每日一文

 
Others: 
 Jan.  2007  2006  2005  2004  2003  2002  2001

Feb 29, 2008 Gene Regulation in the Postgenomic Era: Technology Takes the Wheel
  Transcriptional regulation in eukaryotes is a complicated set of processes involving hundreds of proteins. The past decade has seen significant progress in the development of technologies that allow the dissection of the interplay between these regulatory factors. These methodologies have advanced the field to the point where regulation can be examined at the genome level and where intricate regulatory questions can be addressed in multicellular organisms. The application of these technologies over the coming decade promises exciting views of how complexes integrate to create defined regulatory networks.
Feb 28, 2008 Heart mitochondria: gates of life and death
  Mitochondria are important generators of energy, providing ATP through oxidative phosphorylation. However, mitochondria also monitor complex information from the environment and intracellular milieu, including the presence or absence of growth factors, oxygen, reactive oxygen species, and DNA damage. Mitochondria have been implicated in the loss of cells in various cardiac pathologies, including ischaemia/reperfusion injury, cardiomyopathy, and congestive heart failure. The release of factors such as cytochrome c, Smac, Omi/Htr2A, and AIF from mitochondria serves to activate a highly complex and regulated cell death program. Furthermore, mitochondrial calcium overload might trigger opening of the mitochondrial permeability transition pore, causing uncoupling of oxidative phosphorylation, swelling of the mitochondria due to influx of water, and rupture of the mitochondrial outer membrane. In this review, we discuss the role of mitochondria in the control of cell death in cardiac myocytes.
Feb 27, 2008 Pulmonary diseases and the heart
  The complex nature of interactions between the pulmonary and cardiovascular systems is becoming increasingly appreciated. Pulmonary vascular abnormalities are frequently present in patients with respiratory disorders, including chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, sarcoidosis, neuromuscular or chest wall disorders, and disorders of ventilatory control including sleep apnea syndromes and obesity hypoventilation syndrome. Pulmonary hypertension, classified as group III in the World Health Organization classification scheme for pulmonary hypertension, may result in severe right ventricular dysfunction caused by lung disease, also known as cor pulmonale...
Feb 26, 2008 The Age of Crosstalk: Phosphorylation, Ubiquitination, and Beyond
  Crosstalk between different types of posttranslational modification is an emerging theme in eukaryotic biology. Particularly prominent are the multiple connections between phosphorylation and ubiquitination, which act either positively or negatively in both directions to regulate these processes.
Feb 25, 2008 Endothelial Progenitor Cells for Cardiovascular Regeneration
  Endothelial progenitor cells (EPCs) are peripheral blood mononuclear cells that can differentiate into mature endothelial cells. Adult EPCs were first discovered in human peripheral blood in 1997. Since then, the potency of EPCs for cardiovascular regeneration has been demonstrated in several preclinical studies; and investigators are beginning to evaluate the therapeutic utility of EPCs in early-phase clinical trials. This review summarizes the progression of basic, preclinical, and clinical research into the potential use of EPC therapy for cardiovascular regeneration.
Feb 24, 2008 Why Myc? An Unexpected Ingredient in the Stem Cell Cocktail
  Screening cocktails of candidate genes for induction of pluripotency and self-renewal in nonstem cells has identified a surprising new embryonic stem cell regulator, the myc proto-oncogene. Here the possible mechanisms by which myc controls self-renewal and pluripotency are discussed.
Feb 23, 2008 Gene therapy: targeting the myocardium
  Effective clinical delivery of gene therapy to the heart requires understanding and design of complex biological systems to deliver therapeutic gene expression. The development of vectors that specifically target the myocardium, in particular bioengineered recombinant viruses, has improved the efficiency of gene delivery to the heart. These tools, coupled with advances in selection and design of the genetic payload, have led to effective cardiac gene therapy in preclinical models. This technology is currently translating to the clinic with a new wave of gene therapy trials for myocardial disease.
Feb 22, 2008 RNA 1997–2007: A Remarkable Decade of Discovery
  The past decade has witnessed spectacular progress in the field of RNA biology and biochemistry; old problems have been solved, and new ones have emerged. This perspective briefly reviews where we are today and where we might be 10 years hence.
Feb 21, 2008 Synaptic plasticity, memory and the hippocampus: a neural network approach to causality
  Two facts about the hippocampus have been common currency among neuroscientists for several decades. First, lesions of the hippocampus in humans prevent the acquisition of new episodic memories; second, activity-dependent synaptic plasticity is a prominent feature of hippocampal synapses. Given this background, the hypothesis that hippocampus-dependent memory is mediated, at least in part, by hippocampal synaptic plasticity has seemed as cogent in theory as it has been difficult to prove in practice. Here we argue that the recent development of transgenic molecular devices will encourage a shift from mechanistic investigations of synaptic plasticity in single neurons towards an analysis of how networks of neurons encode and represent memory, and we suggest ways in which this might be achieved. In the process, the hypothesis that synaptic plasticity is necessary and sufficient for information storage in the brain may finally be validated.
Feb 20, 2008 Alignment Uncertainty and Genomic Analysis
  The statistical methods applied to the analysis of genomic data do not account for uncertainty in the sequence alignment. Indeed, the alignment is treated as an observation, and all of the subsequent inferences depend on the alignment being correct. This may not have been too problematic for many phylogenetic studies, in which the gene is carefully chosen for, among other things, ease of alignment. However, in a comparative genomics study, the same statistical methods are applied repeatedly on thousands of genes, many of which will be difficult to align. Using genomic data from seven yeast species, we show that uncertainty in the alignment can lead to several problems, including different alignment methods resulting in different conclusions.
Feb 19, 2008 Steady progress and recent breakthroughs in the accuracy of automated genome annotation
  The unprecedented epizootic of avian influenza a (h5n1) viruses among birds continues to cause human disease with high mortality and to pose the threat of a pandemic. This review updates a 2005 report1 and incorporates information recently published or presented at the Second World Health Organization (WHO) Consultation on Clinical Aspects of Human Infection with Avian Influenza A (H5N1) Virus.
Feb 18, 2008 Steady progress and recent breakthroughs in the accuracy of automated genome annotation
  The sequencing of large, complex genomes has become routine, but understanding how sequences relate to biological function is less straightforward. Although much attention is focused on how to annotate genomic features such as developmental enhancers and non-coding RNAs, there is still no higher eukaryote for which we know the correct exon-intron structure of at least one ORF for each gene. Despite this uncomfortable truth, genome annotation has made remarkable progress since the first drafts of the human genome were analysed. By combining several computational and experimental methods, we are now closer to producing complete and accurate gene catalogues than ever before.
Feb 17, 2008 Aldosterone and Vascular Inflammation
  Oxidative stress and inflammation contribute to increased cardiovascular morbidity and mortality associated with activation of the renin-angiotensin (Ang)-aldosterone system (RAAS). Studies in cultured cells in vitro and in rodent models in vivo demonstrate that aldosterone and/or mineralocorticoid receptor (MR) activation cause oxidative stress and vascular inflammation. Translational studies in humans suggest that endogenous aldosterone increases inflammatory biomarkers through an MR-dependent pathway.
Feb 16, 2008 The influence of genetic variation on gene expression
  The view that changes to the control of gene expression rather than alterations to protein sequence are central to the evolution of organisms has become something of a truism in molecular biology. In reality, the direct evidence for this is limited, and only recently have we had the ability to look more globally at how genetic variation influences gene expression, focusing upon inter-individual variation in gene expression and using microarrays to test for differences in mRNA levels. Here, we review the scope of these experimental analyses, what they are designed to tell us about genetic variation, and what are their limitations from both a technical and a conceptual viewpoint. We conclude that while we are starting to understand the impact of this class of genetic variation upon steady-state mRNA levels, we are still far from identifying the potential phenotypic and evolutionary outcomes.
Feb 15, 2008 Nanotechnology in regenerative medicine: the materials side
  Regenerative medicine is an emerging multidisciplinary field that aims to restore, maintain or enhance tissues and hence organ functions. Regeneration of tissues can be achieved by the combination of living cells, which will provide biological functionality, and materials, which act as scaffolds to support cell proliferation. Mammalian cells behave in vivo in response to the biological signals they receive from the surrounding environment, which is structured by nanometre-scaled components. Therefore, materials used in repairing the human body have to reproduce the correct signals that guide the cells towards a desirable behaviour. Nanotechnology is not only an excellent tool to produce material structures that mimic the biological ones but also holds the promise of providing efficient delivery systems. The application of nanotechnology to regenerative medicine is a wide issue and this short review will only focus on aspects of nanotechnology relevant to biomaterials science. Specifically, the fabrication of materials, such as nanoparticles and scaffolds for tissue engineering, and the nanopatterning of surfaces aimed at eliciting specific biological responses from the host tissue will be addressed.
Feb 14, 2008 Artificial cells: building bioinspired systems using small-scale biology
  Artificial cells have generated much interest since the concept was introduced by Aleksandr Oparin in the 1920s, and they have had an impact on the pharmaceutical and biotechnology industry in various areas, including potential therapeutic applications. Here, we discuss the development of small-scale, bio-inspired artificial cell components that recreate the function of key cellular and physiological systems. We describe artificial cells, selected current applications and how small-scale biology could be used to provide what might be a next-generation approach in this area. We believe that this type of work is in its infancy and that exploiting small-scale biological inspiration in the field of artificial cells has great potential for successes in the future.
Feb 13, 2008 The interplay between MYC and HIF in cancer
  The interaction of MYC and hypoxia inducible factors (HIFs) under physiological, non-tumorigenic conditions provides insights into normal homeostatic cellular responses to low oxygen levels (hypoxia). Many tumours contain genetic alterations, such as MYC activation, that can collaborate with HIF to confer metabolic advantages to tumour cells, which tend to exist in a hypoxic microenvironment. This Perspective emphasizes the differences between the transcriptional network that operates under normal homeostatic conditions and the network in a tumorigenic milieu.
Feb 12, 2008 Targeting microRNA expression to regulate angiogenesis
  MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the post-transcriptional level by either degradation or translational repression of a target mRNA. More than 400 miRNAs have been identified in the human genome, but the relevance of most of them to physiological and pathological processes remains unclear. Although downregulation of the miRNA-processing enzymes Dicer and Drosha is known to impair angiogenesis, only a few specific miRNAs targeting endothelial cell function and angiogenesis have been identified. miR-221 and miR-222 block endothelial cell migration, proliferation and angiogenesis in vitro by targeting the stem cell factor receptor c-Kit and indirectly regulating expression of endothelial nitric oxide synthase. A pro-angiogenic function has been established for the miR-17-92 cluster, which promotes tumor angiogenesis in vivo. Expression of let7-f and miR-27b contributes to in vitro angiogenesis. We review recent studies on the involvement of miRNA in angiogenesis and discuss their implications for miRNA-based therapeutic strategies targeting this process in disease.
Feb 11, 2008 Immune memory, immune oblivion: A lesson from Funes the memorious
  We commonly think of the immune system as having a memory. However, memory is always accompanied by a complementary process of oblivion. Is there immune oblivion? In this theoretical paper, I address this question and suggest that oblivion is an integral aspect of memorization. In this context, I suggest that immune memory is an orchestration of reversible and irreversible processes of biological computation through feedback loops. Drawing on the linguistic metaphor, I inquire into the implications of this idea for a better understanding of immune memory and immune deficiency among the elderly.
Feb 10, 2008 The DNA Damage Response: Ten Years After
  The DNA damage response (DDR), through the action of sensors, transducers, and effectors, orchestrates the appropriate repair of DNA damage and resolution of DNA replication problems, coordinating these processes with ongoing cellular physiology. In the past decade, we have witnessed an explosion in understanding of DNA damage sensing, signaling, and the complex interplay between protein phosphorylation and the ubiquitin pathway employed by the DDR network to execute the response to DNA damage. These findings have important implications for aging and cancer.
Feb 9, 2008 Drug-eluting stents: a critique
  Despite advances in the design of balloons and stents, restenosis remains a major drawback of coronary angioplasty. Multiple randomised trials have demonstrated that drug-eluting stents (DES) can significantly reduce rates of restenosis by 60-75% across both lesion and patient subsets. In recent years there has been an exponential increase in the worldwide use of DES. This expansion has occurred as a result of an enthusiastic extrapolation of results from randomised trials leading to "off-label" use of DES in anatomical or clinical high-risk scenarios, or both. However, emerging medium- to long-term follow-up data have raised concerns about the safety of DES. A number of analyses have recently shown increased rates of late stent thrombosis in patients with DES. The exact mechanisms leading to stent thrombosis remain unclear. This article critically reviews the available efficacy and safety data on DES and discusses the factors influencing our current practice and perception of the net value of DES.
Feb 8, 2008 β Cells Can Be Generated from Endogenous Progenitors in Injured Adult Mouse Pancreas
  Novel strategies in diabetes therapy would obviously benefit from the use of beta (beta) cell stem/progenitor cells. However, whether or not adult beta cell progenitors exist is one of the most controversial issues in today's diabetes research. Guided by the expression of Neurogenin 3 (Ngn3), the earliest islet cell-specific transcription factor in embryonic development, we show that beta cell progenitors can be activated in injured adult mouse pancreas and are located in the ductal lining. Differentiation of the adult progenitors is Ngn3 dependent and gives rise to all islet cell types, including glucose responsive beta cells that subsequently proliferate, both in situ and when cultured in embryonic pancreas explants. Multipotent progenitor cells thus exist in the pancreas of adult mice and can be activated cell autonomously to increase the functional beta cell mass by differentiation and proliferation rather than by self-duplication of pre-existing beta cells only.
Feb 7, 2008 Systematic evaluation of microRNA processing patterns in tissues, cell lines, and tumors
  Very little is known regarding regulation of microRNA (miRNA) biogenesis in normal tissues, tumors, and cell lines. Here, we profiled the expression of 225 precursor and mature miRNAs using real-time PCR and compared the expression levels to determine the processing patterns. RNA from 22 different human tissues, 37 human cancer cell lines, and 16 pancreas and liver tissues/tumors was profiled. The relationship between precursor and mature miRNA expression fell into the following four categories: (1) a direct correlation exists between the precursor and mature miRNA expression in all cells/tissues studied; (2) direct correlation of the precursor and mature miRNA exists, yet the expression is restricted to specific cell lines or tissues; (3) there is detectable expression of mature miRNA in certain cells and tissues while the precursor is expressed in all or most cells/tissues; or (4) both precursor and mature miRNA are not expressed. Pearson correlation between the precursor and mature miRNA expression was closer to one for the tissues but was closer to zero for the cell lines, suggesting that processing of precursor miRNAs is reduced in cancer cell lines. By using Northern blotting, we show that many of these miRNAs (e.g., miR-31, miR-105 and miR-128a) are processed to the precursor, but in situ hybridization analysis demonstrates that these miRNA precursors are retained in the nucleus. We provide a database of the levels of precursor and mature miRNA in a variety of cell types. Our data demonstrate that a large number of miRNAs are transcribed but are not processed to the mature miRNA.
Feb 6, 2008 Circulating progenitor cells in stable coronary heart disease and acute coronary syndromes: relevant reparatory mechanism?
  Bone marrow-derived cells which may be involved in cardiac repair/regeneration after ischaemic injury must undergo mobilisation into peripheral blood with subsequent homing and engraftment into the target organ. Mobilisation of the heterogeneous population of stem/progenitor cells in endothelial injury or myocardial ischaemia has been described recently. The number of circulating stem/progenitor cells reflects the endothelial damage, and turnover may be a surrogate marker reflecting the burden of cardiovascular risk factors and prognostic markers in stable coronary heart disease and acute coronary syndromes. Acute coronary syndromes are associated with increased levels of inflammatory and haematopoietic cytokines which, in turn, can mobilise progenitor cells from the bone marrow. Myocardial infarction increases the number of endothelial progenitor cells and other less well-defined subpopulations, such as CD34/c-kit(+) and CD34/CXCR4(+) cells, which may take part in cardiac repair after ischaemic injury. Data on mobilisation of stem/progenitor cells in acute coronary syndromes are summarised here. Cell types, mechanisms of mobilisation, homing and engraftment are discussed and their relevance to clinical outcomes.
Feb 5, 2008 Hematopoietic cytokines
  The production of hematopoietic cells is under the tight control of a group of hematopoietic cytokines. Each cytokine has multiple actions mediated by receptors whose cytoplasmic domains contain specialized regions initiating the various responses-survival, proliferation, differentiation commitment, maturation, and functional activation. Individual cytokines can be lineage specific or can regulate cells in multiple lineages, and for some cell types, such as stem cells or megakaryocyte progenitors, the simultaneous action of multiple cytokines is required for proliferative responses. The same cytokines control basal and emergency hematopoietic cell proliferation. Three cytokines, erythropoietin, granulocyte colony-stimulating factor, and granulocyte-macrophage colony-stimulating factor, have now been in routine clinical use to stimulate cell production and in total have been used in the management of many millions of patients. In this little review, discussion will be restricted to those cytokines well established as influencing the production of hematopoietic cells and will exclude newer candidate regulators and those active on lymphoid cells. As requested, this account will describe the cytokines in a historical manner, using a sequential format of discovery, understanding, validation, and puzzlement, a sequence that reflects the evolving views on these cytokines over the past 50 years.
Feb 4, 2008 Fuzzy complexes: polymorphism and structural disorder in protein–protein interactions
  The notion that all protein functions are determined through macromolecular interactions is the driving force behind current efforts that aim to solve the structures of all cellular complexes. Recent findings, however, demonstrate a significant amount of structural disorder or polymorphism in protein complexes, a phenomenon that has been largely overlooked thus far. It is our view that such disorder can be classified into four mechanistic categories, covering a continuous spectrum of structural states from static to dynamic disorder and from segmental to full disorder. To emphasize its generality and importance, we suggest a generic term, 'fuzziness', for this phenomenon. Given the crucial role of protein disorder in protein-protein interactions and in regulatory processes, we envision that fuzziness will become integral to understanding the interactome.
Feb 3, 2008 Innate immunity, insulin resistance and type 2 diabetes
  Recent evidence has disclosed previously unrecognized links among insulin resistance, obesity, circulating immune markers, immunogenetic susceptibility, macrophage function and chronic infection. Genetic variations leading to altered production or function of circulating innate immune proteins, cellular pattern-recognition receptors and inflammatory cytokines have been linked with insulin resistance, type 2 diabetes, obesity and atherosclerosis. Cellular innate immune associations with obesity and insulin resistance include increased white blood cell count and adipose tissue macrophage numbers. The innate immune response is modulated possibly by both predisposition (genetic or fetal programming), perhaps owing to evolutionary pressures caused by acute infections at the population level (pandemics), and chronic low exposure to environmental products or infectious agents. The common characteristics shared among innate immunity activation, obesity and insulin resistance are summarized.
Feb 2, 2008 Paradigms for the Three Rs: DNA Replication, Recombination, and Repair
  The recent decade has engendered a convergence of the otherwise distinct fields of DNA replication, recombination, and repair, as we are learning how these essential transactions can operate in coordination to achieve genomic stability and to ensure cellular viability. In the next decade, we can anticipate a functional understanding of the roles of posttranslational protein modifications in the regulation and prioritizing of pathways for genomic maintenance. The fundamental knowledge gained should lead to more effective clinical intervention in human disease.
Feb 1, 2008 Dendritic mRNA: transport, translation and function
  Many cellular functions require the synthesis of a specific protein or functional cohort of proteins at a specific time and place in the cell. Local protein synthesis in neuronal dendrites is essential for understanding how neural activity patterns are transduced into persistent changes in synaptic connectivity during cortical development, memory storage and other long-term adaptive brain responses. Regional and temporal changes in protein levels are commonly coordinated by an asymmetric distribution of mRNAs. This Review attempts to integrate current knowledge of dendritic mRNA transport, storage and translation, placing particular emphasis on the coordination of regulation and function during activity-dependent synaptic plasticity in the adult mammalian brain.

Jan.  2007  2006  2005  2004  2003  2002  2001