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| January 31, 2007 | Genome-wide natural antisense transcription: coupling its regulation to its different regulatory mechanisms | |||||||||
| Many genomic loci contain transcription units on both strands, therefore two oppositely oriented transcripts can overlap. Often, one strand codes for a protein, whereas the transcript from the other strand is non-encoding. Such natural antisense transcripts (NATs) can negatively regulate the conjugated sense transcript. NATs are highly prevalent in a wide range of species—for example, around 15% of human protein-encoding genes have an associated NAT. The regulatory mechanisms by which NATs act are diverse, as are the means to control their expression. Here, we review the current understanding of NAT function and its mechanistic basis, which has been gathered from both individual gene cases and genome-wide studies. In parallel, we survey findings about the regulation of NAT transcription. Finally, we hypothesize that the regulation of antisense transcription might be tailored to its mode of action. | ||||||||||
| January 30, 2007 | Gene Circuitry Controlling a Stem Cell Niche | |||||||||
| Many stem cell populations interact with stromal cells via signaling pathways, and understanding these interactions is key for understanding stem cell biology.In Drosophila, germline stem cell (GSC) maintenance requires regulation of several genes, including dpp, piwi, pumilio, and bam [1–5]. GSCs also maintain continuous contact with cap cells that probably secrete the signaling ligands necessary for controlling expression of these genes [6, 7]. For example, dpp signaling acts by silencing transcription of the differentiation factor, bam, in GSCs [5]. Despite numerous studies, it is not clear what roles piwi, primarily a cap cell factor, and pumilio, a germ cell factor, play in maintaining GSC function. With molecular and genetic experiments, we show that piwi maintains GSCs by silencing bam. In contrast, pumilio is not required for bam silencing, indicating that pumilio maintains GSC fate by a mechanism not dependent on bam transcription. | ||||||||||
| January 29, 2007 | Nitric oxide and atherosclerosis | |||||||||
| Nitric oxide (NO) is a molecule that has gained recognition as a crucial modulator of vascular disease. NO has a number of intracellular eVects that lead to vasorelaxation, endothelial regeneration, inhibition of leukocyte chemotaxis, and platelet adhesion. Endothelium damage induced by atherosclerosis leads to the reduction in bioactivity of endothelial NO synthase (eNOS) with subsequent impaired release of NO together with a local enhanced degradation of NO by increased generation of reactive oxygen species with subsequent cascade of oxidation-sensitive mechanisms in the arterial wall. Many commonly used vasculoprotective agents have their therapeutic actions through the production of NO. L-Arginine, the precursor of NO, has demonstrated beneWcial eVects in atherosclerosis and disturbed shear stress. | ||||||||||
| January 28, 2007 | The potential of oligonucleotides for therapeutic applications | |||||||||
| Viral-derived particles have been widely used and described in gene therapy clinical trials. Although substantial results have been achieved, major safety issues have also arisen. For more than a decade, oligonucleotides have been seen as an alternative to gene complementation by viral vectors or DNA plasmids, either to correct the genetic defect or to silence gene expression. The development of RNA interference has strengthened the potential of this approach. Recent clinical trials have also tested the ability of aptamer molecules and decoy oligonucleotides to sequestrate pathogenic proteins. Here, we review the potential of oligonucleotides in gene therapy, outline what has already been accomplished, and consider what remains to be done. | ||||||||||
| January 27, 2007 | MicroRNA expression and function in cancer | |||||||||
| MicroRNAs are small non-coding RNAs of 19–24 nucleotides in length that downregulate gene expression during various crucial cell processes such as apoptosis, differentiation and development. Recent work supports a role for miRNAs in the initiation and progression of human malignancies. Large high-throughput studies in patients revealed that miRNA profiling have the potential to classify tumors with high accuracy and predict outcome. Functional studies, some of which involve animal models, indicate that miRNAs act as tumor suppressors and oncogenes. Here, we summarize miRNA-profiling studies in human malignancies and examine the role of miRNAs in the pathogenesis of cancer. We also discuss the implications of these findings for the diagnosis and treatment of cancer. | ||||||||||
| January 26, 2007 | Heart repair and stem cells | |||||||||
| Of the medical conditions currently being discussed in the context of possible treatments based on cell transplantation therapy, few have received more attention than the heart.Much focus has been on the potential application of bone marrow-derived cell preparations, which have already been introduced into double-blind, placebo-controlled clinical trials. The consensus is that bone marrow may have therapeutic benefit but that this is not based on the ability of bone marrow cells to transdifferentiate into cardiac myocytes. Are there potential stem cell sources of cardiac myocytes that may be useful in replacing those lost or dysfunctional aftermyocardial infarction? Here, this question is addressed with a review of the recent literature. | ||||||||||
| January 25, 2007 | Targeting dendritic cells with biomaterials: developing the next generation of vaccines | |||||||||
| Current vaccine and immunotherapy technology faces ongoing challenges in both efficacy and practicality: many chronic diseases cannot yet be addressed by vaccination, and several vaccines that do function well require multiple injections, which is a substantial limitation in various parts of the world. A possible key to developing the next generation of vaccines is the ability to deliver antigen to dendritic cells (DCs) more specifically and induce the subsequent activation of T-cell immunity. However, antigen delivery to, and activation of, DCs is a complex problem, involving antigen transport to DC-rich areas, DC binding and antigen uptake, and antigen processing and presentation. Addressing these challenges requires novel and multidisciplinary approaches, for example, the application of biomaterials to immunotechnology. | ||||||||||
| January 24, 2007 | PPARα and PPARγ dual agonists for the treatment of type 2 diabetes and the metabolic syndrome | |||||||||
| The discovery of the crucial role of peroxisome proliferatoractivated receptors (PPARs) as regulators of lipid and glucose metabolism has raised interest in the development of synthetic ligands as potential tools for therapeutic intervention in type 2 diabetes and the metabolic syndrome. PPARα activators primarily improve dyslipidemia, whereas thiazolidinediones are potent PPARγ activators that improve insulin resistance. Important research programs to develop agonists that combine the therapeutic effects of both PPARα- and PPARγ-selective agonists, creating the expectation of greater efficacy and other advantages in the treatment of type 2 diabetes and the metabolic syndrome, have therefore been undertaken. Among these dual PPARα/γ agonists, compounds that belong to the glitazar class are in the most advanced stage of development. | ||||||||||
| January 23, 2007 | Acute myeloid leukaemia | |||||||||
| Acute myeloid leukaemia(AML)is a heterogenous clonal disorder of haemopietic progenitor cells and the most common malignant myeloid disorder in adults.The median age at presentation for patients with AML is 70 years.In the past few years,research in molecular biology has been instrumental in deciphering the pathogenesis of the disease.Genetic defects are thought to be the most important factors in determining the response to chemotherapy and outcome.Whereas significant progress has been made in the treatment of younger adults,the prospects for elderly patients have remained dismal,with median survival times of only a few months.This difference is related to comorbidities associated with ageing and to disease biology,Current efforts in clinical research focus on the assessment of targeted therapies.Such new approaches will probably lead to an increase in the cure rate. | ||||||||||
| January 22, 2007 | The Year in Heart Failure | |||||||||
| Although it has been customary to highlight the results of pivotal clinical trials in this review, the year 2006 is best characterized as a year of consensus building in heart failure. Guidelines from several major cardiology societies worldwide have been revised, updated, and compared, and large registries have provided further observational insights into contemporary issues for the care for patients with heart failure. Challenges in drug development continue, and a noticeable shift has occurred toward better understanding of acute heart failure syndromes (AHFS), especially regarding the preservation of renal function. We summarize herein our view of a number of important publications and pivotal presentations from international meetings within this past year in the area of heart failure. | ||||||||||
| January 21, 2007 | Genetics of obesity and the prediction of risk for health | |||||||||
| Obesity has always existed in human populations, but until very recently was comparatively rare. The availability of abundant, energy-rich processed foods in the last few decades has, however, resulted in a sharp rise in the prevalence of obesity in westernized countries. Although it is the obesogenic environment that has resulted in this major healthcare problem, it is acting by revealing a sub-population with a pre-existing genetic predisposition to excess adiposity. There is substantial evidence for the heritability of obesity, and research in both rare and common forms of obesity has identified genes with significant roles in its aetiology. Application of this understanding to patient care has been slower. | ||||||||||
| January 20, 2007 | Clinical evaluation of inhaled insulin | |||||||||
| Diabetes affects over 18.2 million individuals in the United States alone. Current therapy to treat type 1 diabetes relies on subcutaneous insulin administration either by injection or continuous infusion. In addition, patients with type 2 diabetes who fail lifestyle intervention and oral therapy require subcutaneous insulin. Optimal injection protocols to achieve tight metabolic control often prove burdensome to patients. Thus, development of pulmonary insulin delivery to supplement and/or replace subcutaneous insulin injections may be an effective alternative, allowing patients to achieve intensive diabetes management. This review will discuss the devices in development for the delivery of inhaled insulin. | ||||||||||
| January 19, 2007 | Toll-like receptors in systemic autoimmune disease | |||||||||
| Toll-like receptors (TLRs) have a crucial role in the early detection of pathogenassociated molecular patterns and the subsequent activation of the adaptive immune response. Whether TLRs also have an important role in the recognition of endogenous ligands has been more controversial. Numerous in vitro studies have documented activation of both autoreactive B cells and plasmacytoid dendritic cells by mammalian TLR ligands. The issue of whether these in vitro observations translate to an in vivo role for TLRs in either the initiation or the progression of systemic autoimmune disease is a subject of intense research; data are beginning to emerge showing that this is the case. | ||||||||||
| January 18, 2007 | The expanding transcriptome | |||||||||
| The central dogma of molecular biology inspired by classical work in prokaryotic organisms accounts for only part of the genetic agenda of complex eukaryotes. First, posttranscriptional events lead to the generation of multiple mRNAs, proteins and functions from a single primary transcript, revealing regulatory networks distinct in mechanism and biological function from those controlling RNA transcription. Second, a variety of populous families of small RNAs (small nuclear RNAs, small nucleolar RNAs, microRNAs, siRNAs and shRNAs) assemble on ribonucleoprotein complexes and regulate virtually all aspects of the gene expression pathway, with profound biological consequences. Third, high-throughput methods of genomic analysis reveal that RNAs other than non-protein-coding RNAs (ncRNAs) represent a major component of the transcriptome that may perform novel functions in gene regulation and beyond. | ||||||||||
| January 17, 2007 | Molecular imaging of myocardial infarction | |||||||||
| Molecular tools are rapidly elucidating the molecular and cellular processes underlying myocardial infarction. To further understand these biological processes in vivo, investigators are embracing the burgeoning field of molecular imaging. Here we review important aspects of molecular imaging technology and then devote the majority of the text to studies that shed light on the in vivo pathogenesis of myocardial infarction. In particular, we focus on post-infarction healing and remodeling and discuss molecular imaging of proteolytic activity, angiogenesis, transglutaminase activity, and apoptosis. In the future, novel reporter agents and high-resolution cardiac imaging systems should enable imaging of emerging targets such as activated macrophages and myeloperoxidase activity, as well as stem cell-based and gene therapy-based myocardial regenerative strategies, in both experimental and clinical subjects. | ||||||||||
| January 16, 2007 | Strategies for developing vaccines against H5N1 influenza A viruses | |||||||||
| Recent outbreaks of highly pathogenic avian influenza A virus (H5N1 subtype) infections in poultry and humans (through direct contact with infected birds) have raised concerns that a new influenza pandemic might occur in the near future. Effective vaccines against H5N1 virus are, therefore, urgently needed. Reverse-genetics-based inactivated vaccines have been prepared according to World Health Organization (WHO) recommendations and are now undergoing clinical evaluation in several countries. Here, we review the current strategies for the development of H5N1 influenza vaccines, and future directions for vaccine development. | ||||||||||
| January 15, 2007 | Centrosome Function in Normal and Tumor Cells | |||||||||
| Centrosomes nucleate microtubules that form the mitotic spindle and regulate the equal division of chromosomes during cell division. In cancer, centrosomes are often found amplified to greater than two per cell, and these tumor cells frequently have aneuploid genomes. In this review, we will discuss the cellular factors that regulate the proper duplication of the centrosome and how these regulatory steps can lead to abnormal centrosome numbers and abnormal mitoses. In particular, we highlight the newly emerging role of the Breast Cancer 1 (BRCA1) ubiquitin ligase in this process. | ||||||||||
| January 14, 2007 | Mitochondrial DNA polymerase-γ and human disease | |||||||||
| The maintenance of mitochondrial DNA (mtDNA) is critically dependent upon polymerase-γ (pol-γ), encoded by the nuclear gene POLG. Over the last 5 years, it has become clear that mutations of POLG are a major cause of human disease. Secondary mtDNA defects characterize these disorders, with mtDNA depletion, multiple mtDNA deletions or multiple point mutations of mtDNA in clinically affected tissues. The secondary mtDNA defects cause cell and tissue-specific deficiencies of mitochondrial oxidative phosphorylation, leading to organ dysfunction and human disease. | ||||||||||
| January 13, 2007 | Telomere Biology and Cardiovascular Disease | |||||||||
| Accumulation of cellular damage with advancing age leads to atherothrombosis and associated cardiovascular disease. Ageing is also characterized by shortening of the DNA component of telomeres, the specialized genetic segments located at the end of eukaryotic chromosomes that protect them from end-to-end fusions. By inducing genomic instability, replicative senescence and apoptosis, shortening of the telomeric DNA is thought to contribute to organismal ageing. In this Review, we discuss experimental and human studies that have linked telomeres and associated proteins to several factors which influence cardiovascular risk, as well as to neovascularization and the pathogenesis of atherosclerosis and heart disease. | ||||||||||
| January 12, 2007 | Immune therapies of autoimmune diseases: are we approaching a real cure? | |||||||||
| In developed countries, autoimmune diseases represent the third major cause of morbidity and mortality after cancer and atherosclerosis and their incidence has steadily increased over the past three decades. Conventional therapeutic approaches are essentially palliative, anti-inflammatory or immunosuppressive; in addition, they are non-specific, unrelated to the antigens involved in disease pathogenesis. This explains the growing attention to modern technologies that made new biological agents and methods available. A few of these are already approved for regular clinical practice; others are still in clinical development but hold great promise. The question is: will these new tools allow us to develop a real cure for autoimmunity, restoring self-tolerance to target autoantigens? This goal is ambitious, namely harnessing the pathogenic immune response while preserving the host response to exogenous or unrelated antigens. | ||||||||||
| January 11, 2007 | The balance between heritable and environmental aetiology of human disease | |||||||||
| The Human Genome Project and the ensuing International HapMap Project were largely motivated by human health issues. But the distance from a DNA sequence variation to a novel disease gene is considerable; for complex diseases, closing this gap hinges on the premise that they arise mainly from heritable causes. Using cancer as an example of complex disease, we examine the scientific evidence for the hypothesis that human diseases result from interactions between genetic variants and the environment. | ||||||||||
| January 10, 2007 | ATP-Binding Cassette Cholesterol Transporters and Cardiovascular Disease | |||||||||
| A hallmark of atherosclerotic cardiovascular disease (CVD) is the accumulation of cholesterol in arterial macrophages. Factors that modulate circulating and tissue cholesterol levels have major impacts on initiation, progression, and regression of CVD. Four members of the ATP-binding cassette (ABC) transporter family play important roles in this modulation. ABCA1 and ABCG1 export excess cellular cholesterol into the HDL pathway and reduce cholesterol accumulation in macrophages. ABCG5 and ABCG8 form heterodimers that limit absorption of dietary sterols in the intestine and promote cholesterol elimination from the body through hepatobiliary secretion. All 4 transporters are induced by the same sterol-sensing nuclear receptor system. | ||||||||||
| January 9, 2007 | Type-2 diabetes: a cocktail of genetic discovery | |||||||||
| Diabetes is one of the most challenging health problems of the 21st century with an alarming increase in the prevalence of type-2 diabetes mellitus (T2DM) and associated conditions such as hypertension, dyslipidemias and obesity. T2DM is a complex genetic disease comprised of many metabolic disorders with a common phenotype of glucose intolerance. Patients with T2DM would have inherited a variety of different genetic factors that together with environmental factors combine as the primary cause. This complicates the genetic study of the disease and means that different methodological approaches are needed if we hope to identify susceptibility genes and genetic variants. | ||||||||||
| January 8, 2007 | ‘Relaxin’ the stiffened heart and arteries | |||||||||
| Although originally characterised as a reproductive hormone, relaxin has emerged as a multi-functional endocrine and paracrine factor that plays a number of important roles in several organs, including the normal and diseased cardiovascular system. The recent discovery of the H3/ relaxin-3 gene, and the elusive receptors for relaxin (Relaxin family peptide receptor; RXFP1) and relaxin-3 (RXFP3/RXFP4) have led to the reclassification of a distinct relaxin peptide/receptor family. Additionally, the identification of relaxin and RXFP1 mRNA and/or relaxin binding sites in the heart and blood vessels has confirmed that the cardiovascular system is a target for relaxin peptides. While evidence for the production of relaxins within the cardiovascular system is limited, several studies have established that the relaxin genes are upregulated in the diseased human and rodent heart where they likely act as cardioprotective agents. | ||||||||||
| January 7, 2007 | Tenascin-C induced signaling in cancer | |||||||||
| Tenascin-C is an adhesion modulatory extracellular matrix molecule that is highly expressed in the microenvironment of most solid tumors. High tenascin-C expression reduces the prognosis of disease-free survival in patients with some cancers. The possible role of tenascin-C in tumor initiation and progression is addressed with emphasis on underlying signaling mechanisms. How tenascin-C affects malignant transformation, uncontrolled proliferation, angiogenesis, metastasis and escape from tumor immunosurveillance is summarized. Finally, we discuss how the phenotypes of tenascin-C knock-out mice may help define the roles of tenascin-C in tumorigenesis and how this knowledge could be applied to cancer therapy. | ||||||||||
| January 6, 2007 | A chemical toolkit for proteins — an expanded genetic code | |||||||||
| Recently, a method to encode unnatural amino acids with diverse physicochemical and biological properties genetically in bacteria, yeast and mammalian cells was developed. Over 30 unnatural amino acids have been cotranslationally incorporated into proteins with high fidelity and efficiency using a unique codon and corresponding transfer-RNA:aminoacyl–tRNA-synthetase pair. This provides a powerful tool for exploring protein structure and function in vitro and in vivo, and for generating proteins with new or enhanced properties. | ||||||||||
| January 5, 2007 | In Search of New Targets for Plasma High-Density Lipoprotein Cholesterol Levels | |||||||||
| Many lines of evidence suggest that raising plasma high-density lipoprotein cholesterol (HDL-C) levels may inhibit, perhaps even reverse, atherosclerosis. Quantitative trait locus (QTL) analysis has been performed in both humans and mice. So far, ~40 high-density lipoprotein (HDL)-regulating QTLs have been identified in each species. To compare human and mouse HDL-C QTLs, we generate human–mouse comparative chromosome maps based on homologous genes in humans and mice. The comparative maps reveal that most human and mouse HDL-C QTLs are concordant, which suggests that identifying the underlying QTL genes in mice will facilitate identifying their homologs in humans. | ||||||||||
| January 4, 2007 | Biological Systems Modeling and Analysis: A Biomolecular Technique of the Twenty-first Century | |||||||||
| It is proposed that computational systems biology should be considered a biomolecular technique of the twenty-first century, because it complements experimental biology and bioinformatics in unique ways that will eventually lead to insights and a depth of understanding not achievable without systems approaches. This article begins with a summary of traditional and novel modeling techniques. Iin the second part, it proposes concept map modeling as a useful link between experimental biology and biological systems modeling and analysis. Cconcept map modeling requires the collaboration between biologist and modeler. The biologist designs a regulated connectivity diagram of processes comprising a biological system and also provides semi-quantitative information on stimuli and measured or expected responses of the system. | ||||||||||
| January 3, 2007 | How will HPV vaccines affect cervical cancer? | |||||||||
| Cancer of the uterine cervix is the second largest cause of cancer deaths in women, and its toll is greatest in populations that lack screening programmes to detect precursor lesions. Persistent infection with ‘high risk’ genotypes of human papillomavirus (HPV) is necessary, although not sufficient, to cause cervical carcinoma. Therefore, HPV vaccination provides an opportunity to profoundly affect cervical cancer incidence worldwide. A recently licensed HPV subunit vaccine protects women from a high proportion of precursor lesions of cervical carcinoma and most genital warts. Here we examine the ramifications and remaining questions that surround preventive HPV vaccines. | ||||||||||
| January 2, 2007 | Gene Regulatory Networks in the Evolution and Development of the Heart | |||||||||
| The heart, an ancient organ and the first to form and function during embryogenesis, evolved by the addition of new structures and functions to a primitive pump. Heart development is controlled by an evolutionarily conserved network of transcription factors that connect signaling pathways with genes for muscle growth, patterning, and contractility. During evolution, this ancestral gene network was expanded through gene duplication and co-option of additional networks. Mutations in components of the cardiac gene network cause congenital heart disease, the most common human birth defect. The consequences of such mutations reveal the logic of organogenesis and the evolutionary origins of morphological complexity. | ||||||||||
| January 1, 2007 | Acute renal failure | |||||||||
| Acute renal failure is characterised by a rapid fall in glomerular filtration rate, clinically manifest as an abrupt and sustained rise in urea and creatinine. Life threatening consequences include volume overload, hyperkalaemia, and metabolic acidosis. Acute renal failure is both common and costly and carries a high morbidity and mortality. As it is often preventable, identification of patients at risk and institution of appropriate preventive measures are crucial. In incipient or established acute renal failure rapid recognition and treatment may prevent irreversible loss of nephrons. |
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