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September 30,2005 The genetic epidemiology of neurodegenerative disease
  Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.
September 29,2005 Vaccinology at the beginning of the 21st century
  Today, the main challenges for vaccinologists include improving vaccines against as yet undefeated pathogens, rapid identification and response to emerging diseases and successful intervention in chronic diseases in which ongoing immune responses are insufficient. Reverse genetics and reverse vaccinology are now used to generate rapidly new vaccine strains and to mine whole genomes in the search for promising antigens. The rational design of adjuvants has become possible as a result of the discovery of the receptors that recognize microbial patterns and lead to dendritic cell activation. Antigen-loaded dendritic cells, DNA in naked, formulated or viral form, and other delivery systems are used to maximize immune responses.
September 28,2005 Bone marrow stem cell transplantation for cardiac repair
  Cardiomyocytes respond to physiological or pathological stress only by hypertrophy and not by an increase in the number of functioning cardiomyocytes. However, recent evidence suggests that adult cardiomyocytes have the ability, albeit limited, to divide to compensate for the cardiomyocyte loss in the event of myocardial injury. Similarly, the presence of stem cells in the myocardium is a good omen. Their activation to participate in the repair process is, however, hindered by some as-yet-undetermined biological impediments. The rationale behind the use of adult stem cell transplantation is to supplement the inadequacies of the intrinsic repair mechanism of the heart and compensate for the cardiomyocyte loss in the event of injury.
September 27,2005 Disordered RNA chaperone proteins
  RNA chaperones are ubiquitous proteins that play pivotal roles in cellular RNA metabolism and RNA virus replication. Here we propose that they act by organizing complex and highly dynamic networks of RNARNA, RNA-protein and protein-protein interactions. How this is achieved and how their malfunction may lead to disease will be discussed through the examples of human immunodeficiency virus type 1 nucleocapsid protein (NCp7), the fragile X mental retardation protein and the prion protein.
September 26,2005 Pathophysiology of Coronary Artery Disease
  During the past decade, our understanding of the pathophysiology of coronary artery disease (CAD) has undergone a remarkable evolution. We review here how these advances have altered our concepts of and clinical approaches to both the chronic and acute phases of CAD. Previously considered a cholesterol storage disease, we currently view atherosclerosis as an inflammatory disorder. The appreciation of arterial remodeling (compensatory enlargement) has expanded attention beyond stenoses evident by angiography to encompass the biology of nonstenotic plaques. Revascularization effectively relieves ischemia, but we now recognize the need to attend to nonobstructive lesions as well.
September 25,2005 Cytokine and Growth Factor Receptors in the Nucleus
  Signaling via cell surface receptors that are anchored by a single transmembrane domain is a wellestablished paradigm. Ligand binding to the extracellular domain of the receptor facilitates receptor dimerization, which juxtaposes the intracellular domains, typically activating intrinsic or associated kinases. Two large families of tyrosine kinase activating receptors have been particularly well characterized: the receptor-type protein tyrosine kinases and the receptors for the a-helical cytokines, which activate non-covalently bound JAK family tyrosine kinases. Despite the wellestablished function of these receptors at the cell surface, both intact and cleaved receptors belonging to these families have been repeatedly detected in the nucleus.
September 24,2005 RNA interference in biology and disease
  RNA interference (RNAi) is a conserved biologic response to double-stranded RNA that results in the sequence-specific silencing of target gene expression. Over the past 5 years, an intensive research effort has facilitated the rapid movement of RNAi from a relatively obscure biologic phenomenon to a valuable tool used to silence target gene expression and perform large-scale functional genomic screens. In fact, recent studies reported in this journal and others have demonstrated success using RNAi to address the role of oncogene expression in leukemia cell lines and to validate the therapeutic potential of RNAi for treating these blood disorders. In order to advance these applications and gain an appreciation for the future of RNAi both in basic research and in the treatment of diseases caused by aberrant gene expression, it is important to have an understanding of the process of RNAi and its limitations.
September 23,2005 Extracellular Proteases in Atherosclerosis and Restenosis
  Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases (matrix metalloproteinases, adamalysins, or pappalysins), serine proteases (elastase, coagulation factors, plasmin, tissue plasminogen activator, urokinase plasminogen activator), and the cysteine proteases (such cathepsins).
September 22,2005 Developments in transgenic technology: applications for medicine
  Recent advances in the efficiency of transgenic technology have important implications for medicine. The production of therapeutic proteins from animal bioreactors is well established and the first products are close to market. The genetic modification of pigs to improve their suitability as organ donors for xenotransplantation has been initiated, but many challenges remain. The use of transgenesis, in combination with the method of RNA interference to knock down gene expression, has been proposed as a method for making animals resistant to viral diseases, which could reduce the likelihood of transmission to humans. Here, the latest developments in transgenic technology and their applications relevant to medicine and human health will be discussed.
September 21,2005 Genetic epidemiology of diabetes
  Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information.
September 20,2005 ACAT2 Is a Target for Treatment of Coronary Heart Disease Associated With Hypercholesterolemia
  The inhibition of intracellular cholesterol esterification as a means to prevent atherosclerosis has been considered to have potential for many years. Two different ACAT enzymes were discovered about 7 years ago, and it has become clear that the two enzymes provide separate physiologic functions. Much has been learned from mice with gene deletions for either ACAT1 or ACAT2. Deletion of ACAT2 has consistently been atheroprotective whereas deletion of ACAT1 has been varyingly problematic. ACAT1 functions in converting cellular cholesterol into cholesteryl ester in response to cholesterol abundance inside the cells.
September 19,2005 Integrin-actin interactions
  The integrin family of extracellular matrix receptors regulates many aspects of cell life, in particular cell adhesion and migration. These two processes depend on organization of the actin cytoskeleton into adhesive and protrusive organelles in response to extracellular signals. Integrins are important switch points for the spatiotemporal control of actin-based motility in higher eukaryotes. Ligands of integrin cytoplasmic tails are central elements of signalling pathways involving small GTPases as well as protein and lipid kinases in the regulation of Factin crosslinking, actin treadmilling and de novo nucleation of actin filaments. We present an overview of common pathways and discuss recent evidence for their differential use by individual integrin receptors.
September 18,2005 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.
September 17,2005 Extracellular Proteases in Atherosclerosis and Restenosis
  Extracellular proteolysis plays a key role in many pathophysiologic processes including cancer, inflammatory diseases, and cardiovascular conditions such as atherosclerosis and restenosis. Whereas matrix metalloproteinases are their best known member, many others are becoming better known. The extracellular proteases are a complex and heterogeneous superfamily of enzymes. They include metalloproteinases , serine proteases , and the cysteine proteases (such cathepsins). In addition to their matrix degradation capabilities, they have other less well known biologic functions that include angiogenesis, growth factor bioavailability, cytokine modulation, receptor shedding, enhancing cell migration, proliferation, invasion, and apoptosis.
September 16,2005 Calpains and Disease
  Calpains are ca 2+ -dependent cysteine proteases (proteolytic enzymes with cysteine in the catalytic site) that modulate cellular function. In humans, 14 independent genes encode members of the calpain superfamily. Some calpain proteases are confined to specific tissues, whereas others are ubiquitous. Tissue-specific calpains have been implicated in diabetes, cataracts, multiple sclerosis, cancer, Duchenne’s muscular dystrophy, and Alzheimer’s disease and are known to cause at least one disorder, autosomal recessive limb-girdle muscular dystrophy type 2A (LGMD2A).
September 15,2005 DNA methylation disturbances as novel therapeutic target in lung cancer: Preclinical and clinical results
  The prognosis of lung cancer is very much limited by the difficulties of diagnosing early stage disease amenable to surgery. Thus, novel diagnostic and therapeutic approaches are urgently needed for this common type of cancer. Recently, epigenetic alterations of tumor cells have been defined for a multitude of tissues and genes. Thus, promoter hypermethylation of tumor suppressor genes, and other targets of neoplasia-associated methylation disturbances, have become the most frequent recurrent alteration in solid tumors and hematologic neoplasia. In lung cancer, several sets of genes including the tumor suppressor gene p16, the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT), E-cadherin and retinoic acid receptor beta have been shownto be frequently methylated and inactivated.
September 14,2005 Molecular mechanisms of fibrinolysis
  The molecular mechanisms that finely co-ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of genetargeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess.
September 13,2005 Complex molecules: do they add value?
  The concept of complexity in chemistry has received much interest in the research community. Various measures to assess molecular complexity have been published, ranging from abstract complexity definitions to very specific application-oriented definitions. In this article we focus on molecular complexity in relation to biological activity. Connectivity and feature-based structural descriptors have been evaluated with reference to their potential as complexity measures. Our goal was to discuss the potential of the complexity concept to support the drug discovery process, helping to design suitable lead candidates. The studies have shown that highly active compounds, on average, are more complex than inactive compounds.
September 12,2005 TRANSCRIPTIONAL NETWORKS IN DEVELOPING AND MATURE B CELLS
  The development of B cells from haematopoietic stem cells proceeds along a highly ordered, yet flexible, pathway. At multiple steps along this pathway, cells are instructed by transcription factors on how to further differentiate, and several check-points have been identified. These check-points are initial commitment to lymphocytic progenitors, specification of pre-B cells, entry to the peripheral B-cell pool, maturation of B cells and differentiation into plasma cells. At each of these regulatory nodes, there are transcriptional networks that control the outcome, and much progress has recently been made in dissecting these networks. This article reviews our current understanding of this exciting field.
September 11,2005 Nuclear Factor κB Signaling in Atherogenesis
  Atherosclerosis is an inflammatory disease, characterized by the accumulation of macrophage-derived foam cells in the vessel wall and accompanied by the production of a wide range of chemokines, cytokines, and growth factors. These factors regulate the turnover and differentiation of immigrating and resident cells, eventually influencing plaque development. One of the key regulators of inflammation is the transcription factor nuclear factor κB (NF-κB), which, for a long time, has been regarded as a proatherogenic factor, mainly because of its regulation of many of the proinflammatory genes linked to atherosclerosis.
September 10,2005 Allosteric Mechanisms of Signal Transduction
  Forty years ago, a simple model of allosteric mechanisms (indirect interactions between distinct sites), used initially to explain feedback-inhibited enzymes, was presented by Monod, Wyman, and Changeux. We review the MWC theory and its applications for the understanding of signal transduction in biology, and also identify remaining issues that deserve theoretical and experimental substantiation.
September 9,2005 The genetic epidemiology of neurodegenerative disease
  Gene defects play a major role in the pathogenesis of degenerative disorders of the nervous system. In fact, it has been the very knowledge gained from genetic studies that has allowed the elucidation of the molecular mechanisms underlying the etiology and pathogenesis of many neurodegenerative disorders. In this review, we discuss the current status of genetic epidemiology of the most common neurodegenerative diseases: Alzheimer disease, Parkinson disease, Lewy body dementia, frontotemporal dementia, amyotrophic lateral sclerosis, Huntington disease, and prion diseases, with a particular focus on similarities and differences among these syndromes.
September 8,2005 Stem Cells and the Regenerating Heart
  Despite current pharmacologic and whole organ transplantation strategies, advanced heart failure remains a common and deadly disease. Limited availability of donor organs for use in orthotopic heart transplantation has prompted the examination of alternative therapies, including cell transfer strategies. Stem cell populations have been identified in virtually all postnatal tissues with the exception of the heart, and these stem cells function in the maintenance and regeneration of the respective tissues. Recent studies challenge preexisting notions regarding cardiac repair and suggest that the heart is capable of limited regeneration through the activation of resident cardiac stem cells or the recruitment of stem cell populations from other tissues such as the bone marrow.
September 7,2005 PREVENTING RE-REPLICATION OF CHROMOSOMAL DNA
  To ensure its duplication, chromosomal DNA must be precisely duplicated in each cell cycle, with no sections left unreplicated, and no sections replicated more than once. Eukaryotic cells achieve this by dividing replication into two non-overlapping phases. During late mitosis and G1, replication origins are ‘licensed’ for replication by loading the minichromosome maintenance (Mcm) 2–7 proteins to form a pre-replicative complex. Mcm2–7 proteins are then essential for initiating and elongating replication forks during S phase. Recent data have provided biochemical and structural insight into the process of replication licensing and the mechanisms that regulate it during the cell cycle.
September 6,2005 Protein families and RNA recognition
  This minireview series examines the structural principles underlying the biological function of RNA-binding proteins. The structural work of the last decade has elucidated the structures of essentially all the major RNAbinding protein families; it has also demonstrated how RNA recognition takes place. The ribosome structures have further integrated this knowledge into principles for the assembly of complex ribonucleoproteins. Structural and biochemical work has revealed unexpectedly that several RNA-binding proteins bind to other proteins in addition to RNA or instead of RNA.
September 5,2005 Tissue-Engineered Blood Vessels
  Although vascular bypass grafting remains the mainstay for revascularization for ischemic heart disease and peripheral vascular disease, many patients do not have healthy vessels suitable for harvest. Thus, prosthetic grafts made of synthetic polymers were developed, but their use is limited to high-flow/low-resistance conditions because of poor elasticity, low compliance, and thrombogenicity of their synthetic surfaces. To fill this need, several laboratories have produced in vivo or in vitro tissue-engineered blood vessels using molds or prosthetic or biodegradable scaffolds, but each artificial graft has significant problems.
September 4,2005 Genetic epidemiology of diabetes
  Conventional genetic analysis focuses on the genes that account for specific phenotypes, while traditional epidemiology is more concerned with the environmental causes and risk factors related to traits. Genetic epidemiology is an alliance of the 2 fields that focuses on both genetics, including allelic variants in different populations, and environment, in order to explain exactly how genes convey effects in different environmental contexts and to arrive at a more complete comprehension of the etiology of complex traits. In this review, we discuss the epidemiology of diabetes and the current understanding of the genetic bases of obesity and diabetes and provide suggestions for accelerated accumulation of clinically useful genetic information.
September 3,2005 New insights into E-protein function in lymphocyte development
  Lymphocyte development has long served as an experimental paradigm, revealing fundamental mechanisms of gene regulation and cellular differentiation in mammals. The study of E-protein-mediated transcriptional regulation in lymphocyte development provides a means to address these mechanistic issues. Both genetic and biochemical studies have defined many important regulatory events during lymphocyte development that are mediated by E-proteins. The E2A gene, one of the three known E-protein genes in mammals, has a particularly important role in B-lymphocyte development. Major progress has been made in recent years towards understanding the physiological targets of E2A during B-lymphocyte development.
September 2,2005 Myeloperoxidase and Cardiovascular Disease
  Myeloperoxidase (MPO) is a leukocyte-derived enzyme that catalyzes the formation of a number of reactive oxidant species. In addition to being an integral component of the innate immune response, evidence has emerged that MPO-derived oxidants contribute to tissue damage during inflammation. MPO-catalyzed reactions have been attributed to potentially proatherogenic biological activities throughout the evolution of cardiovascular disease, including during initiation, propagation, and acute complication phases of the atherosclerotic process. As a result, MPO and its downstream inflammatory pathways represent attractive targets for both prognostication and therapeutic intervention in the prophylaxis of atherosclerotic cardiovascular disease.
September 1,2005 Neural circuitry of judgment and decision mechanisms
  Tracing the neural circuitry of decision formation is a critical step in the understanding of higher cognitive function. To make a decision, the primate brain coordinates dynamic interactions between several cortical and subcortical areas that process sensory, cognitive, and reward information. In selecting the optimal behavioral response, decision mechanisms integrate the accumulating evidence with reward expectation and knowledge from prior experience, and deliberate about the choice that matches the expected outcome. Linkages between sensory input and behavioral output responsible for response selection are shown in the neural activity of structures from the prefrontal-basal gangliathalamo- cortical loop.

August July June May April March February January 2004 2003 2002 2001