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| Aug 31, 2007 | Hydrophobization and bioconjugation for enhanced siRNA delivery and targeting | ||||||||||||||||
| RNA interference (RNAi) is an evolutionarily conserved process by which double-stranded small interfering RNA (siRNA) induces sequence-specific, post-transcriptional gene silencing. Unlike other mRNA targeting strategies, RNAi takes advantage of the physiological gene silencing machinery. The potential use of siRNA as therapeutic agents has attracted great attention as a novel approach for treating severe and chronic diseases. RNAi can be achieved by either delivery of chemically synthesized siRNAs or endogenous expression of small hairpin RNA, siRNA, and microRNA (miRNA). However, the relatively high dose of siRNA required for gene silencing limits its therapeutic applications. This review discusses several strategies to improve therapeutic efficacy as well as to abrogate off-target effects and immunostimulation caused by siRNAs. There is an in-depth discussion on various issues related to the (1) mechanisms of RNAi, (2) methods of siRNA production, (3) barriers to RNAi-based therapies, (4) biodistribution, (5) design of siRNA molecules, (6) chemical modification and bioconjugation, (7) complex formation with lipids and polymers, (8) encapsulation into lipid particles, and (9) target specificity for enhanced therapeutic effectiveness. | |||||||||||||||||
| Aug 30, 2007 | Guideline for Low-Cost Antimicrobial Use in the Outpatient Setting | ||||||||||||||||
| In an effort to increase appropriate prescribing of low-cost antimicrobials in the outpatient setting, an evidence-based guideline was created to identify situations when low-cost medications can be used. A literature search identified relevant clinical trials describing the efficacy of antimicrobials used in the outpatient setting. These were analyzed to identify low-cost medications defined as $15 or less. The information was put into guideline format that includes the level of evidence for recommending the drug and information about cost. Sixteen common infections and their treatments were included in the guideline. | |||||||||||||||||
| Aug 29, 2007 | CD4+CD25+ Regulatory T Cells in Transplantation: Progress, Challenges and Prospects | ||||||||||||||||
| The involvement of CD4(+)CD25(+) regulatory T cells (Treg) in general immune homeostasis and protection from autoimmune syndromes is now well established. Similarly, there has been increasing evidence for Treg involvement in allograft rejection and current immunotherapies. However, despite significant advances in understanding the development, function, and therapeutic efficacy of Treg in certain well-defined rodent models, the relevance of Treg to clinical transplantation remains unclear. In this review, we summarize our current understanding of the role of Treg in immunity and organ transplantation in experimental and clinical settings. In addition, we review advances in using Treg as a form of immune therapy. The goal is to highlight the complexities and opportunities in the field and to provide evidence to support the use of antigen-specific Tregs in the context of transplantation to facilitate a robust and selective state of immune tolerance. | |||||||||||||||||
| Aug 28, 2007 | Salt, blood pressure and cardiovascular disease | ||||||||||||||||
| The evidence for universal salt reduction is strong, and reducing salt from the current intake of 10-12 g/day to the recommended level of 5-6 g/day will have a major effect on blood pressure and cardiovascular mortality. Additionally, this will result in considerable savings on health expenditure as, not only is raised blood pressure the biggest cause of death, but the second biggest cause of disability worldwide. | |||||||||||||||||
| Aug 27, 2007 | Current and Emerging Treatment Options in Chronic Myeloid Leukemia | ||||||||||||||||
| Treatments for chronic myeloid leukemia (CML) represent a success story in molecular medicine. The development of imatinib, a tyrosine kinase inhibitor (TKI) targeted against the causative Bcr-Abl oncoprotein in CML, has resulted in hematologic and cytogenetic remissions in all phases of CML. A significant proportion of patients are resistant to imatinib or develop resistance during treatment. This is often a result of mutated forms of the Bcr-Abl oncoprotein to which imatinib is unable to bind. Several strategies have been developed to overcome the problem of imatinib resistance, including high-dose imatinib, novel targeted agents, and combination treatments. Novel agents include dasatinib, a potent TKI that inhibits several critical oncogenic proteins and which has recently been approved for patients with CML who are resistant or intolerant to imatinib; and nilotinib, a potent selective Bcr-Abl kinase inhibitor currently in clinical development. Other agents in development include SKI-606 and INNO-406. Stem cell transplantation remains a useful option, although it is not generally used as first-line treatment. Overall, there are an increasing number of treatment options available for patients with CML. | |||||||||||||||||
| Aug 26, 2007 | Dystroglycan: a possible mediator for reducing congenital muscular dystrophy? | ||||||||||||||||
| lpha-dystroglycan is a highly glycosylated peripheral protein forming a complex with the membrane-spanning beta-dystroglycan and establishing a connection between the extracellular matrix and the cytoskeleton. In skeletal muscle, as part of the larger dystrophin-glycoprotein complex, dystroglycan is believed to be essential for maintaining the structural and functional stability of muscle fibers. Recent work highlights the role of abnormal dystroglycan glycosylation at the basis of glycosyltransferase-deficient congenital muscular dystrophies. Notably, modulation of glycosyltransferase activity can restore alpha-dystroglycan receptor function in these disorders. Moreover, transgenic approaches favoring the interaction between dystroglycan and the extracellular matrix molecules also represent an innovative way to restore skeletal muscle structure. These pioneering approaches might comprise an important first step towards the design of gene-transfer-based strategies for the rescue of congenital muscular dystrophies involving dystroglycan. | |||||||||||||||||
| Aug 25, 2007 | When biochemistry meets structural biology: the cautionary tale of EmrE | ||||||||||||||||
| When biochemistry meets structural biology a more complete understanding of the mechanism of biological macromolecules is usually achieved. Several high-resolution structures of ion-coupled transporters have enriched the understanding of mechanisms of substrate recognition, translocation and coupling of substrate fluxes. However, two X-ray structures of EmrE, the smallest ion-coupled multi-drug transporter, raised questions over the veracity of the structural model and represented a cautionary tale about the difficulty of determining the 3D structures of membrane proteins and the dangers of ignoring biochemical results. The 3D structures of EmrE have since been retracted because of faulty software, but the suggestion that the protomers in the dimer are in an antiparallel topological orientation sparked controversy that is still ongoing. | |||||||||||||||||
| Aug 24, 2007 | CPEB: a life in translation | ||||||||||||||||
| Nearly two decades ago, Xenopus oocytes were found to contain mRNAs harboring a small sequence in their 3' untranslated regions that control cytoplasmic polyadenylation and translational activation during development. This cytoplasmic polyadenylation element (CPE) is the binding platform for CPE-binding protein (CPEB), which promotes polyadenylation-induced translation. Since then, the biochemistry and biology of CPEB has grown rather substantially: mechanistically, CPEB nucleates a complex of factors that regulates poly(A) elongation through, of all things, a deadenylating enzyme; biologically, CPEB mediates many processes including germ-cell development, cell division and cellular senescence, and synaptic plasticity and learning and memory. These observations underscore the growing complexities of CPEB involvement in cell function. | |||||||||||||||||
| Aug 23, 2007 | A key role for CCR7 in establishing central and peripheral tolerance | ||||||||||||||||
| Early studies identified the CC-chemokine receptor (CCR)7 as an important homing molecule controlling the lymph node entry of naive T cells through high endothelial venules and of activated mature dendritic cells through afferent lymphatics. Consequently, these properties initially branded CCR7 as a central organizer of the primary immune response. However, recent studies have demonstrated that a variety of immune cells crucially rely on CCR7-directed migration not only for the induction of protective immunity but also for the establishment of immunological tolerance. In this review, we therefore highlight some of the recent advances in understanding the multiple roles of CCR7 in the induction and maintenance of central and peripheral tolerance. | |||||||||||||||||
| Aug 22, 2007 | Evo-devo and the evolution of social behavior | ||||||||||||||||
| The integration of evolutionary biology with developmental genetics into the hybrid field of 'evo-devo' resulted in major advances in understanding multicellular development and morphological evolution. Here we show how insights from evo-devo can be applied to study the evolution of social behavior. We develop this idea by reviewing studies that suggest that molecular pathways controlling feeding behavior and reproduction in solitary insects are part of a 'genetic toolkit' underlying the evolution of a particularly complex form of social behavior, division of labor among workers in honeybee colonies. The evo-devo approach, coupled with advances in genomics for non-model genetic organisms, including the recent sequencing of the honeybee genome, promises to advance our understanding of the evolution of social behavior. | |||||||||||||||||
| Aug 21, 2007 | Standards for reporting bioscience data: a forward look | ||||||||||||||||
| Groups representing a number of domains in the life sciences have been developing specifications and resources for the description and transmission of data, including those produced by (high-throughput) omics technologies. Although these developments are individually valuable, there is now a need for coordination to avoid the problem of a multiplicity of competing candidate standards. Three ongoing collaborative projects (FuGE, OBI and MIBBI) offer the promise of support for truly integrated, cross-domain informatics solutions. This article briefly summarizes the status quo with respect to biological and biomedical data standards, and offers an assessment of coming developments. | |||||||||||||||||
| Aug 20, 2007 | 5-Lipoxygenase: regulation of expression and enzyme activity | ||||||||||||||||
| 5-Lipoxygenase (5-LO) catalyzes the first two steps in the biosynthesis of leukotrienes, a group of pro-inflammatory lipid mediators derived from arachidonic acid. Leukotriene antagonists are used in the treatment of asthma, and the potential role of leukotrienes in atherosclerosis, another chronic inflammatory disease, has recently received considerable attention. In addition, some possible effects of 5-LO metabolites in tumorigenesis have emerged. Thus, knowledge of the biochemistry of this enzyme has potential implications for the treatment of various diseases. Recent advances have expanded our understanding of the regulatory mechanisms underlying the expression and control of 5-LO activity. With regard to the control of enzyme activity, many of these findings focus on the N-terminal domain of 5-LO. | |||||||||||||||||
| Aug 19, 2007 | Biological markers in osteoarthritis | ||||||||||||||||
| Osteoarthritis (OA) is a progressive disorder characterized by destruction of articular cartilage and subchondral bone, and by synovial changes. The diagnosis of OA is generally based on clinical and radiographic changes, which occur fairly late during disease progression and have poor sensitivity for monitoring disease progression. Progression of joint damage is likely to result primarily from an imbalance between cartilage degradation and repair, so measuring markers of these processes would seem a promising approach to improve the prediction of disease progression at the individual level. Moreover, genetic markers might be useful predictors of prognosis. The lack of fully effective, chondroprotective medications has limited the use of such potential markers to monitor the effect of treatment for OA. Nevertheless, owing to their dynamic changes in response to treatment, biological markers might provide relevant information more rapidly than imaging techniques (such as radiography and MRI) can, and should contribute to our understanding of mechanisms that underlie the clinical efficacy of OA treatments. Most of the identified genes involved in OA encode signal-transduction proteins, which provide the potential for novel therapeutic approaches. In this Review, we will use the recently proposed BIPED (i.e. burden of disease, investigative, prognostic, efficacy of intervention and diagnostic) classification of OA markers to describe the potential usage of a given marker. | |||||||||||||||||
| Aug 18, 2007 | Antiviral Drug-Resistant HBV: Standardization of Nomenclature and Assays and Recommendations for Management | ||||||||||||||||
| Substantial advances have been made in the treatment of chronic hepatitis B in the past decade. Approved treatments for chronic hepatitis B include 2 formulations of interferon and 4 nucleos(t)ide analogues (NAs). Sustained viral suppression is rarely achieved after withdrawal of a 48-week course of NA therapy, necessitating long, and in many cases, indefinite treatment with increasing risk of development of drug resistance. Antiviral resistance and poor adherence are the most important factors in treatment failure of hepatitis B. Thus, there is a need to standardize nomenclature relating to hepatitis B antiviral resistance, and to define genotypic, phenotypic, and clinical resistance to NA therapy. | |||||||||||||||||
| Aug 17, 2007 | Protein aggregation in silico | ||||||||||||||||
| Protein aggregation is a challenge to the successful manufacture of protein therapeutics; it can impose severe limitations on purification yields and compromise formulation stability. Advances in computer power, and the wealth of computational studies pertaining to protein folding, have facilitated the development of molecular simulation as a tool to investigate protein misfolding and aggregation. Here, we highlight the successes of protein aggregation studies carried out in silico, with a particular emphasis on studies related to biotechnology. To conclude, we discuss future prospects for the field, and identify several biotechnology-related problems that would benefit from molecular simulation. | |||||||||||||||||
| Aug 16, 2007 | p53: new roles in metabolism | ||||||||||||||||
| Virtually all cancers show metabolic changes that result in upregulation of glycolysis and glucose consumption. Although discovered in the 1920s, how this glycolytic switch happens, and whether it is a cause or a consequence of the malignant process, has remained a matter of debate. The p53 tumor suppressor gene, discovered some 30 years ago, has a key role in preventing cancer development. Recent discoveries revealing new functions for p53 in the regulation of glucose metabolism and oxidative stress have brought together these two venerable fields of cancer biology. These activities of p53 appear to be key in tumor suppression, and shed some light on the pathways that underlie the metabolic changes in cancer cells. | |||||||||||||||||
| Aug 15, 2007 | Multiple Less Common Genetic Variants Explain the Association of the Cholesteryl Ester Transfer Protein Gene With Coronary Artery Disease | ||||||||||||||||
| The objective of this study was to identify associations of the cholesteryl ester transfer protein (CETP) gene with coronary artery disease (CAD) with tagging (t) single nucleotide polymorphisms (SNPs) chosen to optimally account for intra-genic variation. The CETP gene plays a critical role in lipoprotein metabolism, but the common and well-studied TaqIB variant is inconsistently predictive of CAD. Multiple, less common SNPs and haplotype variants underlie CETP-related CAD risk, for which the common TaqIB variant is simply a poor marker. The occurrence of risk-related variants on separate haplotypes suggests genetic-risk complexity and allelic heterogeneity. | |||||||||||||||||
| Aug 14, 2007 | Gene methylation and early detection of genitourinary cancer: the road ahead | ||||||||||||||||
| DNA methylation is a common mechanism of inactivation of tumour-suppressor and other cancer genes in neoplastic cells. The advantages of gene methylation as a target for the detection and diagnosis of cancer in biopsy specimens and non-invasive body fluids such as urine or blood has led to many studies of application in genitourinary cancer. Here, we consider the background, promise and status, challenges and future directions of gene methylation and its clinical utility for the early detection of genitourinary cancer. The challenges of, and strategies for, advancing gene-methylation-based detection are relevant to all types of cancer. | |||||||||||||||||
| Aug 13, 2007 | The versatile worm: genetic and genomic resources for Caenorhabditis elegans research. | ||||||||||||||||
| Since its establishment as a model organism, Caenorhabditis elegans has been an invaluable tool for biological research. An immense spectrum of questions can be addressed using this small nematode, making it one of the most versatile and exciting model organisms. Although the many tools and resources developed by the C. elegans community greatly facilitate new discoveries, they can also overwhelm newcomers to the field. This Review aims to familiarize new worm researchers with the main resources, and help them to select the tools that are best suited for their needs. We also hope that it will be helpful in identifying new research opportunities and will promote the development of additional resources. | |||||||||||||||||
| Aug 12, 2007 | How Ebola and Marburg viruses battle the immune system | ||||||||||||||||
| The filoviruses Ebola and Marburg have emerged in the past decade from relative obscurity to serve now as archetypes for some of the more intriguing and daunting challenges posed by such agents. Public imagination is captured by deadly outbreaks of these viruses and reinforced by the specter of bioterrorism. As research on these agents has accelerated, it has been found increasingly that filoviruses use a combination of familiar and apparently new ways to baffle and battle the immune system. Filoviruses have provided thereby a new lens through which to examine the immune system itself. | |||||||||||||||||
| Aug 11, 2007 | When the brain plays music: auditory-motor interactions in music perception and production | ||||||||||||||||
| Music performance is both a natural human activity, present in all societies, and one of the most complex and demanding cognitive challenges that the human mind can undertake. Unlike most other sensory-motor activities, music performance requires precise timing of several hierarchically organized actions, as well as precise control over pitch interval production, implemented through diverse effectors according to the instrument involved. We review the cognitive neuroscience literature of both motor and auditory domains, highlighting the value of studying interactions between these systems in a musical context, and propose some ideas concerning the role of the premotor cortex in integration of higher order features of music with appropriately timed and organized actions. | |||||||||||||||||
| Aug 10, 2007 | Snail, ZEB and bHLH factors in tumour progression: an alliance against the epithelial phenotype? | ||||||||||||||||
| The molecular mechanisms that underlie tumour progression are still poorly understood, but recently our knowledge of particular aspects of some of these processes has increased. Specifically, the identification of Snail, ZEB and some basic helix-loop-helix (bHLH) factors as inducers of epithelial-mesenchymal transition (EMT) and potent repressors of E-cadherin expression has opened new avenues of research with potential clinical implications. | |||||||||||||||||
| Aug 9, 2007 | NMDA receptor trafficking in synaptic plasticity and neuropsychiatric disorders | ||||||||||||||||
| The number and subunit composition of synaptic N-methyl-D-aspartate receptors (NMDARs) are not static, but change in a cell- and synapse-specific manner during development and in response to neuronal activity and sensory experience. Neuronal activity drives not only NMDAR synaptic targeting and incorporation, but also receptor retrieval, differential sorting into the endosomal-lysosomal pathway and lateral diffusion between synaptic and extrasynaptic sites. An emerging concept is that activity-dependent, bidirectional regulation of NMDAR trafficking provides a dynamic and potentially powerful mechanism for the regulation of synaptic efficacy and remodelling, which, if dysregulated, can contribute to neuropsychiatric disorders such as cocaine addiction, Alzheimer's disease and schizophrenia. | |||||||||||||||||
| Aug 8, 2007 | Cytokines in the pathogenesis of rheumatoid arthritis | ||||||||||||||||
| Cytokines regulate a broad range of inflammatory processes that are implicated in the pathogenesis of rheumatoid arthritis. In rheumatoid joints, it is well known that an imbalance between pro- and anti-inflammatory cytokine activities favours the induction of autoimmunity, chronic inflammation and thereby joint damage. However, it remains less clear how cytokines are organized within a hierarchical regulatory network, and therefore which cytokines may be the best targets for clinical intervention a priori. Here, we discuss the crucial effector function of cytokines in the immunological processes that are central to the pathogenesis of rheumatoid arthritis. | |||||||||||||||||
| Aug7, 2007 | Genetic linkage and association analyses for trait mapping in Plasmodium falciparum | ||||||||||||||||
| Genetic studies of Plasmodium falciparum laboratory crosses and field isolates have produced valuable insights into determinants of drug responses, antigenic variation, disease virulence, cellular development and population structures of these virulent human malaria parasites. Full-genome sequences and high-resolution haplotype maps of SNPs and microsatellites are now available for all 14 parasite chromosomes. Rapidly increasing genetic and genomic information on Plasmodium parasites, mosquitoes and humans will combine as a rich resource for new advances in our understanding of malaria, its transmission and its manifestations of disease. | |||||||||||||||||
| Aug 6, 2007 | Nuclear microenvironments in biological control and cancer | ||||||||||||||||
| Nucleic acids and regulatory proteins are compartmentalized in microenvironments within the nucleus. This subnuclear organization may support convergence and the integration of physiological signals for the combinatorial control of gene expression, DNA replication and repair. Nuclear organization is modified in many cancers. There are cancer-related changes in the composition, organization and assembly of regulatory complexes at intranuclear sites. Mechanistic insights into the temporal and spatial organization of machinery for gene expression within the nucleus, which is compromised in tumours, provide a novel platform for diagnosis and therapy. | |||||||||||||||||
| Aug 5, 2007 | The action potential in mammalian central neurons | ||||||||||||||||
| The action potential of the squid giant axon is formed by just two voltage-dependent conductances in the cell membrane, yet mammalian central neurons typically express more than a dozen different types of voltage-dependent ion channels. This rich repertoire of channels allows neurons to encode information by generating action potentials with a wide range of shapes, frequencies and patterns. Recent work offers an increasingly detailed understanding of how the expression of particular channel types underlies the remarkably diverse firing behaviour of various types of neurons. | |||||||||||||||||
| Aug 4, 2007 | The contribution of immunology to the rational design of novel antibacterial vaccines | ||||||||||||||||
| In most cases, a successful vaccine must induce an immune response that is better than the response invoked by natural infection. Vaccines are still unavailable for several bacterial infections and vaccines to prevent such infections will be best developed on the basis of our increasing insights into the immune response. Knowledge of the signals that determine the best possible acquired immune response against a given pathogen - comprising a profound T- and B-cell memory response as well as long-lived plasma cells - will provide the scientific framework for the rational design of novel antibacterial vaccines. | |||||||||||||||||
| Aug 3, 2007 | Assessing intraepithelial neoplasia and drug safety in cancer-preventive drug development | ||||||||||||||||
| Despite significant interest from the research community and the population in general, drug approvals for cancer prevention and/or cancer risk reduction are few. This is due, in part, to the requirement that new cancer-preventive drugs must first be shown to be efficacious in reducing cancer incidence or mortality. Moreover, such drugs need to have proven safety for long-term administration. This process can be improved by focusing on precancer (intraepithelial neoplasia) to identify subjects at risk and prove efficacy in shorter, smaller trials as well as on detecting early markers of potential toxicities of chronic exposure to cancer-preventive drug regimens. | |||||||||||||||||
| Aug 2, 2007 | Intrinsic and cooperative antigen-presenting functions of dendritic-cell subsets in vivo | ||||||||||||||||
| Dendritic cells (DCs) comprise several subsets, and their roles in the presentation of antigens derived from pathogens, vaccines and self tissues are now beginning to be elucidated. Differences in location, life cycle and intrinsic abilities to capture, process and present antigens on their MHC class I and class II molecules enable each DC subset to have distinct roles in immunity to infection and in the maintenance of self tolerance. Unexpected interactions among DC subsets have also been revealed. These interactions, which allow the integration of the intrinsic abilities of different DC types, enhance the ability of the DC network to respond to multiple scenarios of infection. | |||||||||||||||||
| Aug 1, 2007 | Chronic myeloid leukaemia as a model of disease evolution in human cancer | ||||||||||||||||
| Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers? |
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