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| April 30,2006 | The Nitric Oxide Theory of Aging Revisited | ||||||||||
| Bacterial and viral products, such as bacterial lipopolysaccharide (LPS), cause inducible (i) NO synthase (NOS) synthesis, which in turn produces massive amounts of nitric oxide (NO). NO, by inactivating enzymes and leading to cell death, is toxic not only to invading viruses and bacteria, but also to host cells. Injection of LPS induces interleukin (IL)-1β, IL-1α, and iNOS synthesis in the anterior pituitary and pineal glands, meninges, and choroid plexus, regions outside the blood–brain barrier. Thereafter, this induction occurs in the hypothalamic regions ,paraventricular nucleus , and the arcuate nucleus . Aging of the anterior pituitary and pineal with resultant decreased secretion of pituitary hormones and the pineal hormone melatonin, respectively, may be caused by NO. | |||||||||||
| April 29,2006 | Cardiac memory ... new insights into molecular mechanisms | ||||||||||
| ‘Cardiac memory’ describes an electrocardiographic T wave vector change, recorded during normal sinus rhythm that reflects the QRS complex vector during prior periods of ventricular pacing or arrhythmia. In this brief review we consider the mechanisms responsible for cardiac memory, which offer a unique window for relating molecular determinants of repolarization to their expression in the function of ion channels and in the electrophysiology of the heart. Understanding the steps that translate the molecular mechanisms for memory into clinical expression in this relatively straightforwardmodel facilitates our comprehension of the complex pathways that order normal cardiac repolarization and repolarization changes. | |||||||||||
| April 28,2006 | Tolerance Induction by Viral In Vivo Gene Transfer | ||||||||||
| Treatment of genetic disease by protein or gene replacement therapy is hampered by immune responses to the therapeutic protein.An excellent example is formation of inhibitory antibodies to coagulation factors in treatment of the X-linked bleeding disorder hemophilia. Experiments in murine and canine models of hemophilia B (deficiency in factor IX) have demonstrated sustained therapeutic levels of factor IX transgene expression following hepatic adeno-associated viral gene transfer in animals with deletion and nonsense mutations in the factor IX gene. This article reviews experimental evidence for induction of immune tolerance to the factor IX transgene product by hepatic adeno-associated viral gene transfer, which has been shown to limit T helper cell responses and to substantially reduce the risk of antibody responses. | |||||||||||
| April 27,2006 | The new biology of aldosterone | ||||||||||
| Classically, aldosterone is synthesised in the adrenal zona glomerulosa and binds to specific mineralocorticoid receptors located in the cytosol of target epithelial cells. Translocation of the resulting steroid receptor complex to the cell nucleus modulates gene expression and translation of specific ‘aldosterone-induced’ proteins that regulate electrolyte and fluid balance. However, non-epithelial and rapid non-genomic actions of aldosterone have also been described that account for a variety of actions of aldosterone that contribute to blood pressure homeostasis. These include key actions on endothelial cells and on cardiac tissue. | |||||||||||
| April 26,2006 | Functional Properties of Human Embryonic Stem Cell–Derived Cardiomyocytes | ||||||||||
| Regeneration of the diseased myocardium by cardiac cell transplantation is an attractive therapeutic modality. Yet, because the transplanted cardiomyocytes should functionally integrate within the diseased myocardium, it is preferable that their properties resemble those of the host. To determine the functional adaptability of human embryonic stem cell–derived cardiomyocytes (hESC-CM) to the host myocardium, the authors investigated the excitation–contraction (E-C) coupling and the responsiveness to common physiological stimuli. | |||||||||||
| April 25,2006 | Caveolae and Lipid Rafts | ||||||||||
| A growing body of data indicates that multiple signal transduction events in the heart occur via plasma membrane receptors located in signaling microdomains. Lipid rafts, enriched in cholesterol and sphingolipids, form one such microdomain along with a subset of lipid rafts, caveolae, enriched in the protein caveolin. In the heart, a key caveolin is caveolin-3, whose scaffolding domain is thought to serve as an anchor for other proteins. In spite of the original morphologic definition of caveolae (“little caves”), most work related to their role in compartmenting signal transduction molecules has involved subcellular fractionation or immunoprecipitation with anti-caveolin antibodies. | |||||||||||
| April 24,2006 | Current efforts in the analysis of RNAi and RNAi target genes | ||||||||||
| RNAi is RNA interference by short RNAs. It influences gene-expression by down-regulation of mRNAs, typically by complementarity to the 3' UTR (untranslated region) of the mRNA. microRNAs (miRNAs) are short RNAs acting as natural RNAi. miRNAs mediate downregulation of many mRNAs from developmental genes and transcription factor genes. Natural examples for this additional level of post-transcriptional control are increasing. Suitable computer-based search strategies for new miRNA candidates include precursor folding as well as different compositional search strategies. Example programs for this are presented. New own and other data are provided for an overview on such strategies. A strategy feasible in plants for miRNA target identification is direct base pairing of miRNAs to potential mRNA target 3' UTRs. | |||||||||||
| April 23,2006 | Regulation of Cardiac Energetics:Role of Redox State and Cellular Compartmentation during Ischemia | ||||||||||
| The heart is capable of altering its metabolic rate during exercise or ischemia. Under most state transitions, the heart maintains the concentration of adenosine triphosphate (ATP) at relatively constant values, in spite of large fluctuations in metabolic rate or in the delivery of fuels and oxygen. However, the mechanisms responsible for the regulation of cardiac energetics under conditions of increased demand or reduced supply are still under debate. To improve quantitative understanding of the regulation of glycolysis and oxidative phosphorylation under physiological and pathological conditions, it is essential to assess the dynamics of cytosolic and mitochondrial nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) during stress (e.g., ischemia, exercise). | |||||||||||
| April 22,2006 | A Novel Reagent for Safe, Effective Delivery of Substances into Cells | ||||||||||
| Delivering large molecules into the cytosol of animal cells without damaging the cells has been one of the toughest challenges in biology. Endo- Porter is a weak-base amphiphilic peptide that was designed to deliver morpholino antisense oligomers and other non-ionic substances into the cytosol/ nuclear compartment of cells by an endocytosis-mediated process that avoids damaging the plasma membrane of the cell. This prevents the loss of vital cell contents and the attendant high cell toxicity typical of most delivery systems. To deliver a substance into cells simply add that substance to the medium covering the cells, followed by addition of the pre-formulated Endo-Porter solution and swirl to mix. | |||||||||||
| April 21,2006 | Proteomics approaches to biomarker detection | ||||||||||
| The development of mass spectrometry (MS) technologies has brought the ability to gather massive amounts of data characterising the proteomes of complex mixtures. A major focus in proteomics is to leverage this data-gathering capability to conduct comparative analyses of biofluids from healthy and disease-affected patients for the identification of highly specific biomarkers and/or the development of MS-based diagnostic platforms. Much effort has gone into optimising the biofluid proteome coverage that can be obtained using these technologies, leaving proteomics poised to make an important impact in disease diagnostics in the future. | |||||||||||
| April 20,2006 | Endothelial focal adhesions and barrier function | ||||||||||
| Focal adhesions composed of integrins provide an important structural basis for anchoring the endothelial lining to its surrounding matrices in the vascular wall. Complex molecular reactions occur at the endothelial cell–matrix contact sites in response to physical and chemical stress present in the circulatory system. Recent experimental evidence points to the importance of focal adhesions in the regulation of microvascular barrier function. On one hand, the adhesive interaction between integrins and their extracellular ligands is essential to the maintenance of endothelial barrier properties, and interruption of integrin–matrix binding leads to leaky microvessels. On the other hand, focal adhesion assembly and activation serve as important signalling events in modulating endothelial permeability under stimulatory conditions in the presence of angiogenic factors, inflammatory mediators, or physical forces. | |||||||||||
| April 19,2006 | Genetic Contribution to Aging | ||||||||||
| For the best understanding of aging, we must consider a genetic pool in which genes with negative effects interact with genes with positive effects (helpful genes that promote longevity) in a constant epistatic relationship that results in a modulation of the final expression under particular environmental influences. Examples of deleterious genes affecting aging (predisposition to early-life pathology and disease) are those that confer risk for developing vascular disease in the heart, brain, or peripheral vessels, a gene associated with sporadic late-onset Alzheimer’s disease (APOE E4), a polymorphism (COLIA1 Sp1) associated with an increased fracture risk, and several genetic polymorphisms involved in hormonal metabolism that affect adverse reactions to estrogen replacement in postmenopausal women. | |||||||||||
| April 18,2006 | Analysis of evolution of exon–intron structure of eukaryotic genes | ||||||||||
| The availability of multiple, complete eukaryotic genome sequences allows one to address many fundamental evolutionary questions on genome scale. One such important, long-standing problem is evolution of exon–intron structure of eukaryotic genes. Analysis of orthologous genes from completely sequenced genomes revealed numerous shared intron positions in orthologous genes from animals and plants and even between animals, plants and protists. The data on shared and lineage-specific intron positions were used as the starting point for evolutionary reconstruction with parsimony and maximum-likelihood approaches. Parsimony methods produce reconstructions with intron-rich ancestors but also infer lineage-specific, in many cases, high levels of intron loss and gain. | |||||||||||
| April 17,2006 | Executive Summary: HFSA 2006 Comprehensive Heart Failure Practice Guideline | ||||||||||
| Heart failure (HF) is a syndrome characterized by high mortality, frequent hospitalization, reduced quality of life, and a complex therapeutic regimen. Knowledge about HF is accumulating so rapidly that individual clinicians may be unable to readily and adequately synthesize new information into effective strategies of care for patients with this syndrome. Trial data, though valuable, often do not give direction for individual patient management. These characteristics make HF an ideal candidate for practice guidelines. | |||||||||||
| April 16,2006 | Expression genomics and drug development: Towards predictive pharmacology | ||||||||||
| Expression genomics can be defined as the study of the dynamic transciptome and its regulatory elements. Technologies are available that can assess transcripts on a genome-wide scale over time and across many samples. This comprehensive and dynamic database is being used to decipher signalling pathways and to identify new biomarkers and targets. Biomarkers emerging from these studies have prognostic potential and can be used to predict therapeutic outcome. The multiplex nature of this approach not only telescopes the time to discovery, but also allows for detection of complex interactions. Taken together, these capabilities, if carefully used, can speed drug development, enhance the identification of potent drug combinations and identify patient populations that will benefit from these new drugs. | |||||||||||
| April 15,2006 | Hormonology: a genomic perspective on hormonal research | ||||||||||
| Recent advances in comparative genomics allow a new paradigm for hormonal research. At the centennial of the first use of the term hormone by Ernest Starling, we reflected on the changing approaches in elucidating hormonal signaling mechanisms and highlighted the inadequacy of the term endocrinology, implying remote activation, to describe the diverse modes of hormone actions. Several examples were presented to underscore the power of comparative genomics in the identification of new polypeptide hormones, receptors, and signaling pathways. We propose the use of the term hormonology to more accurately reflect the expanding boundaries of the discipline. | |||||||||||
| April 14,2006 | Signaling Mechanisms Regulating Endothelial Permeability | ||||||||||
| The microvascular endothelial cell monolayer localized at the critical interface between the blood and vessel wall has the vital functions of regulating tissue fluid balance and supplying the essential nutrients needed for the survival of the organism. The endothelial cell is an exquisite “sensor” that responds to diverse signals generated in the blood, subendothelium, and interacting cells. The endothelial cell is able to dynamically regulate its paracellular and transcellular pathways for transport of plasma proteins, solutes, and liquid. The semipermeable characteristic of the endothelium (which distinguishes it from the epithelium) is crucial for establishing the transendothelial protein gradient (the colloid osmotic gradient) required for tissue fluid homeostasis. | |||||||||||
| April 13,2006 | Proteomics in Tumor Progression and Metastasis | ||||||||||
| With the ultimate goal of systematically identifying and characterizing proteins within an organism, the field of proteomics has generated much excitement in the past few years. Coupled with mass spectrometry, various quantitative and functional techniques are now available that allow for largescale analyses of proteins implicated in cancer. New techniques are just now being applied to identifying the temporal changes in protein levels associated with tumor development. This review will focus on the use and promise of proteomic technologies as they apply to the study of tumor progression and metastasis. | |||||||||||
| April 12,2006 | Neurodegenerative Diseases | ||||||||||
| The variety of names of neurodegenerative diseases (NDDs) does not indicate that there is a wide variety of causes and a multiple number of cures. In fact NDDs derive from a common and repetitive, almost monotonous multicausal origin. NDDs are initiated invariably by a sudden or silent insidious decrease in immunologic resistance of the T cell–dependent or delayed type, produced by a large variety of psychological-emotional and/or environmental “stressors” (e.g., social, family-domestic, economic, alimentary, traumatic, and professional). These stressors increase the vulnerability of tissues (in this case, a section of the central or peripheral nervous system) to attack by a common virus (e.g., adenoviruses and herpesviruses). | |||||||||||
| April 11,2006 | Rho-Kinase Inhibition in the Therapy of Cardiovascular Disease | ||||||||||
| Rho is a GTPase known to be a major mediator in the formation of stress fibers and focal adhesions, cell morphology, and smooth muscle contraction. Its role in smooth muscle contraction has led to exploration into the connection between Rho-mediated kinase activity and cardiovascular disease. The role of Rho-kinase in calcium sensitization for vascular smooth muscle contraction has recently been characterized. Inappropriate coronary artery vasoconstriction resulting from increased Rho-kinase in the vascular system is likely involved in the pathogenesis of exercise-induced myocardial ischemia, spontaneous coronary artery spasm, and hypertension. In clinical trials, Rho-kinase inhibitors such as fasudil and Y-27632 have demonstrated antiischemic, antivasospastic, and antihypertensive effects. | |||||||||||
| April 10,2006 | Antifibrotic Properties and Effects in Models of Disease | ||||||||||
| Fibrosis (progressive scarring) is a leading cause of organ failure worldwide and causes loss of organ function when normal tissue is replaced with excess connective tissue. Several organs are prone to this process regardless of etiology.The pleiotropic hormone, relaxin, is emerging as a novel antifibrotic therapy. Relaxin has been shown to limit collagen production and reorganization, while stimulating increased collagen degradation. It not only prevents fibrogenesis, but also reduces established scarring.This review summarizes (1) the levels at which relaxin inhibits collagen production and existing collagen overexpression in induced models of fibrosis, and (2) the collagen-related phenotypes of relaxin- and LGR7-deficient mice. Recent studies on relaxin-deficient mice have established relaxin as an important, naturally occurring regulator of collagen turnover and provide new insights into the therapeutic potential of relaxin. | |||||||||||
| April 9,2006 | Tumor Reversion: Protein Kinase A Isozyme Switching | ||||||||||
| The regulatory subunit of cAMP-dependent protein kinase (PKA) exists in the isoforms RI and RII, which distinguish PKA isozymes type I (PKA-I) and type II (PKA-II). Evidence obtained from different experimental approaches—such as site-selective cAMP analogs, antisense oligonucleotides, transcription factor decoys, cDNA microarrays, and gene transfer—has shown that PKA-I and -II are expressed in a balance of cell growth and differentiation. Loss of this balance may underlie cancer genesis and progression. DNA microarrays demonstrate that antisense suppression of the RIα, which upregulates RIIβ, downregulates a wide range of genes involved in cell proliferation and transformation while upregulating cell differentiation and reverse transformation genes in PC3M prostate tumors that undergo regression. | |||||||||||
| April 8,2006 | Phosphoinositide-derived messengers in endocrine signaling | ||||||||||
| One of the fundamental questions in endocrinology is how circulating or locally produced hormones affect target cell functions by activating specific receptors linked to numerous signal-transduction pathways. An important subset of G protein-coupled cell-surface receptors can activate phospholipase C enzymes to hydrolyze a small but critically important class of phospholipids, the phosphoinositides. Although this signaling pathway has been extensively explored over the last 20 years, this has proven to be only the tip of the iceberg, and the multiplicity and diversity of the cellular functions controlled by phosphoinositides have surpassed any imagination. Phosphoinositides have been found to be key regulators of ion channels and transporters, and controllers of vesicular trafficking and the transport of lipids between intracellular membranes. | |||||||||||
| April 7,2006 | Cardiac Stem Cells and Mechanisms of Myocardial Regeneration | ||||||||||
| This review discusses current understanding of the role that endogenous and exogenous progenitor cells may have in the treatment of the diseased heart. In the last several years, a major effort has been made in an attempt to identify immature cells capable of differentiating into cell lineages different from the organ of origin to be employed for the regeneration of the damaged heart. Embryonic stem cells (ESCs) and bone marrow-derived cells (BMCs) have been extensively studied and characterized, and dramatic advances have been made in the clinical application of BMCs in heart failure of ischemic and nonischemic origin. However, a controversy exists concerning the ability of BMCs to acquire cardiac cell lineages and reconstitute the myocardium lost after infarction. | |||||||||||
| April 6,2006 | The Raf-1 pathway: a molecular target for treatment of select neuroendocrine tumors? | ||||||||||
| Neuroendocrine (NE) tumors such as medullary thyroid cancer, carcinoid, small cell lung cancer and pheochromocytoma are metastatic in nature, and secrete biogenic amines and hormones. In this review, we will discuss the possibility that activation of the Ras/Raf signaling pathway may be a therapeutic target for patients with select NE tumors. In-vitro activation of Raf-1 in NE tumors either by expression of the ectopic catalytic domain of Raf-1 or by a pharmacologic drug, ZM336372, resulted in growth inhibition. In addition, activation of the Ras/Raf pathway led to a significant reduction in NE markers such as serotonin, chromogranin A and calcitonin. These data support development of Raf-1-activating compounds for treatment of patients with NE tumors of selective subtypes. | |||||||||||
| April 5,2006 | Regulation of Pancreatic Beta-Cell Mass | ||||||||||
| Beta-cell mass regulation represents a critical issue for understanding diabetes, a disease characterized by a near-absolute (type 1) or relative (type 2) deficiency in the number of pancreatic beta cells. The number of islet beta cells present at birth is mainly generated by the proliferation and differentiation of pancreatic progenitor cells, a process called neogenesis. Shortly after birth, beta-cell neogenesis stops and a small proportion of cycling beta cells can still expand the cell number to compensate for increased insulin demands, albeit at a slow rate. The low capacity for self-replication in the adult is too limited to result in a significant regeneration following extensive tissue injury. Likewise, chronically increased metabolic demands can lead to beta-cell failure to compensate. | |||||||||||
| April 4,2006 | Nitric Oxide and the Heart | ||||||||||
| The role of nitric oxide (NO) as a regulator of cardiac contraction was suggested in the early nineties, but a consensual view of its main functions in cardiac physiology has only recently emerged with the help of experiments using genetic deletion or overexpression of the three nitric oxide synthase (NOS) isoforms in cardiomyocytes. Contrary to the effects of exogenous, pharmacologic NO donors, signaling by endogenous NO is restricted to intracellular effectors co-localized with NOS in specific subcellular compartments. This both ensures coordinate signaling by the three NOS isoforms on different aspects of the cardiomyocyte function and helps to reconcile previous apparently contradictory observations based on the use of non-isoform–specific NOS inhibitors. | |||||||||||
| April 3,2006 | Dietary Fat and Health: The Evidence and the Politics of Prevention | ||||||||||
| Every year, more young people start the slow progressive injury that eventually becomes cardiovascular disease and death. It could be prevented with nutrition education, but medical efforts focus more on treatments for older people than on preventing primary causes of disease in young people. Two avoidable risks are prevented by simple dietary interventions: (1) Eat more omega-3 and less omega-6 fats, so tissues have less intense n-6 eicosanoid action, and (2) eat less food per meal to lower vascular postprandial oxidant stress. An empirical diet–tissue relationship was developed and put into an interactive personalized software program to aid informed food choices. | |||||||||||
| April 2,2006 | Ryanodine Receptor-Targeted Anti-Arrhythmic Therapy | ||||||||||
| Cardiac arrhythmia is an important cause of death in patients with heart failure (HF) and inherited arrhythmia syndromes, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). Alterations in intracellular calcium handling play a prominent role in the generation of arrhythmias in the failing heart. Diastolic calcium leak from the sarcoplasmic reticulum (SR) via cardiac ryanodine receptors (RyR2) may initiate delayed afterdepolarizations and triggered activity leading to arrhythmias. Similarly, SR Ca 2+ leak through mutant RyR2 channels may cause triggered activity during exercise in patients with CPVT. | |||||||||||
| April 1,2006 | Alterations in DNA Repair Gene Expression under Hypoxia | ||||||||||
| Hypoxia is a common feature of solid tumors and is associated with genetic instability and tumor progression. It has been shown previously that alterations in the expression of DNA repair genes in response to hypoxic stress may account for a proportion of such genetic instability. Here, we demonstrate that the expression of RAD51, a critical mediator of homologous recombination (HR), is repressed by hypoxia in numerous cell lines derived from a wide range of tissues. Repression of this gene by hypoxia occurs in a cell cycle– and hypoxiainducible factor (HIF)–independent manner, and decreased RAD51 expression was observed to persist during the post-hypoxic period. |
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