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| March 31,2005 | Another step forward for SELEXive splicing | ||||||||
| Splicing alterations are being increasingly reported to cause human diseases. However, predicting beforehand whether a given mutation might lead to aberrant splicing is often hampered by insufficient knowledge of which cis-acting sequences affect exon recognition. To better define these sequences, experimental methods have been developed that integrate pre-mRNA splicing with sequence selection assays. Recently, a novel in vivo selection method based on a partially randomized fulllength exon has enabled the identification of new splicing-controlling elements in SMN exon 7. Skipping of this exon results in an aberrant protein and is involved in proximal spinal muscular atrophy (SMA). Hopefully, this approach will provide novel targets for nascent RNA molecular medicine approaches for the recovery of abnormal pre-mRNA splicing events. | |||||||||
| March 30,2005 | Innate Immunity and Angiogenesis | ||||||||
| Activation of an innate immune response is among the first lines of defense after tissue injury. Restoring blood flow to the site of injured tissue is often a necessary prerequisite for mounting an initial immune response to pathogens and for subsequent initiation of a successful repair of wounded tissue. The multiple links among pathogen recognition and suppression, increased angiogenesis, and tissue repair are the topics of this review, which examines of the roles of antimicrobial peptides, mammalian toll-like receptors (TLRs), inflammatory cytokines, and putative “danger” signals, among other signaling pathways, in triggering, sustaining, and then terminating an angiogenic response. | |||||||||
| March 29,2005 | The human protein disulphide isomerase family: substrate interactions and functional properties | ||||||||
| The process of disulphide bond formation in the endoplasmic reticulum of eukaryotic cells was one of the first mechanisms of catalysed protein folding to be discovered. Protein disulphide isomerase (PDI) is now known to catalyse all of the reactions that are involved in native disulphide bond formation, but despite more than 40 years of study, its mechanism of action is still not fully understood. This review discusses recent advances in our understanding of the human PDI family of enzymes and focuses on their functional properties, substrate interactions and some recently identified family members. | |||||||||
| March 28,2005 | GALECTINS AS MODULATORS OF TUMOUR PROGRESSION | ||||||||
| Galectins are a family of animal lectins with diverse biological activities. They function both extracellularly, by interacting with cell-surface and extracellular matrix glycoproteins and glycolipids, and intracellularly, by interacting with cytoplasmic and nuclear proteins to modulate signalling pathways. Current research indicates that galectins have important roles in cancer; they contribute to neoplastic transformation, tumour cell survival, angiogenesis and tumour metastasis. They can modulate the immune and inflammatory responses and might have a key role helping tumours to escape immune surveillance. How do the different members of the Galectin family contribute to these diverse aspects of tumour biology? | |||||||||
| March 27,2005 | Role of Caveolae and Caveolins in Health and Disease | ||||||||
| Although they were discovered more than 50 years ago, caveolae have remained enigmatic plasmalemmal organelles. With their characteristic “flasklike” shape and virtually ubiquitous tissue distribution, these interesting structures have been implicated in a wide range of cellular functions. Similar to clathrin-coated pits, caveolae function as macromolecular vesicular transporters, while their unique lipid composition classifies them as plasma membrane lipid rafts, structures enriched in a variety of signaling molecules. The caveolin proteins (caveolin-1, -2, and -3) serve as the structural components of caveolae, while also functioning as scaffolding proteins, capable of recruiting numerous signaling molecules to caveolae, as well as regulating their activity. | |||||||||
| March 26,2005 | Transcriptional Regulation of Renin | ||||||||
| Renin, as a component of the renin-angiotensin system, plays important roles in the regulation of blood pressure, electrolyte homeostasis, and mammalian renal development. Transcription of renin genes is subject to complex developmental and tissue-specific regulation. Progress has been made recently in elucidating the molecular mechanisms involved in renin gene expression. Using mouse As4.1 cells, which have many features characteristic of the renin-expressing juxtaglomerular cells of kidney, a proximal promoter region (-197 to -50 bp) and an enhancer (-2866 to -2625 bp) have been identified in the mouse renin gene, Ren-1c, that are critical for its expression. | |||||||||
| March 25,2005 | 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. | |||||||||
| March 24,2005 | ANTIGEN-SPECIFI CMEMORY B CELL DEVELOPMENT | ||||||||
| Helper T (Th) cell–regulated B cell immunity progresses in an ordered cascade of cellular development that culminates in the production of antigen-specific memory B cells. The recognition of peptide MHC class II complexes on activated antigen-presenting cells is critical for effective Th cell selection, clonal expansion, and effector Th cell function development (Phase I). Cognate effector Th cell–B cell interactions then promote the development of either short-lived plasma cells (PCs) or germinal centers (GCs) (Phase II). These GCs expand, diversify, and select highaffinity variants of antigen-specific B cells for entry into the long-lived memory B cell compartment (Phase III). | |||||||||
| March 23,2005 | PROGRESS TOWARD AN HIV VACCINE | ||||||||
| The development of an HIV vaccine is proving to be an unprecedented challenge. The difficulty in creating this vaccine arises from the enormous genetic variation of the virus and the unusual importance of cytotoxic T lymphocytes (CTL) in controlling its spread. Whereas traditional vaccine strategies are unlikely to confer safe and effective HIV protection, novel strategies for eliciting CTL have provided substantial clinical benefits in nonhuman primate model systems. These vaccine strategies, including plasmid DNA and live recombinant vectors, are currently being evaluated in human clinical trials. | |||||||||
| March 22,2005 | 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. | |||||||||
| March 21,2005 | Proteomic analysis for the early detection and rational treatment of cancer—realistic hope? | ||||||||
| Proteomics is an emerging field in medical science focused on the library of proteins specific to a given biosystem, the proteome, and understanding relationships therein. This field incorporates technologies that can be applied to serum and tissue in order to extract important biological information to aid clinicians and scientists in understanding the dynamic biology of their system of interest, such as a patient with cancer. These tools include laser capture microdissection, tissue lysate arrays and mass spectrometry approaches. These new technologies are more potent coupled with advanced bioinformatics analysis. They are used to characterize the content of, and changes in, the proteome induced by physiological changes, benign and pathologic. | |||||||||
| March 20,2005 | Immune complex-mediated tissue injury: a multistep paradigm | ||||||||
| Antigen–antibody complexes can damage tissues by triggering inflammation. Recent studies have enabled the description of a sequence of steps, which depend on the intra- or perivascular location of complex formation. Acute lethal toxicity and circulatory shock as a result of the acute release of inflammatory mediators can occur after intravascular complex formation. The lesions associated with perivascular complexes are characterized by plasma leakage and the recruitment of polymorphonuclear leukocytes. These lesions are modulated by mediators released from endothelial cells, namely nitric oxide, endothelins and lipid mediators, and provide an appropriate basis for the activation of both arms of hemostasis: coagulation and fibrinolysis. The balance between both activation systems can explain the late occurrence of both tissue fibrosis and organ remodeling. | |||||||||
| March 19,2005 | Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis | ||||||||
| Proper regulation of the phosphoinositide 3-kinase–Akt pathway is critical for the prevention of both insulin resistance and tumorigenesis. Many recent studies have characterized a negative feedback loop in which components of one downstream branch of this pathway, composed of the mammalian target of rapamycin and ribosomal S6 kinase, block further activation of the pathway through inhibition of insulin receptor substrate function. These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher’s syndrome), and human cancers. | |||||||||
| March 18,2005 | DNA REPAIR DEFECTS IN STEM CELL FUNCTION AND AGING | ||||||||
| Cellular DNA is under constant challenge by exogenous and endogenous genotoxic stress, which results in both transient and accumulated DNA damage and genomic instability. All cells are equipped with DNA damage response pathways that trigger DNA repair, cell cycle arrest, and, if need be, apoptosis, to eliminate DNA damage or damaged cells. The consequences of these processes for stem cells can be profound: diminution in stem cell pools, or, because of altered gene expression, an increased chance for stem cell differentiation or malignant transformation. Furthermore, a number of DNA repair abnormalities are linked to premature aging syndromes, and these are associated with defects in the stem cell population. | |||||||||
| March 17,2005 | Oncogene addiction: Sometimes a temporary slavery | ||||||||
| Tumors induced in conditional oncomice can show remarkable different responses to subsequent oncogene deprivation. Complete sustained regression, concomitant with massive differentiation and/or apoptosis, and partial regression are both observed. In the latter case, tumor growth either resumes without being dependent any longer on the oncogene, or requires reactivation of the oncogene in cells that have become dormant.These models reflect many of the features we also witness in human cancer and can therefore assist us in understanding the underlying mechanisms and in designing more effective treatment protocols. | |||||||||
| March 16,2005 | DNA DEGRADATION IN DEVELOPMENT AND PROGRAMMED CELL DEATH | ||||||||
| Most mammalian cells have nuclei that contain DNA, which replicates during cell proliferation. DNA is destroyed by various developmental processes in mammals. It is degraded during programmed cell death that accompanies mammalian development. The nuclei of erythrocytes and eye lens fiber cells are also removed during their differentiation into mature cells. If DNA is not properly degraded in these processes, it can cause various diseases, including tissue atrophy, anemia, cataract, and autoimmune diseases, which indicates that DNA can be a pathogenic molecule. Here, I present how DNA is degraded during programmed cell death, erythroid cell differentiation, and lens cell differentiation. I discuss what might be or will be learned from understanding the molecular mechanisms of DNA degradation that occurs during mammalian development. | |||||||||
| March 15,2005 | G PROTEIN POLYMORPHISMS IN HYPERTENSION, ATHEROSCLEROSIS, AND DIABETES | ||||||||
| A common C825T polymorphism in the gene GNB3, which encodes the β3 subunit of heterotrimeric G proteins, was identified in cell lines from patients with hypertension. The 825T allele is associated with increased intracellular signal transduction. Many population-based and case-control studies in different ethnicities have investigated an association between this polymorphism and hypertension, obesity, and atherosclerosis. A critical assessment of published studies suggests that 825T allele carriers have an increased risk for hypertension combined with features of the metabolic syndrome, such as dyslipidemia, hypercholesterolemia, insulin resistance, and obesity. It is anticipated that this polymorphism will be used in clinical practice to better characterize hypertension and for individualized treatment regimens. | |||||||||
| March 14,2005 | PPARγ-mediated insulin sensitization: the importance of fat versus muscle | ||||||||
| Peroxisome proliferator-activated receptor-γ (PPARγ) is a nuclear hormone receptor that functions as a transcriptional regulator in a variety of tissues. PPARγ activation, e.g., through binding of the synthetic glitazones or thiazolidinediones (TZD), results in a marked improvement in type 2 diabetic patients of insulin and glucose parameters resulting from an improvement of whole body insulin sensitivity. The role of different metabolic tissues (fat, skeletal muscle, liver) in mediating PPARγ function in glucose and insulin homeostasis is still unclear. Recently, the function of PPARγ in adipose tissue and skeletal muscle has been intensively characterized by using targeted deletion of PPARγ in those tissues. In those studies, adipose PPARγ has been identified as an essential mediator for the maintainance of whole body insulin sensitivity. | |||||||||
| March 13,2005 | Biotechnology, the brain and the future | ||||||||
| Several new approaches to illness, inspired by recent advances in molecular biology, informatics and nanoscience, are readily applicable to diseases of the central nervous system. Novel classes of drugs will widen the scope of therapeutic action beyond merely modifying transmitter function and stem cell and gene therapies could offer an even more selective mode of targeting. Further into the future, nanotechnology has the potential to allow development of new medicines and novel access routes via miniaturized monitoring and screening devices: these systems, together with increasing use of carbon–silicon interfacing, will challenge traditional neuropharmacology. | |||||||||
| March 12,2005 | MOLECULAR GENETICS OFTCELL DEVELOPMENT | ||||||||
| T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them, during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. | |||||||||
| March 11,2005 | Regulatory Mechanisms and Function of ERK MAP Kinases | ||||||||
| Spatiotemporal control of the Ras/ERK MAP kinase signaling pathway is a key factor for determining the specificity of cellular responses including cell proliferation, cell differentiation and cell survival. The fidelity of this signaling is regulated by docking interactions as well as scaffolding. Subcellular localization of ERK is controlled by cytoplasmic ERK anchoring proteins that have a nuclear export signal (NES), such as MEK. In quiescent cells, ERK and MEK localize to the cytoplasm. In response to stimulation, dissociation of the MEK-ERK complex is induced and activated ERK translocates to the nucleus. Recently, several negative regulators for Ras/ERK signaling have been identified and their detailed molecular mechanisms have been analyzed. | |||||||||
| March 10,2005 | Dissecting innate immune responses with the tools of systems biology | ||||||||
| Systems biology strives to derive accurate predictive descriptions of complex systems such as innate immunity. The innate immune system is essential for host defense, yet the resulting inflammatory response must be tightly regulated. Current understanding indicates that this system is controlled by complex regulatory networks, which maintain homoeostasis while accurately distinguishing pathogenic infections from harmless exposures. Recent studies have used high throughput technologies and computational techniques that presage predictive models and will be the foundation of a systems level understanding of innate immunity. | |||||||||
| March 9,2005 | GENE-ENVIRONMENT INTERACTIONS IN ASTHMA AND OTHER RESPIRATORY DISEASES | ||||||||
| It is generally agreed that many lung diseases such as asthma and chronic obstructive pulmonary disease (COPD) have polygenic inheritance, and that the association of a specific genotype or genotypes with the disease is likely to vary between populations. Furthermore, it is recognized that the etiology of many lung diseases involves a complex interplay between genetic background and exposure to multiple environmental stimuli, and understanding the mechanisms through which genes and environment interact represents a major challenge for pulmonary researchers. | |||||||||
| March 8,2005 | SEVERE ACUTE RESPIRATORY SYNDROME (SARS): A Year in Review | ||||||||
| Severe acute respiratory syndrome (SARS) emerged from China as an untreatable and rapidly spreading respiratory illness of unknown etiology. Following point source exposure in February 2003, more than a dozen guests infected at a Hong Kong hotel seeded multi-country outbreaks that persisted through the spring of 2003. The World Health Organization responded by invoking traditional public health measures and advanced technologies to control the illness and contain the cause. A novel coronavirus was implicated and its entire genome was sequenced by mid-April 2003. The urgency of responding to this threat focused scientific endeavor and stimulated global collaboration. | |||||||||
| March 7,2005 | 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. Now, as many cellular signaling molecules have been discovered and ordered into certain pathways, we can better understand why particular signaling proteins are associated with tumorigenesis. | |||||||||
| March 6,2005 | Regulatory T-cells in type 1 diabetes | ||||||||
| Type 1 diabetes is a T-cell-mediated autoimmune disease, resulting in destruction of the insulin-producing beta cells in the pancreas. Disease progression is thought to involve the action of T-cells, particularly those producing Th1-type cytokines. Given the complexity in understanding the precise etiology of autoimmune diseases, the diversity of autoantigens, and the variability that exists between individual patients, it might be very difficult to eliminate autoaggressive T-cell responses without resorting to generalized means of immunosuppression. However, recent evidence shows that autoimmune processes are composed not only of autoaggressive Tcell responses but also of autoreactive regulatory components. Enhancing regulatory T-cell responses, therefore, has become an area of intense focus as a means of treating autoimmune diseases like type 1 diabetes. | |||||||||
| March 5,2005 | Role of Oxidative Modifications in Atherosclerosis | ||||||||
| This review focuses on the role of oxidative processes in athero-sclerosis and its resultant cardiovascular events. There is now a consensus that atherosclerosis represents a state of heightened oxidative stress characterized by lipid and protein oxidation in the vascular wall. The oxidative modification hypothesis of atherosclerosis predicts that low-density lipoprotein (LDL) oxidation is an early event in atherosclerosis and that oxidized LDL contributes to atherogenesis. In support of this hypothesis, oxidized LDL can support foam cell formation in vitro, the lipid in human lesions is substantially oxidized, there is evidence for the presence of oxidized LDL in vivo, oxidized LDL has a number of potentially proatherogenic activities, and several structurally unrelated antioxidants inhibit atherosclerosis in animals. | |||||||||
| March 4,2005 | IMMUNOREGULATORY FUNCTIONS OF SURFACTANT PROTEINS | ||||||||
| Because the lungs function as the body’s gas-exchange organ, they are inevitably exposed to air that is contaminated with pathogens, allergens and pollutants. Host-defence mechanisms within the lungs must facilitate clearance of inhaled pathogens and particles while minimizing an inflammatory response that could damage the thin, delicate gas-exchanging epithelium. Pulmonary surfactant is a complex of lipids and proteins that enhances pathogen clearance and regulates adaptive and innate immune-cell functions. In this article, I review the structure and functions of the surfactant proteins SP-A and SP-D in regulating host immune defence and in modulating inflammatory responses. | |||||||||
| March 3,2005 | Genome–genome interactions: bacterial communities in initial dental plaque | ||||||||
| The usual context for genome–genome interactions is DNA–DNA interactions, but the manifestation of the genome is the cell. Here we focus on cell–cell inter-actions and relate them to the process of building multi-species biofilm communities. We propose that dental plaque communities originate as a result of intimate interactions between cells (genomes) of different species and not through clonal growth of genetically identical cells. Although DNA exchange might occur between cells within these communities, we limit our opinions to discussions of the spatiotemporal and metabolic relationships that exist here. We believe the multi-species interactions occurring during the early stages of biofilm formation determine the species com-position and nature of the mature biofilm. | |||||||||
| March 2,2005 | Immunomodulation of Atherosclerosis | ||||||||
| A number of studies have shown activation of the immune system throughout various stages of atherosclerosis. Recent observations have suggested that activation of immune responses may promote atherosclerosis on one hand by inducing and perpetuating arterial inflammation, whereas on the other hand, selective activation of certain immune functions may inhibit atherosclerosis and arterial inflammation. These observations suggest the possibility that selective suppression of proatherogenic immune responses or selective activation of antiatherogenic immune responses may provide new approaches for atherosclerosis prevention and treatment. Several antigens activating immune responses affecting development of atherosclerosis have been identified. | |||||||||
| March 1,2005 | Mobilizing the proteolytic machine: cell biological roles of proteasome activators and inhibitors | ||||||||
| Proteasomes perform the majority of proteolysis that occurs in the cytosol and nucleus of eukaryotic cells and, thereby, perform crucial roles in cellular regulation and homeostasis. Isolated proteasomes are inactive because substrates cannot access the proteolytic sites. PA28 and PA200 are activators that bind to proteasomes and stimulate the hydrolysis of peptides. Several protein inhibitors of the proteasome have also been identified, and the properties of these activators and inhibitors have been characterized biochemically. By contrast, their physiological roles – which have been reported to include production of antigenic peptides, proteasome assembly and DNA repair – are controversial. |
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