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Jun 30, 2007 Prospects for a dengue virus vaccine
  The number of cases of severe dengue disease continues to grow in endemic areas of southeast Asia, Central and South America, and other subtropical regions. Children bear the greatest burden of disease, and the development of an effective vaccine remains a global public health priority. A tetravalent vaccine is urgently needed and must be effective against all four dengue virus serotypes, be cost-effective and provide long-term protection. In this Review we discuss the unique immunological concerns in dengue virus vaccine development and the current prospects for the development of an acceptable vaccine, a goal that is likely to be reached in the near future.
Jun 29, 2007 Which transposable elements are active in the human genome
  Although a large proportion (44%) of the human genome is occupied by transposons and transposon-like repetitive elements, only a small proportion (<0.05%) of these elements remain active today. Recent evidence indicates that approximately 35-40 subfamilies of Alu, L1 and SVA elements (and possibly HERV-K elements) remain actively mobile in the human genome. These active transposons are of great interest because they continue to produce genetic diversity in human populations and also cause human diseases by integrating into genes. In this review, we examine these active human transposons and explore mechanistic factors that influence their mobilization.
Jun 28, 2007 Acute risk factors for myocardial infarction
  Increased knowledge concerning the triggering of acute cardiovascular diseases has yielded a change in philosophical approach to this field. During the last decade, clinical evidence suggested that the term acute risk factors can be used for the activities and events that suddenly and transiently increase the risk of acute cardiac diseases. External triggers, such as heavy physical activity, emotional stress, eating, cold or heat exposure, coffee or alcohol consumption, cocaine or marijuana use and sexual intercourse are recognized as most important acute risk factors. It is likely that the morning hours may be considered as an endogenous, external triggering independent acute risk factor related to physiological sympathetic arousal. The features of triggering have been best described for an acute myocardial infarction whose moment of onset appears to be the result of a dynamic interaction between an endogenous response to acute risk factors and patient vulnerability. In this article, pathophysiological changes implicated as internal triggering mechanisms are summarized and the terms sympathetic and parasympathetic triggering patterns are introduced. A highly individual approach tailored both to protect against acute risk factors and to reduce patient vulnerability could provide a more complete protection from myocardial infarction and other coronary incidents. Lifestyle modifications, regular physical activity and adequate drug regimens may at least prove able to defer the occurrence of coronary thrombosis, thereby providing time for the development of collateral vessels, plaque stabilization or invasive/surgical treatment.
Jun 27, 2007 Cancer epigenomics: DNA methylomes and histone-modification maps
  An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.
Jun 26, 2007 New bioinformatic tools for analysis of nucleotide modifications in eukaryotic rRNA
  This report presents a valuable new bioinformatics package for research on rRNA nucleotide modifications in the ribosome, especially those created by small nucleolar RNA:protein complexes (snoRNPs). The interactive service, which is not available elsewhere, enables a user to visualize the positions of pseudouridines, 2'-O-methylations, and base methylations in three-dimensional space in the ribosome and also in linear and secondary structure formats of ribosomal RNA. Our tools provide additional perspective on where the modifications occur relative to functional regions within the rRNA and relative to other nearby modifications. This package of new tools is presented as a major enhancement of an existing but significantly upgraded yeast snoRNA database available publicly at http://people.biochem.umass.edu/sfournier/fournierlab/snornadb/. The other key features of the enhanced database include details of the base pairing of snoRNAs with target RNAs, genomic organization of the yeast snoRNA genes, and information on corresponding snoRNAs and modifications in other model organisms.
Jun 25, 2007 Phosphorylation-independent attenuation of GPCR signalling
  The uncoupling of G-protein-coupled receptors (GPCRs) from their cognate heterotrimeric G proteins provides an essential physiological 'feedback' mechanism that protects against both acute and chronic overstimulation of receptors. The primary mechanism by which GPCR activity is regulated is the feedback phosphorylation of activated GPCRs by kinases that are dependent on second messengers, GPCR kinases (GRKs) and arrestins. It has recently become apparent, however, that GRK2-mediated regulation of GPCR responsiveness also involves a phosphorylation-independent component that requires both heterotrimeric G-protein alpha-subunit interactions and GPCR binding. Moreover, in addition to GRK2, a growing number of GPCR-interacting proteins might contribute to the phosphorylation-independent G-protein uncoupling of GPCRs. Here, new information about the mechanisms underlying this phosphorylation-independent regulation of receptor and G-protein coupling is reviewed.
Jun 24, 2007 Monitoring tolerance after human liver transplantation
  The validation of reliable, non-invasive immunological assays evaluating anti-donor responsiveness in allograft recipients would provide a clinically relevant tool for the early detection of ongoing rejection process as well as for the identification of operational tolerance in the long term. A sequential approach towards immunological monitoring of allografts is proposed in this review: (i) investigations exploring the initial donor-recipient alloresponses, including the analysis of the cytokine network; (ii) investigations regarding graft acceptance and operational tolerance in long-term transplant patients, consisting in the analysis of regulatory T cells and of circulating precursors of dendritic cells, in the measurement of T cell alloreactivity as well as in the study of T cell receptor repertoires. Beside the conventional in vivo and in vitro immunological techniques, the potential applications of molecular imaging in transplantation also deserve further exploration, with particular respect to allograft immune monitoring. Enforced collaboration between transplant clinicians and immunologists will be required to develop the translational research protocols required for the development of immunological monitoring, within an international multicentric network.
Jun 23, 2007 Autosomal dominant polycystic kidney disease
  Autosomal dominant polycystic kidney disease is the most prevalent, potentially lethal, monogenic disorder. It is associated with large interfamilial and intrafamilial variability, which can be explained to a large extent by its genetic heterogeneity and modifier genes. An increased understanding of the disorder's underlying genetic, molecular, and cellular mechanisms and a better appreciation of its progression and systemic manifestations have laid out the foundation for the development of clinical trials and potentially effective treatments.
Jun 22, 2007 Environmental epigenomics and disease susceptibility
  Epidemiological evidence increasingly suggests that environmental exposures early in development have a role in susceptibility to disease in later life. In addition, some of these environmental effects seem to be passed on through subsequent generations. Epigenetic modifications provide a plausible link between the environment and alterations in gene expression that might lead to disease phenotypes. An increasing body of evidence from animal studies supports the role of environmental epigenetics in disease susceptibility. Furthermore, recent studies have demonstrated for the first time that heritable environmentally induced epigenetic modifications underlie reversible transgenerational alterations in phenotype. Methods are now becoming available to investigate the relevance of these phenomena to human disease.
Jun 21, 2007 Long-term depression: multiple forms and implications for brain function
  Long-term potentiation (LTP) and long-term depression (LTD) remain widely accepted vertebrate models for the cellular and molecular mechanisms that underlie synaptic changes during learning and memory. Although LTD is a phenomenon that occurs in many regions of the CNS, it is clear that the mechanisms recruited in its induction and expression can vary, depending on many factors, including brain region and developmental time point. LTD in the hippocampus and cerebellum is probably the best characterized, although there are also other brain areas where mechanisms of LTD are well understood, and where it is thought to have a functional role.
Jun 20, 2007 Complement and coagulation: strangers or partners in crime?
  The convergence between complement and the clotting system extends far beyond the chemical nature of the complement and coagulation components, both of which form proteolytic cascades. Complement effectors directly enhance coagulation. These effects are supplemented by the interactions of complement with other inflammatory mediators that can increase the thrombogenicity of blood. In addition, complement inhibits anticoagulant factors. The crosstalk between complement and coagulation is also well illustrated by the ability of certain coagulation enzymes to activate complement components. Understanding the interplay between complement and coagulation has fundamental clinical implications in the context of diseases with an inflammatory pathogenesis, in which complement-coagulation interactions contribute to the development of life-threatening complications. Here, we review the interactions of the complement system with hemostasis and their roles in various diseases.
Jun 19, 2007 Cardiology and the Critical Care Crisis
  With an aging U.S. population and a declining physician supply, the care of critically ill patients will soon be reaching a level of crisis. At the same time, the evidence continues to mount in support of intensivist staffing to improve both patient outcomes and resource utilization in intensive care units (ICUs). Whereas the vast majority of medical and surgical ICUs are staffed by physicians trained in critical care medicine, that is not commonly the case in coronary care units (CCUs) in this country. Despite that, the breadth and diversity of comorbidities in patients that occupy our CCU beds is continuously growing. No longer is the CCU merely an observation unit for peri-infarction complications, but rather it has truly become an ICU for patients with cardiovascular disease. With this in mind, there becomes a growing need for intensivist-trained cardiologists and a push for the development of critical care training pathways in our cardiovascular fellowship programs.
Jun 18, 2007 Epigenetic signatures of stem-cell identity
  Pluripotent stem cells, similar to more restricted stem cells, are able to both self-renew and generate differentiated progeny. Although this dual functionality has been much studied, the search for molecular signatures of 'stemness' and pluripotency is only now beginning to gather momentum. While the focus of much of this work has been on the transcriptional features of embryonic stem cells, recent studies have indicated the importance of unique epigenetic profiles that keep key developmental genes 'poised' in a repressed but activatable state. Determining how these epigenetic features relate to the transcriptional signatures of ES cells, and whether they are also important in other types of stem cell, is a key challenge for the future.
Jun 17, 2007 A pair of new statistical parameters for quality control in RNA interference high-throughput screening assays
  RNA interference (RNAi) high-throughput screening (HTS) enables massive parallel gene silencing and is increasingly being used to reveal novel connections between genes and disease-relevant phenotypes. The application of genome-scale RNAi relies on the development of high-quality RNAi HTS assays. To obtain high-quality HTS assays, there is a strong need for an easily interpretable and theoretically based quality control (QC) metric. Signal-to-noise ratio (S/N), signal-to-background ratio (S/B), and Z-factor have been adopted as QC metrics in HTS assays. In this paper, I proposed a pair of new parameters, strictly standardized mean difference (SSMD) and coefficient of variability in difference (CVD), as QC metrics in RNAi HTS assays. Compared to S/B and S/N, SSMD and CVD capture the variabilities in both compared populations. Compared to Z-factor, SSMD and CVD have a clear probability interpretation and a solid statistical basis. Accordingly, the cutoff criteria of using SSMD or CVD as a QC metric in HTS assays are fully theoretically based. In addition, I discuss the relationship between the SSMD-based criterion and the popular Z-factor-based criterion and elucidate why p-value from t-test of testing mean difference fails to serve as a QC metric.
Jun 16, 2007 Evolution of cancer stem cells
  Cancer as a disease driven by cancer stem cells is a concept that has emerged over the last few years. However, several issues relating to this phenomenon as yet remain unaddressed. A fundamental question is one relating to the identification of events leading to transformation of a normal tissue stem cell to a cancer stem cell. Complete knowledge of this evolutionary process may be crucial for the development of novel effective therapies that influence patient prognosis. The scope of this review is to discuss reports that have begun to elucidate stem cell transformation either as an isolated event or as a progression as an attempt towards understanding some of the critical events involved in the process.
Jun 15, 2007 The JNK signal transduction pathway
  The c-Jun NH(2)-terminal kinases (JNKs) are an evolutionarily conserved sub-group of mitogen-activated protein (MAP) kinases. Recent studies have improved our understanding of the physiological function of the JNK pathway. Roles of novel molecules that participate in the JNK pathway have been defined and new insight into the role of JNK in survival signaling, cell death, cancer and diabetes has been achieved.
Jun 14, 2007 Insulin-expressing engineered cell lines and primary cells: surrogate b cells from liver, gut, and other sources
  Islet transplantation is being used to treat type 1 diabetes but is currently limited by the shortage of tissue available and by insufficient long-term function of transplanted islets. Thus, there remains significant interest in developing substitute sources of insulin-producing cells. Here we review progress in this area, focusing on insulin gene therapy and generation of new insulin-producing cells by redirecting hepatic and intestinal tissues towards a b-cell phenotype.
Jun 13, 2007 The epigenetic regulation of mammalian telomeres
  Increasing evidence indicates that chromatin modifications are important regulators of mammalian telomeres. Telomeres provide well studied paradigms of heterochromatin formation in yeast and flies, and recent studies have shown that mammalian telomeres and subtelomeric regions are also enriched in epigenetic marks that are characteristic of heterochromatin. Furthermore, the abrogation of master epigenetic regulators, such as histone methyltransferases and DNA methyltransferases, correlates with loss of telomere-length control, and telomere shortening to a critical length affects the epigenetic status of telomeres and subtelomeres. These links between epigenetic status and telomere-length regulation provide important new avenues for understanding processes such as cancer development and ageing, which are characterized by telomere-length defects.
Jun 12, 2007 Acute liver failure: liver support therapies
  PURPOSE OF REVIEW: We summarize the therapeutic approach to patients with acute liver failure with the main focus on bioartificial and artificial liver support. We also describe specific and general therapeutic approaches based upon recent advances in the understanding of the pathophysiology of acute liver failure. RECENT FINDINGS: Bioartificial liver support systems use hepatocytes in an extracorporeal device connected to the patient's circulation. Artificial liver support is intended to remove protein-bound toxins and water-soluble toxins without providing synthetic function. Both systems improve clinical and biochemical parameters and can be applied safely to patients. Although bioartificial liver-assist devices have not been shown to improve the survival of patients with acute liver failure, further development is underway. Artificial liver support systems have been shown to alter several pathophysiological mechanisms involved in the development of acute liver failure but survival data are still limited. SUMMARY: Mortality in patients with acute liver failure is still unacceptably high. The most effective treatment, liver transplantation, is a limited resource and so other therapeutic options to bridge patients to recovery or stabilization have to be considered. Better understanding of the pathophysiology of acute liver failure and device development is necessary to achieve the elusive goal of effective extracorporeal liver assist.
Jun 11, 2007 A-kinase anchoring proteins take shape
  A-kinase anchoring proteins (AKAPs) are signaling scaffolds that contribute to various aspects of cAMP signaling. They do this by tethering protein kinase-A to specific subcellular sites, thereby focusing its activity toward relevant substrates. Recently the structural basis for these protein-protein interactions has been elucidated by x-ray crystallography. Recent reports have identified AKAPs that bind to adenylyl cyclases to regulate cAMP synthesis and that sequester phosphodiesterases to break down this second messenger locally. Another emerging aspect of AKAP function is their role in integrating cAMP signaling with other signaling pathways. For example, molecular and genetic approaches have been used to show that the neuronal anchoring protein WAVE1 integrates signaling from PKA and Cdk5 to regulate actin polymerization and cytoskeletal events.
Jun 10, 2007 Flavoenzymes
  Flavoenzymes are colourful oxidoreductases that catalyze a large variety of different types of reactions. Flavoenzymes have been extensively studied for their structural and mechanistic properties and are gaining momentum in industrial biocatalytic applications. Some of these enzymes catalyze the oxidative modification of protein substrates. New insights in oxidative flavoenzymes and in particular in novel family members point towards their potential application in the pharmaceutical, fine-chemical and food industries.
Jun 9, 2007 Biomarker discovery using high-dimensional lipid analysis
  PURPOSE OF REVIEW: High-dimensional lipid analysis technologies (lipidomics) provide researchers with an opportunity to measure lipids on an unprecedented scale. They do not, however, guarantee a fast track to new knowledge. The vast amount of data produced by these platforms presents a major hurdle to assembling valid knowledge and to the discovery of mechanistic biomarkers. This review examines strategies for improving the quality of high-dimensional lipid data and streamlining data analysis to increase the value of lipidomics platforms to research and commercial applications. RECENT FINDINGS: Recent articles focus on careful study design and data analysis protocols. Authors offer detailed descriptions of study populations, analytical methods and data analysis, and highlight the use of practical data preprocessing and the incorporation of biological knowledge into data analysis. SUMMARY: The field is moving towards more methodical and structured approaches to biomarker identification. Experimental designs focusing on well-defined outcomes have a better chance of producing biologically relevant results. The high-dimensional lipid analysis techniques available are varied, have different strengths and weaknesses, and must be chosen carefully depending on the experimental design and application. Many techniques for data analysis are available, but the most successful are those incorporating existing biological knowledge into the statistical analysis.
Jun 8, 2007 Cancer epigenomics: DNA methylomes and histone-modification maps
  An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.
Jun 7, 2007 Conventional Light Chains Inhibit the Autonomous Signaling Capacity of the B Cell Receptor
  Signals from the B cell antigen receptor (BCR), consisting of mu heavy chain (muHC) and conventional light chain (LC), and its precursor the pre-BCR, consisting of muHC and surrogate light chain (SLC), via the adaptor protein SLP-65 regulate the development and function of B cells. Here, we compare the effect of SLC and conventional LC expression on receptor-induced Ca(2+) flux in B cells expressing an inducible form of SLP-65. We found that SLC expression strongly enhanced an autonomous ability of muHC to induce Ca(2+) flux irrespective of additional receptor crosslinking. In contrast, LC expression reduced this autonomous muHC ability and resulted in antigen-dependent Ca(2+) flux. These data indicate that autonomous ligand-independent signaling can be induced by receptor forms other than the pre-BCR. In addition, our data suggest that conventional LCs play an important role in the inhibition of autonomous receptor signaling, thereby allowing further B cell differentiation.
Jun 6, 2007 A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence
  Autism is a neurodevelopmental disorder with high heritability and a likely complex genetic architecture. Much genetic evidence has accumulated in the last 20 years but no gene has been unequivocally identified as containing risk variants for autism. In this article we review the past and present literature on neuro-pathological, genetic linkage, genetic association, and gene expression studies in this disorder. We sought convergent evidence to support particular genes or chromosomal regions that might be likely to contain risk DNA variants. The convergent evidence from these studies supports the current hypotheses that there are multiple genetic loci predisposing to autism, and that genes involved in neurodevelopment are especially important for future genetic studies. Convergent evidence suggests the chromosome regions 7q21.2-q36.2, 16p12.1-p13.3, 6q14.3-q23.2, 2q24.1-q33.1, 17q11.1-q21.2, 1q21-q44 and 3q21.3-q29, are likely to contain risk genes for autism. Taken together with results from neuro-pathological studies, genes involved in brain development located at the above regions should be prioritized for future genetic research.
Jun 5, 2007 NSAIDs and Alzheimer disease: Epidemiological, animal model and clinical studies
  This review reports correlations between four independent fields related to inflammation and Alzheimer disease: fundamental pathology, epidemiology, transgenic animal studies and clinical trials. Activated microglia, along with a spectrum of inflammatory mediators, have been identified in association with the lesions of Alzheimer disease (AD), suggesting that antiinflammatory agents such as NSAIDs should protect against the disease. In multiple epidemiological investigations testing this hypothesis, a significant risk reduction, or a trend towards such a reduction has been observed in long term as opposed to short term users of traditional NSAIDs. In studies where such NSAIDs have been administered to AD transgenic mice, a dose dependent reduction in pathology was observed. The selective C0X-2 inhibitors were ineffective. Results of clinical investigations have so far been disappointing but have nevertheless correlated with fundamental pathological findings and with transgenic mouse results. Four clinical trials using selective COX-2 inhibitors failed which is in keeping with the animal results and is consistent with pathological findings demonstrating that COX-1 and not COX-2 is the appropriate target in activated human microglia. A low dose trial of the traditional NSAID naproxen also failed, but pilot trials using therapeutically established doses of indomethacin and diclofenac/misoprostol showed promise. Further clinical investigations with relatively high doses of traditional NSAIDs might be warranted, although significant side effects should be anticipated.
Jun 4, 2007 The Two TORCs and Akt
  The regulatory circuits that control the activities of the two distinct target of rapamycin (TOR) complexes, TORC1 and TORC2, and of Akt have been a focus of intense research in recent years. It has become increasingly evident that these regulatory circuits control some of the most fundamental aspects of metabolism, cell growth, proliferation, survival, and differentiation at both the cellular and organismal levels. As such, they also play a pivotal role in the genesis of diseases including cancer, diabetes, aging, and degenerative diseases. This review highlights recent developments aimed at deciphering the interplay between Akt and mTORCs as well as their role in embryonic development and in cancer.
Jun 3, 2007 Nitric Oxide, a Double Edged Sword in Cancer Biology: Searching forTherapeutic Opportunities
  Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes. The last decade has witnessed major advances in dissecting NO biology and its role in cancer pathogenesis. However, the complexity of the interactions between different levels of NO and several aspects of tumor development/progression has led to apparently conflicting findings. Furthermore, both anti-NO and NO-based anticancer strategies appear effective in several preclinical models. This paradoxical dichotomy is leaving investigators with a double challenge: to determine the net impact of NO on cancer behavior and to define the therapeutic role of NO-centered anticancer strategies. Only a comprehensive and dynamic view of the cascade of molecular and cellular events underlying tumor biology and affected by NO will allow investigators to exploit the potential antitumor properties of drugs interfering with NO metabolism. Available data suggest that NO should be considered neither a universal target nor a magic bullet, but rather a signal transducer to be modulated according to the molecular makeup of each individual cancer and the interplay with conventional antineoplastic agents.
Jun 2, 2007 Incidence and Risk Factors for Stroke in Type 2 Diabetic Patients The DAI Study
  BACKGROUND AND PURPOSE: Type 2 diabetes mellitus is a strong predictor of cerebrovascular disease, yet few studies have assessed the incidence of stroke and the role of other risk factors in unselected type 2 diabetes mellitus populations. METHODS: We prospectively followed-up 14,432 type 2 diabetes mellitus patients, aged 40 to 97 years, with and without a history of cardiovascular disease at enrollment, and we estimated the incidence of stroke and the hazards ratios with respect to clinical variables. RESULTS: During a 4-year follow-up, 296 incident stroke events were recorded. In persons with no history of cardiovascular disease, the age-standardized incidence of stroke (per 1000 person-years) was 5.5 (95% confidence interval, 4.2 to 6.8) in men and 6.3 (95% confidence interval, 4.5 to 8.2) in women. In persons with a history of cardiovascular disease, it was 13.7 (95% confidence interval, 7.5 to 19.8) in men and 10.8 (95% confidence interval, 7.3 to 14.4) in women. The hazards ratios of stroke incidence varied according to age, sex, and history of cardiovascular disease. Among men with no history, HbA1c and smoking were predictors of stroke. Among patients with a history, the risk factors were, in men, therapy with insulin plus oral agents, treated high total cholesterol and low HDL cholesterol, whereas in women microvascular complications were a risk factor. Previous stroke was a strong predictor of stroke in both sexes. CONCLUSIONS: Age and previous stroke are the main predictors of stroke in diabetes. The combined role of Hba1c, microvascular complications, low HDL cholesterol, and treatment with insulin plus oral agents highlights the importance of diabetic history and clinical background in the development of stroke.
Jun 1, 2007 Signalling to suit function: tailoring phosphoinositide 3-kinase during T-cell activation
  Members of the CD28 family of co-receptors are crucial determinants of the outcome of T-cell activation. These receptors interact with ligands in the B7 family and either costimulate or co-inhibit signals through antigen-specific receptors. The T-cell-costimulatory molecules CD28 and inducible costimulator recruit and activate class 1A phosphoinositide 3-kinase (PI3K). Interestingly, the co-inhibitory molecules cytotoxic T lymphocyte antigen-4 and B and T lymphocyte attenuator also interact with class 1A PI3K. However, all co-inhibitory receptors share an ability to oppose activation of the key PI3K effector protein kinase B (also known as Akt). Recent evidence suggests that distinct mechanisms exist to limit Akt activation by different co-inhibitory receptors. This article examines how differential positive or negative regulation of the PI3K-Akt signalling pathway by CD28 family receptors enables functional differences between the receptors.

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