mostov, Su, and ter Beest, 2003, Nat. Cell Biol. 5, 287–293). Here, I review recent data that indicate a role for membrane trafficking in mRNA localization. Specifically, I review evidence that some localized mRNAs are anchored to specific membrane domains and/or transported on membranous organelles or vesicles to specific subcellular sites. This review is not intended as a discussion on indirect influences of membrane trafficking on mRNA localization.
July 19,2005 Glucagon-like peptide 1(GLP-1) in biology and pathology
  Post-translational proteolytic processing of the preproglucagon gene in the gut results in the formation of glucagon-like peptide 1 (GLP-1). Owing to its glucose-dependent insulinotropic effect, this hormone was postulated to primarily act as an incretin, i.e. to augment insulin secretion after oral glucose or meal ingestion. In addition, GLP-1 decelerates gastric emptying and suppresses glucagon secretion. Under physiological conditions, GLP-1 acts as a part of the ‘ileal brake’, meaning that is slows the transition of nutrients into the distal gut. Animal studies suggest a role for GLP-1 in the development and growth of the endocrine pancreas. In light of its multiple actions throughout the body, different therapeutic applications of GLP-1 are possible.
July 18,2005 Role of Progenitor Cells in Transplant Arteriosclerosis
  To date, chronic transplant dysfunction (CTD) is recognized as the major cause of transplant loss long term after transplantation. CTD has the remarkable histologic feature that the luminal areas of the intragraft arteries become obliterated as a result of occlusive neointima formation. Neointimal lesions contain predominantly vascular smooth muscle cells (VSMCs) and extracellular matrix admixed with inflammatory cells. At the luminal side, neointimal lesions are covered with a monolayer of endothelial cells (ECs).
July 17,2005 CELL BIOLOGY OF ANTIGEN PROCESSING IN VITRO AND IN VIVO
  The conversion of exogenous and endogenous proteins into immunogenic peptides recognized by T lymphocytes involves a series of proteolytic and other enzymatic events culminating in the formation of peptides bound to MHC class I or class II molecules. Although the biochemistry of these events has been studied in detail, only in the past few years has similar information begun to emerge describing the cellular context in which these events take place. This review thus concentrates on the properties of antigen-presenting cells, especially those aspects of their overall organization, regulation, and intracellular transport that both facilitate and modulate the processing of protein antigens.
July 16,2005 MMUNOSUPPRESSIVE NETWORKS IN THE TUMOUR ENVIRONMENT AND THEIR THERAPEUTIC RELEVANCE
  It is well known that many tumours are potentially immunogenic, as corroborated by the presence of tumour-specific immune responses in vivo. Nonetheless, spontaneous clearance of established tumours by endogenous immune mechanisms is rare. Therefore, the focus of most cancer immunotherapies is to supplement essential immunogenic elements to boost tumour-specific immunity. Why then has tumour immunotherapy resulted in a generally poor clinical efficiency? The reason might lie in the increasingly documented fact that tumours develop diverse strategies that escape tumour-specific immunity.
July 15,2005 Device Therapy in the Management of Congestive Heart Failure
  Despite significant advancements in the treatment of heart failure over the past 2 decades, this patient population is still subject to considerably high morbidity and mortality rates. In recent years, the field of device therapy as adjunctive treatment to the medical management of congestive heart failure has grown in the wake of the large number of randomized trials that have demonstrated the safety and efficacy of these devices. The implantable defibrillator currently represents the standard of care in certain segments of the heart failure population, even in those without a prior arrhythmic event. Biventricular pacing systems appear to have a role in heart failure patients with prolongation of their QRS duration in improving ventricular performance and symptoms, if not mortality.
July 14,2005 MARGINAL ZONE B CELLS
  Our views regarding the origins and functions of splenic marginal zone B cells have changed considerably over the past few years. Perspectives regarding the development and function of these cells vary considerably between investigators studying human and rodent immunology. Marginal zone B cells are now recognized to constitute a distinct naive B lymphoid lineage. Considerable progress has been made regarding the mechanisms involved in marginal zone B cell development in the mouse. Many of the molecular events that participate in the retention of this lineage of B cells in the marginal zone have been identified.
July 13,2005 The metabolic syndrome
  The metabolic syndrome is a common metabolic disorder that results from the increasing prevalence of obesity. The disorder is defined in various ways, but in the near future a new definition(s) will be applicable worldwide. The pathophysiology seems to be largely attributable to insulin resistance with excessive flux of fatty acids implicated. A proinflammatory state probably contributes to the syndrome. The increased risk for type 2 diabetes and cardiovascular disease demands therapeutic attention for those at high risk. The fundamental approach is weight reduction and increased physical activity; however, drug treatment could be appropriate for diabetes and cardiovascular disease risk reduction.
July 12,2005 Angiogenesis: Where Do We Stand Now?
  The concept of modulating blood vessel growth—stimulation or inhibition—to serve a desired clinical goal has an enormous intellectual appeal. It can be used to relieve ischemia in tissues with compromised arterial blood supply, improve edema in areas of impaired lymphatic drainage, and inhibit the growth of tumors. Other applications involve facilitating reendothelialization and inhibiting neointima formation after vascular injury, preventing the progression of atherosclerotic plaque, and promoting “vascular health” in general. The least-explored application of this concept involves modulating body and organ size by regulating the endothelial cell mass.
July 11,2005 GENE–ENVIRONMENT INTERACTIONS IN HUMAN DISEASES
  Studies of gene–environment interactions aim to describe how genetic and environmental factors jointly influence the risk of developing a human disease. Gene–environment interactions can be described by using several models, which take into account the various ways in which genetic effects can be modified by environmental exposures, the number of levels of these exposures and the model on which the genetic effects are based. Choice of study design, sample size and genotyping technology influence the analysis and interpretation of observed gene–environment interactions. Current systems for reporting epidemiological studies make it difficult to assess whether the observed interactions are reproducible, so suggestions are made for improvements in this area.
July 10,2005 TUMOUR STEM CELLS AND DRUG RESISTANCE
  The contribution of tumorigenic stem cells to haematopoietic cancers has been established for some time, and cells possessing stem-cell properties have been described in several solid tumours. Although chemotherapy kills most cells in a tumour, it is believed to leave tumour stem cells behind, which might be an important mechanism of resistance. For example, the ATP-binding cassette (ABC) drug transporters have been shown to protect cancer stem cells from chemotherapeutic agents. Gaining a better insight into the mechanisms of stem-cell resistance to chemotherapy might therefore lead to new therapeutic targets and better anticancer strategies.
July 9,2005 Leptin receptor action and mechanisms of leptin resistance
  The adipose tissue-derived hormone leptin regulates energy balance and neuroendocrine function. Resistance to the appetite-suppressing effects of leptin is associated with common forms of obesity. Here, we review the mechanisms by which leptin activates intracellular signals and the roles that these signals play in leptin action in vivo. Furthermore, we discuss potential mechanisms of leptin resistance, specifically focusing on data regarding the neuroanatomical locus of leptin resistance and potential mechanisms by which expression of the suppressor of cytokine signaling-3 may impair leptin action.
July 8,2005 Embryonic Stem Cells: Prospects for Developmental Biology and Cell Therapy
  Stem cells represent natural units of embryonic development and tissue regeneration. Embryonic stem (ES) cells, in particular, possess a nearly unlimited self-renewal capacity and developmental potential to differentiate into virtually any cell type of an organism. Mouse ES cells, which are established as permanent cell lines from early embryos, can be regarded as a versatile biological system that has led to major advances in cell and developmental biology. Human ES cell lines, which have recently been derived, may additionally serve as an unlimited source of cells for regenerative medicine. Before therapeutic applications can be realized, important problems must be resolved. Ethical issues surround the derivation of human ES cells from in vitro fertilized blastocysts.
July 7,2005 Signal transducer and activator of transcription (STAT) signalling and T-cell lymphomas
  Interaction of cytokines with their cognate receptors leads to the activation of latent transcription factors – the signal transducers and activators of transcription (STAT) proteins – whose biological activities ultimately regulate many critical aspects of cell growth, survival and differentiation. Dysregulation of the JAK-STAT pathway is frequently observed in many primary human tumours, reflecting the importance of this pathway in the maintenance of cellular integrity. Here we review the current progress in STAT structure and function, and the contribution of STAT signalling to the pathogenesis of T-cell lymphomas.
July 6,2005 Signaling Mechanisms in Cerebral Vasospasm
  The elusive nature of events that sustain cerebral vasospasm after subarachnoid hemorrhage resulting from a ruptured aneurysm presents major challenges in designing effective therapies for this frequently devastating condition. Protracted cerebral artery constriction entails several dynamic components in intracellular signaling events initiated by endothelial factors, products of hemolysate, and numerous kinases, as well as increased intracellular Ca2+. The rationale for potential treatment modalities and their efficacy are discussed in this brief review.
July 5,2005 Genetics of Type 2 diabetes
  Type 2 diabetes (T2D) has become a health-care problem worldwide, with the rise in disease prevalence being all the more worrying as it not only affects the developed world but also developing nations with fewer resources to cope with yet another major disease burden. Furthermore, the problem is no longer restricted to the ageing population, as young adults and children are also being diagnosed with T2D. In recent years, there has been a surge in the number of genetic studies of T2D in attempts to identify some of the underlying risk factors. In this review, I highlight the main genes known to cause uncommon monogenic forms of diabetes , as well as describe some of the main approaches used to identify genes involved in the more common forms of T2D that result from the interaction between environmental risk factors and predisposing genotypes.
July 4,2005 Concepts in nuclear architecture
  Genomes are defined by their primary sequence. The functional properties of genomes, however, are determined by far more complex mechanisms and depend on multiple layers of regulatory control processes. A key emerging contributor to genome function is the architectural organization of the cell nucleus. The spatial and temporal behavior of genomes and their regulatory proteins are now being recognized as important, yet still poorly understood, control mechanisms in genome function. Combined cell biological, molecular and computational analysis of architectural aspects of genome function has added a further dimension to the investigation of some of the most fundamental cellular processes including transcription and maintenance of genome integrity.
July 3,2005 Regulation of Vascular Calcification
  Vascular calcification is prevalent in aging as well as a number of pathological conditions, and it is now recognized as a strong predictor of cardiovascular events in the general population as well as diabetic and end-stage renal disease patients. Vascular calcification is a highly regulated process involving inductive and inhibitory mechanisms. This article focuses on two molecules, phosphate and osteopontin, that have been implicated in the induction or inhibition of vascular calcification, respectively. Elevated phosphate is of interest because hyperphosphatemia is recognized as a major nonconventional risk factor for cardiovascular disease mortality in end-stage renal disease patients.
July 2,2005 Why Ribonucleases Induce Tumor Cell Death
  The characteristics and the possible mechanisms of action of cytotoxic ribonucleases (RNases), promising antitumor drugs, are described. Original experimental data and the results of analysis of recent publications have made it possible to identify the cellular components providing for the selective effects of exogenous RNases on tumor cells, on the one hand, and to estimate the contributions of individual molecular determinants to the enzyme cytotoxicity, on the other hand. The predominant effect of the electric charge of the RNase molecule on the induction of cell death has been demonstrated. The cytotoxic effects of RNases are determined by the catalytic cleavage of accessible RNA, the action of the products of its hydrolysis, and the noncatalytic electrostatic interaction of the exogenous enzyme with cell components.
July 1,2005 China’s environment in a globalizing world
  China's environmental problems dominate those of the world, not only because China contains a fifth of the world's people, but also because China's economy is so big and developing so rapidly. The expanding links of globalization mean that China's problems are the world's problems too. In a Feature this week, Jianguo Liu and Jared Diamond look at the effects of China's sweeping environmental change and socio-economic challenges, synthesizing detailed literature that is scattered even for Chinese readers and largely inaccessible to western readers. On the cover, crowds on Nanjing Lu, Shanghai's famous shopping street where global influences are clear to see (Mark Henley/Panos). Elsewhere in the issue, Peter Aldhous reports on how China plans to cope with its exploding need for energy.

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