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| Jan 31, 2008 | Molecular basis of the differences between normal and tumor tissues of gastric cancer | ||||||||||
| To be able to describe the differences between the normal and tumor tissues of gastric cancer at a molecular level would be essential in the study of the disease. We investigated the gene expression pattern in the two types of tissues from gastric cancer by performing expression profiling of 86 tissues on 17K complementary DNA microarrays. To select for the differentially expressed genes, class prediction algorithm was employed. For predictor selection, samples were first divided into a training (n=58), and a test set (n=28). A group of 894 genes was selected by a t-test in a training set, which was used for cross-validation in the training set and class (normal or tumor) prediction in the test set. Smaller groups of 894 genes were individually tested for their ability to correctly predict the normal or tumor samples based on gene expression pattern. The expression ratios of the 5 genes chosen from microarray data can be validated by real time RT-PCR over 6 tissue samples, resulting in a high level of correlation, individually or combined. When a representative predictor set of 92 genes was examined, pathways of 'focal adhesion' (with gene components of THBS2, PDGFD, MAPK1, COL1A2, COL6A3), 'ECM-receptor interaction' pathway (THBS2, COL1A2, COL6A3, FN1) and 'TGF-beta signaling' (THBS2, MAPK1, INHBA) represent some of the main differences between normal and tumor of gastric cancer at a molecular level. | |||||||||||
| Jan 30, 2008 | Endoplasmic Reticulum Stress in the Heart | ||||||||||
| Over the last decade, it has become clear that the accumulation of misfolded proteins contributes to a number of neurodegenerative, immune, and endocrine pathologies, as well as other age-related illnesses. Recent interest has focused on the possibility that the accumulation of misfolded proteins can also contribute to vascular and cardiac diseases. In large part, the misfolding of proteins takes place during synthesis on free ribosomes in the cytoplasm or on endoplasmic reticulum ribosomes. In fact, even under optimal conditions, approximately 30% of all newly synthesized proteins are rapidly degraded, most likely because of improper folding. Accordingly, stresses that perturb the folding of proteins during or soon after synthesis can lead to the accumulation of misfolded proteins and to potential cellular dysfunction and pathological consequences. To avert such outcomes, cells have developed elaborate protein quality-control systems for detecting misfolded proteins and making appropriate adjustments to the machinery responsible for protein synthesis and/or degradation. Important contributors to protein quality control include cytosolic and organelle-targeted molecular chaperones, which help fold and stabilize proteins from unfolding, and the ubiquitin proteasome system, which degrades terminally misfolded proteins. Both of these systems play important roles in cardiovascular biology. The focus of this review is the endoplasmic reticulum stress response, a protein quality-control and signal-transduction system that has not been well studied in the context of cardiovascular biology but that could be important for vascular and cardiac health and disease. | |||||||||||
| Jan 29, 2008 | Pathophysiology of anemia and erythrocytosis | ||||||||||
| An increasing understanding of the process of erythropoiesis raises some interesting questions about the pathophysiology, diagnosis and treatment of anemia and erythrocytosis. The mechanisms underlying the development of many of the erythrocytoses, previously characterised as idiopathic, have been elucidated leading to an increased understanding of oxygen homeostasis. Characterisation of anemia and erythrocytosis in relation to serum erythropoietin levels can be a useful addition to clinical diagnostic criteria and provide a rationale for treatment with erythropoiesis stimulating agents (ESAs). Recombinant human erythropoietin as well as other ESAs are now widely used to treat anemias associated with a range of conditions, including chronic kidney disease, chronic inflammatory disorders and cancer. There is also heightened awareness of the potential abuse of ESAs to boost athletic performance in competitive sport. The discovery of erythropoietin receptors outside of the erythropoietic compartment may herald future applications for ESAs in the management of neurological and cardiac diseases. The current controversy concerning optimal hemoglobin levels in chronic kidney disease patients treated with ESAs and the potential negative clinical outcomes of ESA treatment in cancer reinforces the need for cautious evaluation of the pleiotropic effects of ESAs in non-erythroid tissues. | |||||||||||
| Jan 28, 2008 | Interaction of Cardiovascular Risk Factors with Myocardial Ischemia/Reperfusion Injury, Preconditioning, and Postconditioning | ||||||||||
| Therapeutic strategies to protect the ischemic myocardium have been studied extensively. Reperfusion is the definitive treatment for acute coronary syndromes, especially acute myocardial infarction; however, reperfusion has the potential to exacerbate lethal tissue injury, a process termed "reperfusion injury." Ischemia/reperfusion injury may lead to myocardial infarction, cardiac arrhythmias, and contractile dysfunction. Ischemic preconditioning of myocardium is a well described adaptive response in which brief exposure to ischemia/reperfusion before sustained ischemia markedly enhances the ability of the heart to withstand a subsequent ischemic insult... | |||||||||||
| Jan 27, 2008 | Anti-inflammatory actions of PPAR ligands: new insights on cellular and molecular mechanisms | ||||||||||
| The peroxisome proliferator-activated receptors (PPARalpha, -gamma, and -beta/delta) are nuclear receptors with distinct patterns of expression in many cell types both within and outside the immune system. PPAR ligands have anti-inflammatory activity in a variety of mouse models for acute and chronic inflammation. In macrophages, PPARgamma ligands repress expression of a subset of Toll-like receptor (TLR) target genes by a molecular mechanism termed ligand-dependent transrepression. In chronic inflammation, ligand-bound PPARalpha represses production of IFNgamma and IL-17 by CD4(+) T cells, and PPARgamma ligands modulate dendritic cell function to elicit the development of anergic CD4(+) T cells. PPAR ligands also repress expression of cell adhesion molecules on endothelial cells and the secretion of chemokines by epithelial and other cells, decreasing the recruitment of leukocytes to the site of inflammation. The anti-inflammatory activity of PPAR ligands in mouse models suggests their possible use for treating human inflammatory and autoimmune diseases. | |||||||||||
| Jan 26, 2008 | Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice | ||||||||||
| OBJECTIVE: Aortic calcification is prevalent in type II diabetes (T2DM), enhancing morbidity and tracking metabolic syndrome parameters. Ldlr(-/-) mice fed high-fat "Westernized" diets (HFD) accumulate aortic calcium primarily in the tunica media, mediated via osteogenic morphogens and transcriptional programs that induce aortic alkaline phosphatase (ALP). Because elevated TNF-alpha is characteristic of obesity with T2DM, we examined contributions of this inflammatory cytokine. METHODS AND RESULTS: HFD promoted obesity, hyperglycemia, and hyperlipidemia, and upregulated serum TNF-alpha in Ldlr(-/-) mice. Serum haptoglobin (inflammatory marker) was increased along with aortic expression of BMP2, Msx2, Wnt3a, and Wnt7a. Dosing with the TNF-alpha neutralizing antibody infliximab did not reduce obesity, hypercholesterolemia, or hyperglycemia; however, haptoglobin, aortic BMP2, Msx2, Wnt3a, and Wnt7a and aortic calcium accumulation were downregulated by infliximab. Mice with vascular TNF-alpha augmented by a transgene (SM22-TNFalphaTg) driven from the SM22 promoter upregulated aortic Msx2, Wnt3a, and Wnt7a. Furthermore, SM22-TNFalphaTg;TOPGAL mice exhibited greater aortic beta-galactosidase reporter staining versus TOPGAL sibs, indicating enhanced mural Wnt signaling. In aortic myofibroblast cultures, TNF-alpha upregulated Msx2, Wnt3a, Wnt7a, and ALP. ALP induction was inhibited by Dkk1, an antagonist of paracrine Wnt actions. CONCLUSIONS: TNF-alpha promote aortic Msx2-Wnt programs that contribute to aortic calcium accumulation in T2DM. | |||||||||||
| Jan 25, 2008 | Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation | ||||||||||
| Chronic heart failure (HF) is characterized by sympathetic hyperactivity reflected by increased circulating catecholamines (CAs), which contributes significantly to its morbidity and mortality. Therefore, sympatholytic treatments, that is, treatments that reduce sympathetic hyperactivity, are being pursued currently for the treatment of HF. Secretion of CAs from the adrenal gland, which is a major source of CAs, is regulated by alpha(2)-adrenoceptors (alpha(2)ARs), which inhibit, and by beta-adrenoceptors (betaARs), which enhance CA secretion. All ARs are G-protein-coupled receptors (GPCRs), whose signaling and function are regulated tightly by the family of GPCR kinases (GRKs). Despite the enormous potential of adrenal ARs for the regulation of sympathetic outflow, elucidation of their properties has only begun recently. Here, recent advances regarding the roles of adrenal ARs in the regulation of sympathetic outflow in HF and the regulatory properties of ARs are discussed, along with the potential benefits and challenges of harnessing their function for HF therapy. | |||||||||||
| Jan 24, 2008 | Switching from Repression to Activation: MicroRNAs Can Up-Regulate Translation | ||||||||||
| AU-rich elements (AREs) and microRNA target sites are conserved sequences in messenger RNA (mRNA) 3' untranslated regions (3'UTRs) that control gene expression posttranscriptionally. Upon cell cycle arrest, the ARE in tumor necrosis factor-alpha (TNFalpha) mRNA is transformed into a translation activation signal, recruiting Argonaute (AGO) and fragile X mental retardation-related protein 1 (FXR1), factors associated with micro-ribonucleoproteins (microRNPs). We show that human microRNA miR369-3 directs association of these proteins with the AREs to activate translation. Furthermore, we document that two well-studied microRNAs-Let-7 and the synthetic microRNA miRcxcr4-likewise induce translation up-regulation of target mRNAs on cell cycle arrest, yet they repress translation in proliferating cells. Thus, activation is a common function of microRNPs on cell cycle arrest. We propose that translation regulation by microRNPs oscillates between repression and activation during the cell cycle. | |||||||||||
| Jan 23, 2008 | New therapies for treatment of rheumatoid arthritis | ||||||||||
| Rheumatoid arthritis is characterised by pain, swelling, and destruction of joints, with resultant disability. Only disease-modifying antirheumatic drugs can interfere with the disease process. In the past few years, biological agents, especially inhibitors of tumour necrosis factor, have allowed for hitherto unseen therapeutic benefit, although even with these drugs the frequency and degree of responses are restricted. Therefore, new agents are needed, and three novel biological compounds for treatment of rheumatoid arthritis have already been used in practice or are on the horizon: rituximab (anti-CD20), abatacept (cytotoxic T-lymphocyte antigen 4 immunoglobulin), and tocilizumab (anti-interleukin 6 receptor). We discuss the targets of these drugs, the roles of these targets in the pathogenesis of rheumatoid arthritis, and the efficacy and adverse effects of these agents from clinical trial data. Novel therapeutic strategies in conjunction with optimised disease assessment for better treatment of rheumatoid arthritis and an outlook into potential future targets are also presented. | |||||||||||
| Jan 22, 2008 | Human diseases of telomerase dysfunction: insights into tissue aging | ||||||||||
| There are at least three human diseases that are associated with germ-line mutations of the genes encoding the two essential components of telomerase, TERT and TERC. Heterozygous mutations of these genes have been described for patients with dyskeratosis congenita, bone marrow failure and idiopathic pulmonary fibrosis. In this review, we will detail the clinical similarities and difference of these diseases and review the molecular phenotypes observed. The spectrum of mutations in TERT and TERC varies for these diseases and may in part explain the clinical differences observed. Environmental insults and genetic modifiers that accelerate telomere shortening and increase cell turnover may exaggerate the effects of telomerase haploinsufficiency, contributing to the variability of age of onset as well as tissue-specific organ pathology. A central still unanswered question is whether telomerase dysfunction and short telomeres are a much more prominent factor than previously suspected in other adult-onset, age-related diseases. Understanding the biological effects of these mutations may ultimately lead to novel treatments for these patients. | |||||||||||
| Jan 21, 2008 | Distinct mechanisms of tumor invasion and metastasis | ||||||||||
| Most cancer deaths are caused by metastasis rather than the primary tumor. Cancer cells invade normal tissue as epithelial sheets or single cells by inducing expression of programs characteristic of developmental processes. Depending on their tissue of origin, cancer cells subsequently spread to distinct target organs where they seed secondary tumors (metastasis). Recent experimental evidence suggests that metastasis requires changes not only in cancer cells but also in the tumor microenvironment and in the metastatic target site. For example, a premetastatic niche is formed in target organs that attract cancer cells. Understanding the distinct mechanisms used by cancer cells to form metastasis will enable better patient evaluation and the design of innovative therapeutic approaches. | |||||||||||
| Jan 20, 2008 | Metalloproteinases and Vulnerable Atherosclerotic Plaquesi | ||||||||||
| Plaque rupture is the main cause of myocardial infarctions and strokes. Ruptured plaques have thin, highly inflamed, and collagen-poor fibrous caps that contain elevated levels of proteases, including metalloproteinases (MMPs), which might weaken plaque caps and promote rupture. On the other hand, MMPs facilitate migration and proliferation vascular smooth muscle cells, which should promote fibrous cap stability. Given the dual effects of MMPs, therapies should selectively target harmful MMPs or the processes that cause MMP activity to rise to destructive levels. | |||||||||||
| Jan 19, 2008 | Therapeutic application of RNAi: is mRNA targeting finally ready for prime time? | ||||||||||
| With unprecedented speed, RNA interference (RNAi) has advanced from its basic discovery in lower organisms to becoming a powerful genetic tool and perhaps our single most promising biotherapeutic for a wide array of diseases. Numerous studies document RNAi efficacy in laboratory animals, and the first clinical trials are underway and thus far suggest that RNAi is safe to use in humans. Yet substantial hurdles have also surfaced and must be surmounted before therapeutic RNAi applications can become a standard therapy. Here we review the most critical roadblocks and concerns for clinical RNAi transition, delivery, and safety. We highlight emerging solutions and concurrently discuss novel therapeutic RNAi-based concepts. The current rapid advances create realistic optimism that the establishment of RNAi as a new and potent clinical modality in humans is near. | |||||||||||
| Jan 18, 2008 | Genome-wide association scans for Type 2 diabetes: new insights into biology and therapy | ||||||||||
| Type 2 diabetes is a complex, multifactorial disease, for which genetic and environmental factors jointly determine susceptibility. Disentangling the genetic aetiology of Type 2 diabetes has proven a challenging task, rewarded, until recently, with only limited success. However, the field of Type 2 diabetes genetics has been transformed over the past few months, with the publication of six genome-wide association scans, leading to the establishment of novel genomic regions that harbour disease susceptibility loci. Here, we provide an overview of the main recent findings and discuss their significance in providing biological insights and their translational implications. | |||||||||||
| Jan 17, 2008 | A dual function for a bacterial small RNA: SgrS performs base pairing-dependent regulation and encodes a functional polypeptide | ||||||||||
| SgrS is a 227-nt small RNA that is expressed in Escherichia coli during glucose-phosphate stress, a condition associated with intracellular accumulation of glucose-6-phosphate caused by disruption of glycolytic flux. Under stress conditions, SgrS negatively regulates translation and stability of the ptsG mRNA, encoding the major glucose transporter, by means of a base pairing-dependent mechanism requiring the RNA chaperone Hfq. SgrS activity mitigates the effects of glucose-phosphate stress, and the present study has elucidated a function of SgrS that is proposed to contribute to the stress response. The 5' end of SgrS, upstream of the nucleotides involved in base pairing with the ptsG mRNA, contains a 43-aa ORF, sgrT, that is conserved in most species that contain SgrS-like small RNAs. The sgrT gene is translated in E. coli under conditions of glucose-phosphate stress. Analysis of alleles that separate the base pairing function of SgrS from the sgrT coding sequence revealed that either of these functions alone are sufficient for previously characterized SgrS phenotypes. SgrS-dependent down-regulation of ptsG mRNA stability does not require SgrT and SgrT by itself has no effect on ptsG mRNA stability. Cells expressing sgrT alone had a defect in glucose uptake even though they had nearly wild-type levels of PtsG (IICB(Glc)). Together, these data suggest that SgrS represents a previously unrecognized paradigm for small RNA (sRNA) regulators as a bifunctional RNA that encodes physiologically redundant but mechanistically distinct functions contributing to the same stress response. | |||||||||||
| Jan 16, 2008 | Immune memory, immune oblivion: A lesson from Funes the memorious | ||||||||||
| We commonly think of the immune system as having a memory. However, memory is always accompanied by a complementary process of oblivion. Is there immune oblivion? In this theoretical paper, I address this question and suggest that oblivion is an integral aspect of memorization. In this context, I suggest that immune memory is an orchestration of reversible and irreversible processes of biological computation through feedback loops. Drawing on the linguistic metaphor, I inquire into the implications of this idea for a better understanding of immune memory and immune deficiency among the elderly. | |||||||||||
| Jan 15, 2008 | Circulating progenitor cells in stable coronary heart disease and acute coronary syndromes: relevant reparatory mechanism? | ||||||||||
| Bone marrow-derived cells which may be involved in cardiac repair/regeneration after ischaemic injury must undergo mobilisation into peripheral blood with subsequent homing and engraftment into the target organ. Mobilisation of the heterogeneous population of stem/progenitor cells in endothelial injury or myocardial ischaemia has been described recently. The number of circulating stem/progenitor cells reflects the endothelial damage, and turnover may be a surrogate marker reflecting the burden of cardiovascular risk factors and prognostic markers in stable coronary heart disease and acute coronary syndromes. Acute coronary syndromes are associated with increased levels of inflammatory and haematopoietic cytokines which, in turn, can mobilise progenitor cells from the bone marrow. Myocardial infarction increases the number of endothelial progenitor cells and other less well-defined subpopulations, such as CD34/c-kit(+) and CD34/CXCR4(+) cells, which may take part in cardiac repair after ischaemic injury. Data on mobilisation of stem/progenitor cells in acute coronary syndromes are summarised here. Cell types, mechanisms of mobilisation, homing and engraftment are discussed and their relevance to clinical outcomes. | |||||||||||
| Jan 14, 2008 | Telomerase and its potential for therapeutic intervention | ||||||||||
| Telomerase and telomeres are attractive targets for anticancer therapy. This is supported by the fact that the majority of human cancers express the enzyme telomerase which is essential to maintain their telomere length and thus, to ensure indefinite cell proliferation--a hallmark of cancer. Tumours have relatively shorter telomeres compared to normal cell types, opening the possibility that human cancers may be considerably more susceptible to killing by agents that inhibit telomere replication than normal cells. Advances in the understanding of the regulation of telomerase activity and the telomere structure, as well as the identification of telomerase and telomere associated binding proteins have opened new avenues for therapeutic intervention. Here, we review telomere and telomerase biology and the various approaches which have been developed to inhibit the telomere/telomerase complex over the past decade. They include inhibitors of the enzyme catalytic subunit and RNA component, agents that target telomeres, telomerase vaccines and drugs targeting binding proteins. The emerging role of telomerase in cancer stem cells and the implications for cancer therapy are also discussed. | |||||||||||
| Jan 13, 2008 | The emerging role of adipokines as mediators of cardiovascular function: physiologic and clinical perspectives | ||||||||||
| Interest in the biology of white adipose tissue has increased dramatically since the discovery of leptin in 1994. The identification of the product of the gene obese (ob) threw light on the role of adipose tissue in the physiopathology of obesity-related diseases and spurred the identification of numerous other adipokines, many of a proinflammatory nature. It has become increasingly evident that white adipose tissue-derived cytokines mediate between obesity-related exogenous factors (nutrition and lifestyle) and the molecular events that lead to metabolic syndrome, inflammation, and cardiovascular diseases. Here we review recent adipokine research, with particular attention to the roles of adiponectin, leptin, resistin, visfatin, apelin, omentin, and chemerin in such conditions. | |||||||||||
| Jan 12, 2008 | Modeling the adaptive immune system: predictions and simulations | ||||||||||
| MOTIVATION: Immunological bioinformatics methods are applicable to a broad range of scientific areas. The specifics of how and where they might be implemented have recently been reviewed in the literature. However, the background and concerns for selecting between the different available methods have so far not been adequately covered. SUMMARY: Before using predictions systems, it is necessary to not only understand how the methods are constructed but also their strength and limitations. The prediction systems in humoral epitope discovery are still in their infancy, but have reached a reasonable level of predictive strength. In cellular immunology, MHC class I binding predictions are now very strong and cover most of the known HLA specificities. These systems work well for epitope discovery, and predictions of the MHC class I pathway have been further improved by integration with state-of-the-art prediction tools for proteasomal cleavage and TAP binding. By comparison, class II MHC binding predictions have not developed to a comparable accuracy level, but new tools have emerged that deliver significantly improved predictions not only in terms of accuracy, but also in MHC specificity coverage. Simulation systems and mathematical modeling are also now beginning to reach a level where these methods will be able to answer more complex immunological questions. | |||||||||||
| Jan 11, 2008 | Computational epigenetics | ||||||||||
| Epigenetic research aims to understand heritable gene regulation that is not directly encoded in the DNA sequence. Epigenetic mechanisms such as DNA methylation and histone modifications modulate the packaging of the DNA in the nucleus and thereby influence gene expression. Patterns of epigenetic information are faithfully propagated over multiple cell divisions, which makes epigenetic regulation a key mechanism for cellular differentiation and cell fate decisions. In addition, incomplete erasure of epigenetic information can lead to complex patterns of non-Mendelian inheritance. Stochastic and environment-induced epigenetic defects are known to play a major role in cancer and ageing, and they may also contribute to mental disorders and autoimmune diseases. Recent technical advances such as ChIP-on-chip and ChIP-seq have started to convert epigenetic research into a high-throughput endeavor, to which bioinformatics is expected to make significant contributions. Here, we review pioneering computational studies that have contributed to epigenetic research. In addition, we give a brief introduction into epigenetics-targeted at bioinformaticians who are new to the field-and we outline future challenges in computational epigenetics. | |||||||||||
| Jan 10, 2008 | ESCRTing proteins in the endocytic pathway | ||||||||||
| The endosomal sorting complex required for transport (ESCRT) machinery is highly conserved and its components have been found in all five major supergroups of eukaryotes. The three ESCRT complexes and associated proteins play critical roles in receptor downregulation, retroviral budding, and other normal and pathological cellular processes. Besides monoubiquitin-dependent protein cargo recognition and sorting, the ESCRT machinery also appears to drive the formation of multivesicular bodies (MVBs). Recent advances in the determination of the function and structure of the ESCRT complexes have improved our understanding of the molecular details underlying the assembly and regulation of the ESCRT machinery. | |||||||||||
| Jan 9, 2008 | Platelet Activation and Atherothrombosis | ||||||||||
| Platelets are essential for primary hemostasis and repair of the endothelium, but they also play a key role in the development of acute coronary syndromes and contribute to cerebrovascular events. In addition, they participate in the process of forming and extending atherosclerotic plaques. Atherosclerosis is a chronic inflammatory process, and inflammation is an important component of acute coronary syndromes. The relation between chronic and acute vascular inflammation is unclear, but platelets are a source of inflammatory mediators, and the activation of platelets by inflammatory triggers may be a critical component of atherothrombosis. This review article describes the role of platelets in atherothrombosis by integrating our knowledge of basic mechanisms with the results of mechanistic studies in humans and clinical trials of inhibitors of platelet function. | |||||||||||
| Jan 8, 2008 | Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors | ||||||||||
| Very little is known regarding regulation of microRNA (miRNA) biogenesis in normal tissues, tumors, and cell lines. Here, we profiled the expression of 225 precursor and mature miRNAs using real-time PCR and compared the expression levels to determine the processing patterns. RNA from 22 different human tissues, 37 human cancer cell lines, and 16 pancreas and liver tissues/tumors was profiled. The relationship between precursor and mature miRNA expression fell into the following four categories: (1) a direct correlation exists between the precursor and mature miRNA expression in all cells/tissues studied; (2) direct correlation of the precursor and mature miRNA exists, yet the expression is restricted to specific cell lines or tissues; (3) there is detectable expression of mature miRNA in certain cells and tissues while the precursor is expressed in all or most cells/tissues; or (4) both precursor and mature miRNA are not expressed. Pearson correlation between the precursor and mature miRNA expression was closer to one for the tissues but was closer to zero for the cell lines, suggesting that processing of precursor miRNAs is reduced in cancer cell lines. By using Northern blotting, we show that many of these miRNAs (e.g., miR-31, miR-105 and miR-128a) are processed to the precursor, but in situ hybridization analysis demonstrates that these miRNA precursors are retained in the nucleus. We provide a database of the levels of precursor and mature miRNA in a variety of cell types. Our data demonstrate that a large number of miRNAs are transcribed but are not processed to the mature miRNA. | |||||||||||
| Jan 7, 2008 | The Molecular Biology Database Collection: 2008 update | ||||||||||
| The Nucleic Acids Research online Molecular Biology Database Collection is a public repository that lists more than 1000 databases described in this and previous Nucleic Acids Research annual database issues, as well as a selection of molecular biology databases described in other journals. All databases included in this Collection are freely available to the public. The 2008 update includes 1078 databases, 110 more than the previous one. The links to more than 80 databases have been updated and 25 obsolete databases have been removed from the list. | |||||||||||
| Jan 6, 2008 | Immunotherapy for Alzheimer’s disease: attacking amyloid-beta from the inside | ||||||||||
| Although extracellular Abeta plaques are a hallmark of Alzheimer's disease, it remains to be determined whether extracellular or intracellular Abeta accumulation initiates the disease process. A recent paper from Gunnar Gouras' group showed that Abeta antibodies lead to reduced intracellular Abeta levels in neurons via antibody internalization after binding to the Abeta domain of amyloid precursor protein (APP) at the plasma membrane. This work suggests novel avenues for the immunotherapy of Alzheimer's disease. | |||||||||||
| Jan 5, 2008 | Efficacy of Drug Therapy in the Secondary Prevention of Cardiovascular Disease and Stroke | ||||||||||
| The proper secondary prevention of cardiovascular disease (CVD) and stroke can have a significant impact on recurrent events. Central to this is the importance of appropriately prescribed drug therapy at the time of an event at the hospital and at the time of discharge. This report relates details of the efficacy of such therapy on the basis of clinical trials and studies. | |||||||||||
| Jan 4, 2008 | New echocardiographic technologies in the clinical management of hypertensive heart disease | ||||||||||
| Doppler echocardiography is a fundamental instrument to understand heart damage during essential arterial hypertension. Left ventricular (LV) hypertrophy may also be conveniently studied in its morphological and functional aspects by ultrasound application. Echocardiography can also provide important morphological and functional information in hypertensive patients for therapeutic management and prognostic stratification. In recent years, echocardiography has been enriched by very refined techniques that are capable of studying the physiopathological intramyocardial phenomena: (i) tissue Doppler (which studies intramyocardial velocities and time intervals and allows the analysis of strain and strain rate); (ii) integrated backscatter (which analyzes variations of myocardial reflectivity in decibels); (iii) transthoracic Doppler derived coronary flow reserve (which quantifies the vasodilator response of coronary velocities to a hyperaemic stimulation); (iv) myocardial echo-contrast-echocardiography (which studies the kinetics of ultrasound contrast microbubbles at the intramyocardial level); and (v) real-time three-dimensional (3-D) echocardiography [which allows a more precise evaluation of left ventricular (LV) volumes and LV mass]. These new methodological approaches have recently been used in the hypertensive clinical setting to provide a deeper knowledge of the complex physiopathological and histopathological mechanisms underlying the modifications induced by arterial hypertension at the myocardial tissue level (myocytes, collagen, microcirculation). This review shows the advancement of high-tech ultrasound applied to hypertensive heart disease, pointing out limitations and incremental potentialities in comparison with conventional echocardiography. | |||||||||||
| Jan 3, 2008 | Functional peptide arrays for high-throughput chemical biology based applications | ||||||||||
| Constant advancements in printing technology, informatics, surface modification strategies and peptide chemistries mean that peptide arrays have, like DNA arrays, become even more miniaturised and complex in terms of not only the numbers of peptides immobilised but also their lengths. As a result peptide-based arrays have become a powerful tool in the interrogation, examination and perturbation of a host of biological systems. | |||||||||||
| Jan 2, 2008 | p53 Enters the MicroRNA World | ||||||||||
| Recently, microRNAs, which are regulated by the transcription factor encoded by the tumor suppressor gene p53, were identified independently by seven groups. Their studies highlight the microRNAs miR-34a and miR-34b/c as direct, conserved p53 target genes that presumably mediate induction of apoptosis, cell cycle arrest, and senescence by p53. Since these microRNAs may regulate the levels of hundreds of different proteins, these findings add a new, challenging layer of complexity to the p53 network. The initial evidence suggesting that miR-34 genes are central mediators of p53 function is summarized here. | |||||||||||
| Jan 1, 2008 | Adrenal adrenoceptors in heart failure: fine-tuning cardiac stimulation | ||||||||||
| Chronic heart failure (HF) is characterized by sympathetic hyperactivity reflected by increased circulating catecholamines (CAs), which contributes significantly to its morbidity and mortality. Therefore, sympatholytic treatments, that is, treatments that reduce sympathetic hyperactivity, are being pursued currently for the treatment of HF. Secretion of CAs from the adrenal gland, which is a major source of CAs, is regulated by alpha(2)-adrenoceptors (alpha(2)ARs), which inhibit, and by beta-adrenoceptors (betaARs), which enhance CA secretion. All ARs are G-protein-coupled receptors (GPCRs), whose signaling and function are regulated tightly by the family of GPCR kinases (GRKs). Despite the enormous potential of adrenal ARs for the regulation of sympathetic outflow, elucidation of their properties has only begun recently. Here, recent advances regarding the roles of adrenal ARs in the regulation of sympathetic outflow in HF and the regulatory properties of ARs are discussed, along with the potential benefits and challenges of harnessing their function for HF therapy. |
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