 |
 |
 |
|||||||||||||||
|
| |||||||||||||||||
|
每日一文 | |||||||||||||||||
|
| |||||||||||||||||
|
| |||||||||||||||||
| December 31,2004 | Therapeutic Potential of RNA Interference | ||||||||||||||||
| Just when scientists thought they had figured out the funda- mental mechanisms through which gene expression is regulated,studies of the nematode Caenorhabditis elegans 1 revealed the existence of a pathway,now known as RNA interference (RNAi),that silences gene expression by promoting degra- dation of RNA.Scientists have discovered ways to control RNAi in order to regulate gene expression in a variety of biologic systems,and they are researching ways to har- ness RNAi to interrupt disease processes such as those caused by human immunodefi- ciency virus type 1 (HIV-1),hepatitis viruses,and influenzavirus. | |||||||||||||||||
| December 30,2004 | Nanoporous microsystems for islet cell replacement | ||||||||||||||||
| The inadequacy of conventional insulin therapy for the treatment of Type I diabetes has stimulated research on several therapeutic alternatives, including insulin pumps and controlled release systems for insulin. One of the most physiological alternatives to insulin injections is the transplantation of insulin-secreting cells. It is the beta cells of the islets that secrete insulin in response to increasing blood glucose concentrations. Ideally, transplantation of such cells (allografts or xenografts) could restore normoglycemia. However, as with most tissue or cellular transplants, the cellular grafts, particularly xenografts, are subjected to immunorejection in the absence of chronic immunosuppression. Thus, it is of great interest to develop new technologies that may be used for islet cell replacement. | |||||||||||||||||
| December 29,2004 | Dimensionality in cardiac modelling | ||||||||||||||||
| The development of mathematical models of the heart has been an ongoing concern for many decades. The initial focus of this work was on single cell models that incorporate varyingly detailed descriptions of the mechanisms that give rise to experimentally observed action potential shapes.Clinically relevant heart rhythm disturbances,however,are multicellular phenomena,and there have been many initiatives to develop multidimensional representations of cardia electromechanical activity. | |||||||||||||||||
| December 28,2004 | Connexins: functions without junctions | ||||||||||||||||
| Gap junctions are composed of intercellular channels that span two plasma membranes and provide a direct pathway for the movement of signaling molecules and ionic cur-rents between adjacent cells. To form the intercellular channel, neighboring cells contribute subunits called connexons or hemichannels that associate in the narrow extracellular space between adjacent plasma membranes. The hemichannels are composed of connexins, a mid-sized family of highly related proteins. Forward and reverse genetic approaches have established that gap junctions critically influence many cellular behaviors . However, the most surprising find-ings of the past few years indicate that connexins have critical functions that don’t involve intercellular channels and, conversely, that connexins are not the only proteins capable of forming intercellular channels. | |||||||||||||||||
| December 27,2004 | Oncogenic transformation of human cells: shortcomings of rodent model systems | ||||||||||||||||
| Long-standing difficulties in the in vitro transformation of human cells have been overcome. Using telomerase, several successful oncogene-mediated transformations of human cells have been reported and the following cellular requirements for human cell transformation have been proposed: the maintenance of telomere sequences, the inactivation of Rb and p53 pathways, the perturbation of protein phosphatase 2A (PP2A) and the expression of activated Ras. Even when all of these requirements are fulfilled, however, the transformed phenotypes of human cells seem to be much less malignant than those of rodent cells meeting the same requirements. This suggests the existence of undefined cell-autonomous mechanisms that render human cells resistant to malignant transformation. | |||||||||||||||||
| December 26,2004 | Protein unfolding in the cell | ||||||||||||||||
| Protein unfolding is an important step in several cellular processes such as protein degradation by ATP-depen-dent proteases and protein translocation across some membranes. Recent studies have shown that the mechanisms of protein unfolding in vivo differ from those of the spontaneous unfolding in vitro measured by solvent denaturation. Proteases and translocases pull at a substrate polypeptide chain and thereby catalyze unraveling by changing the unfolding pathway of that protein. The unfoldases move along the polypeptide chains of their protein substrates. The resistance of a protein to unfolding is then determined by the stability of the region of its structure that is first encountered by the unfoldase. Because unfolding is a necessary step in protein degradation and translocation, the susceptibility of a substrate protein to unfolding contributes to the specificity of these pathways. | |||||||||||||||||
| December 25,2004 | LOBOTOMY OF GENES: USE OF RNA INTERFERENCE IN NEUROSCIENCE | ||||||||||||||||
| Galen of Pergamon studied nerve function by shearing nerves in various species including monkeys, dogs, bulls and even elephants . An analogous strategy to determine gene function by ablating gene expression has recently been developed. RNA interference (RNAi) is a cellular response to double-stranded RNA (dsRNA) apparently as a defense against viral or transposon activity . By activating this ancient defense mechanism through the intro-duction of artificial dsRNA, it is now possible to inhibit ex-pression of almost any gene in almost any cell type, among them neuronal cells. In mammalian cells the active RNAi species must be short, approximately 21 nucleotide RNAs; these 21-bp species are called short interfering RNA (siRNA; Fig. 1). | |||||||||||||||||
| December 24,2004 | Genetic analysis of synaptic target recognition and assembly | ||||||||||||||||
| Formation of synapses by neurons onto specific targets is essential to the function of a nervous system. The iso-lation and analysis of Caenorhabditis elegans and Drosophila mutants with synaptogenesis defects has provided insight into the functions of evolutionarily conserved molecules at single-synapse resolution. Impor-tantly, such studies have uncovered novel molecules and signaling mechanisms. Here, recent progress on synaptic target recognition and synaptic assembly are reviewed. | |||||||||||||||||
| December 23,2004 | MOLECULAR GENETICS AND GENOMICS OF HEART FAILURE | ||||||||||||||||
| Heart failure is a major disease burden worldwide, and its incidence continues to increase as premature deaths from other cardiovascular conditions decline. Although the overall molecular portrait of this multifactorial disease remains incomplete, molecular and genetic studies have implicated, in recent decades, various pathways and genes that participate in the pathophysiology of heart failure. Here, we highlight the current understanding of the molecular and genetic basis of heart failure and show how recently developed genomic tools are providing a new perspective on this complex disease. | |||||||||||||||||
| December 22,2004 | WNT AND β -CATENIN SIGNALLING: DISEASES AND THERAPIES | ||||||||||||||||
| WNT signalling has been studied primarily in developing embryos, in which cells respond to WNTs in a context-dependent manner through changes in survival and proliferation, cell fate and movement. But WNTs also have important functions in adults, and aberrant signalling by WNT pathways is linked to a range of diseases, most notably cancer. What is the full range of diseases that involve WNT pathways? Can inhibition of WNT signalling form the basis of an effective therapy for some cancers? Could activation of WNT signalling provide new therapies for other clinical conditions? Finally, on the basis of recent experiments, might WNTs normally participate in self-renewal, proliferation or differentiation of stem cells? If so, altering WNT signalling might be beneficial to the use of stem cells for therapeutic means. | |||||||||||||||||
| December 21,2004 | Bioinformatics and cancer target discovery | ||||||||||||||||
| The convergence of genomic technologies and the development of drugs designed against specific molecular targets provides many opportunities for using bioinformatics to bridge the gap between biological knowledge and clinical therapy. Identifying genes that have properties similar to known targets is conceptually straightforward. Additionally, genes can be linked to cancer via recurrent genomic or genetic abnormalities. Finally, by integrating large and disparate datasets, gene-level distinctions can be made between the different biological states that the data represents. These bioinformatics approaches and their associated methodologies, which can be applied across a range of technologies, facilitate the rapid identification of new target leads for further experimental validation. | |||||||||||||||||
| December 20,2004 | GenCompass: a universal system for analysing gene expression for any genome | ||||||||||||||||
| Microarrays have become indispensable tools for study-ing the gene expression of particular organisms on a genomic scale. However, despite its widespread use, there are several draw-backs to the current technology. First, it requires prior knowledge of the DNA sequence encoded in the organism of interest, and second, chips must be designed specifically for each genome, greatly increasing the initial cost incurred in manufacturing the arrays. | |||||||||||||||||
| December 19,2004 | DNA methyltransferase inhibitors: old and new drugs for an epigenetic cancer therapy | ||||||||||||||||
| The pharmacological inhibition of DNA methyltransfer-ases provides novel opportunities for the therapy of human cancers. Several Phase III trials of DNA methyl-transferase inhibitors have been completed success-fully, but the efficacy of these compounds appears to be compromised by their lack of specificity. To address this issue, much work has been focused on defining the functional characteristics of human DNA methyltrans-ferases. This knowledge will be essential for the design of a new generation of pharmacological inhibitors that target epigenetic processes. | |||||||||||||||||
| December 18,2004 | GENETICS OF ATHEROSCLEROSIS | ||||||||||||||||
| Atherosclerosis, the primary cause of coronary artery disease (CAD) and stroke, is a disorder with multiple genetic and environmental contributions. Genetic-epidemiologic studies have identified a surprisingly long list of genetic and nongenetic risk factors for CAD. However, such studies indicate that family history is the most sig-nificant independent risk factor (15, 52, 77). Many Mendelian disorders associated with atherosclerosis, such as familial hypercholesterolemia (FH), have been characterized, but they explain only a small percentage of disease susceptibility (although a substan-tial fraction of early CAD). Most cases of myocardial infarction (MI) and stroke result from the interactions of multiple genetic and environmental factors, none of which can cause disease by itself. | |||||||||||||||||
| December 17,2004 | Real-time multiple-particle tracking: applications to drug and gene delivery | ||||||||||||||||
| Complex biological environments, such as the cell cytoplasm or the mucus lining the airways of the lungs, can pose significant barriers to efficient therapeutic drug and gene delivery. Biological barriers are particularly important in controlled drug delivery applications that utilize a large carrier particle, such as a liposome or a polymer micro- or nanosphere. The dynamic transport of particulate drug and gene delivery vehicles through these barriers is poorly understood, having been primarily studied with static methods in the past. Recently, the transport of synthetic drug and gene carriers has been investigated quantitatively with real-time particle tracking technology, providing new insight into particle behavior in complex biological environments that is guiding rational improvements in particle design. | |||||||||||||||||
| December 16,2004 | Quantitative analysis of signaling networks | ||||||||||||||||
| The response ofbiological cells to environmental change is coordinated by protein-based signaling networks.These networks are to be found in both prokaryotes and eukaryotes.In eukaryotes,the signaling networks can be highly complex,some networks comprising of60 or more proteins.The fundamental motif that has been found in all signaling networks is the protein phosphorylation/dephosphorylation cycle —the cascade cycle.At this time,the computational function ofmany ofthe signaling networks is poorly understood.However,it is clear that it is possible to construct a huge variety ofcontrol and computational circuits,both analog and digital from combinations of the cascade cycle.In this review,we will summarize the great versatility ofthe simple cascade cycle as a computational unit and towards the end give two examples,one prokaryotic chemotaxis circuit and the other,the eukaryotic MAPK cascade. | |||||||||||||||||
| December 15,2004 | Boosting the Sensitivity of Real-Time Polymerase-Chain-Reaction Testing for SARS | ||||||||||||||||
| In view of recent concern about the recurrence of severe acute respiratory syndrome (SARS) in Guangdong, China, we would like to highlight the tremendous importance of sensitivity in testing for the SARS-associated coronavirus (SARS-CoV). Because the initial symptoms of SARS are similar to those of other common respiratory diseases, making a specific diagnosis of SARS poses difficulties to medical professionals. Our enhanced real-time (ERT) polymerase-chain-reaction (PCR) method (first presented in June 2003 at a symposium on SARS1) has been designed for the detection of SARS-CoV with high sensitivity and easy-to-interpret results.2 The power of the ERT technique has now been extensively explored with the development of ERT-based diagnostic tests for various infectious diseases, including avian influenza and foot-and-mouth disease. | |||||||||||||||||
| December 14,2004 | Somatic alterations in the human cancer genome | ||||||||||||||||
| Most human malignancies are caused by somatic alterations within the cancer genome, leading to oncogene activation or tumor suppressor gene inactivation.The sequence of the human genome has enabled systematic approaches to identify can-cer genome alterations, including point mutations, copy number increases and decreases, loss of allelic heterozygosity, and chromosome translocations. Systematic cancer genome analysis has recently led to the discovery of somatic mutations in the BRAF, PIK3CA, and EGFRgenes, among others. With further development of targeted cancer therapies and improvement in genome analysis technology, genome-wide surveys of cancer will likely become tools for diagnosis as well as discovery. | |||||||||||||||||
| December 13,2004 | Molecular medicine for the brain: silencing of disease genes with RNA interference | ||||||||||||||||
| The recent discovery of RNA interference (RNAi) has revolutionised biological research and now holds promise as a potential therapy for human diseases. Currently untreatable neurological diseases are especially attractive targets. Scientists have already succeeded in using RNAi to suppress dominant disease genes in vitro; in some cases, this suppression has been allele-specific, silencing the disease-causing allele while maintaining expression of the normal allele. The challenge now is to bring this powerful technology in vivo to animal models to suppress disease genes and correct disease phenotypes. In the confrontation of this challenge, research should benefit from recent advances in viral and non-viral delivery of therapy to the brain. | |||||||||||||||||
| December 12,2004 | Pharmacogenomics in cancer therapy | ||||||||||||||||
| Pharmacogenomics aims to elucidate the genomic determinants of drug disposition and effect. Because cancer chemotherapy is relatively nonspecific and has narrow therapeutic indices, there is great potential for pharmacogenomics to improve treatment outcomes by either reducing toxicity or increasing efficacy. The diversity of therapeutic targets for anticancer drugs and the intensity of clinical pharmacology research in oncology have provided many examples of clinically relevant pharmacogenomic applications. Important elements that are discussed in this article include the association of genetic variability in the metabolism, intracellular transport and targets of anticancer drugs. In addition, we summarize where the field stands cur-rently, and how information from the host and tumor might be integrated into decision making. | |||||||||||||||||
| December 11,2004 | Gene therapy in the clinic | ||||||||||||||||
| Current experience with gene therapy for X-linked severe combined immunodeficiency disorder (X-SCID) suggests that we might now be at the point where it can be considered the ‘standard of care’. This therapy carries an unquantified risk of leukaemia, raising important questions for regulators. How dangerous does a poten-tially curative therapy for a fatal illness need to be before we call it unsafe. How uncertain does a risk need to be for us to regard a therapy as still ‘experimental’? Whose interests should prevail? Here I argue that in X-SCID it is the parents and children whom we should listen to first and foremost. How far does this patient-centred approach to licensing therapies extend? Can it be given a rational basis? | |||||||||||||||||
| December 10,2004 | Interactions between the innate immune and blood coagulation systems | ||||||||||||||||
| Blood coagulation and inflammation are universal responses to infection and there is crosstalk between inflammation and coagulation that can either amplify or dampen the responses. Loss of appropriate interactions between these systems probably contributes to mor-bidity and mortality in infectious diseases. For instance, inflammatory cytokines and leukocyte elastase can downregulate natural anticoagulant proteins that help to maintain endothelial-cell integrity, control clotting, inhibit vasoactive peptides and dampen leukocyte infiltration into the vessel wall. This Review will summarize our current understanding of the mechan-isms involved in the crosstalk between these two important systems. | |||||||||||||||||
| December 9,2004 | High-throughput gene silencing using cell arrays | ||||||||||||||||
| A recently established transfected cell array (TCA) technology has opened new experimental dimensions in the eld of functional genomics.Cell arrays allow for transfection of several thousands different DNA molecules in microarray format.The effects of overexpression of hundred of proteins on cellular physiology can be observed in a single experiment.The TCA technique has also found its application in RNA interference (RNAi) research.Small interfering RNAs (siRNA)as well as plasmid expressing short hairpin RNAs can be transferred into the cell through the proces of reverse transfection. The silencing of numerous genes in spatially separated manner can be thus monitored.This review will provide an overview on current concept concerning combination of cell array and RNAi for high-throughput loss-of-function studies. | |||||||||||||||||
| December 8,2004 | Finding Vulnerable Atherosclerotic Plaques | ||||||||||||||||
| Techniques to identify and treat vulnerable plaques are the focus of enormous research. Some have questioned the benefit of locating individual vulnerable plaque in a multifocal disease. On autopsy, it is found that most deaths are caused by thrombotic occlusion of a single plaque; simultaneous occurrence of 2 occlusive thrombi is rare, but a second vulnerable plaque is common, particularly in acute myocardial infarction (MI). Angiographic progression is poorly predicted by risk factors, and angiographic progression is a weak predictor of MI or death. Intravascular ultrasonography (intravascular ultrasound [IVUS]) studies find plaque rupture in most MI patients and in approximately half with unstable angina, but in only a minority of patients with stable angina. | |||||||||||||||||
| December 7,2004 | The Year In Medicine | ||||||||||||||||
| 《Nature Medicine》 在最近一期（ December 2004, Volume. 10. No. 12 ） 发布了名为 《The Year that was -- 2004 wrap up》的医学2004年大事记略 ——从新闻、人物、科技进展等多方面对2004年的医学进行了一个总结。 CMBI以此报道为蓝本， 搜集了相关的资源和文献，以供大家参考。 | |||||||||||||||||
| December 6,2004 | Genomic imprinting and assisted reproduction | ||||||||||||||||
| Imprinted genes exhibit a parent-of-origin specific pattern of expression. Such genes have been shown to be targets of molecular defects in particular genetic syndromes such as Beckwith-Wiedemann and Angelman syndromes. Recent reports have raised concern about the possibility that assisted reproduction techniques, such as in vitro fertilization or intracytoplasmic sperm injection, might cause genomic imprinting disorders. The number of reported cases of those disorders is still too small to draw firm conclusions and the safety of these widely used assisted reproduction techniques needs to be further evaluated. | |||||||||||||||||
| December 5,2004 | Human tumor suppressor p53 and DNA viruses | ||||||||||||||||
| Human tumor suppressor protein p53 plays a major role in the cell cycle, orchestrating a number of important genes involved in cell-cycle control and apoptosis, and seems to be one of the most important molecules protecting cells from malignant transformation. Mutations in the p53 gene are observed in about 50% of primary tumors, inducing defective p53 protein no longer capable of binding DNA and of activating transcription. Certain DNA viruses are thought to act in a similar way and may also contribute to the progression of invasive cancer in infected tissue. One of the most effective strategies employed by these viruses is the inhibition of p53 protein by interaction with viral oncoproteins, implying a direct but also an indirect role of these viruses in the impairment of p53 structure and function. | |||||||||||||||||
| December 4,2004 | The genetics of HLA-associated disease | ||||||||||||||||
| Type 1 diabetes mellitus (T1D) remains the most intensively studied, and thus the best paradigm, of MHC-associated diseases. Accumulating evidence suggests that MHC susceptibility for T1D is recessive, with susceptibility alleles more common than protective alleles. Updated allele-level and nucleotide sequence analysis of MHC class II T1D susceptibility markers of conserved extended haplotypes underscore the uncertainty surrounding the actual T1D MHC susceptibility locus. Recent studies have established that disease concordance in dizygotic twins is the same as that in siblings generally, for both T1D and the MHC-associated autoimmune disease gluten-sensitive enteropathy, leaving little room for a differential environmental trigger. Epigenetic mechanisms are probably involved in many MHC-associated phenomena, including autoimmunity, and appear to be the best explanation for incomplete penetrance. | |||||||||||||||||
| December 3,2004 | Interleukin-4 receptor signaling pathways in asthma pathogenesis | ||||||||||||||||
| Asthma is a chronic allergic inflammatory disease, the initiation and progression of which is dependent on the cytokines interleukin (IL)-4 and IL-13 acting through related receptor complexes. Disease pathogenesis is effected by intracellular signaling pathways that couple primarily to specific motifs within the intracellular domain of the IL-4 receptor α chain (IL-4Rα), a subunit that is common to the IL-4 and IL-13 receptor complexes. Recent studies using genetic approaches have identified distinct functions for the respective IL-4Rα-coupled signaling pathways in regulating both early and chronic stages of asthma. Polymorphisms in components of the IL-4 and IL-13 cytokine-receptor axes are associated with allergy and asthma, suggesting that variations among individuals in the activity of this pathway contribute to disease susceptibility and manifestations. | |||||||||||||||||
| December 2,2004 | Cardiac tissue engineering: regeneration of the wounded heart | ||||||||||||||||
| New solutions are needed to regenerate hearts damaged by myocardial infarction, to overcome bad prognosis of patients with heart failure, and to address the shortage of heart donors. In the past few years, cardiac tissue engineering has emerged as a new and ambitious approach that combines knowledge from material chemistry with cell biology and medicine. In this short review, we present an overview on the most promising materials and cell-therapy strategies used in the past few years for the regeneration of the wounded heart. | |||||||||||||||||
| December 1,2004 | Gene therapy in clinical medicine | ||||||||||||||||
| Although the field of gene therapy has experienced significant setbacks and limited success,it is one of the most promising and active research fields in medicine.Interest in this therapeutic modality is based on the potential for treatment and cure of some of the most malignant and devastating diseases affecting humans.Over the next decade,the relevance of gene therapy to medical practices will increase and it will become important for physicians to understand the basic principles and strategies that underlie the therapeutic intervention.This report reviews the history, basic strategies,tools,and several current clinical paradigms for application. | |||||||||||||||||
|
| |||||||||||||||||