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Jan. 26, 2011 Signaling to NF-kappaB: regulation by ubiquitination.
  The NF-kappaB pathway is a ubiquitous stress response that activates the NF-kappaB family of transcription factors. Antigen receptors, receptors of the innate immune system, and certain intracellular stressors are potent activators of this pathway. The transcriptional program that is activated is both antiapoptotic and highly proinflammatory. Indeed, any compromise in engagement of the pathway results in immunodeficiency, whereas constitutive activation generates a sustained inflammatory response that may promote malignancy. As such, NF-kappaB activation is under tight regulation by a number of post-translational modifications, including phosphorylation and ubiquitination. This article attempts to synthesize our current knowledge regarding the regulation of NF-kappaB signaling by ubiquitination, specifically highlighting the biochemical basis for both positive and negative feedback loops that function in unison to generate coordinated signals that are essential for the viability of metazoan animals.
Jan. 25, 2011 Whole-heart modeling: applications to cardiac electrophysiology and electromechanics.
  Recent developments in cardiac simulation have rendered the heart the most highly integrated example of a virtual organ. We are on the brink of a revolution in cardiac research, one in which computational modeling of proteins, cells, tissues, and the organ permit linking genomic and proteomic information to the integrated organ behavior, in the quest for a quantitative understanding of the functioning of the heart in health and disease. The goal of this review is to assess the existing state-of-the-art in whole-heart modeling and the plethora of its applications in cardiac research. General whole-heart modeling approaches are presented, and the applications of whole-heart models in cardiac electrophysiology and electromechanics research are reviewed. The article showcases the contributions that whole-heart modeling and simulation have made to our understanding of the functioning of the heart. A summary of the future developments envisioned for the field of cardiac simulation and modeling is also presented. Biophysically based computational modeling of the heart, applied to human heart physiology and the diagnosis and treatment of cardiac disease, has the potential to dramatically change 21st century cardiac research and the field of cardiology.
Jan. 24, 2011 Mechanisms for T cell receptor triggering.
  There is considerable controversy about the mechanism of T cell receptor (TCR) triggering, the process by which the TCR tranduces signals across the plasma membrane after binding to its ligand (an agonist peptide complexed with an MHC molecule). Three main types of mechanism have been proposed, which involve aggregation, conformational change and segregation. Here, we review recently published evidence for each type of mechanism and conclude that all three may be involved. This complexity may reflect the uniquely demanding nature of TCR-mediated antigen recognition, which requires the detection of a very weak 'signal' (very rare foreign peptide-MHC ligands) in the presence of considerable 'noise' (abundant self peptide-MHC molecules).
Jan. 23, 2011 Direct reprogramming of fibroblasts into epiblast stem cells.
  Epiblast stem cells (EpiSCs) derived from epiblast tissue of post-implantation embryos are pluripotent and can give rise to all three germ layers in teratoma assays. Introduction of the four transcription factors Oct4, Sox2, Klf4 and c-Myc into somatic cells has been shown to generate induced pluripotent stem cells (iPSCs) that are very similar to embryonic stem cells (ESCs) in a number of characteristics. However, generation of EpiSCs by the direct reprogramming of somatic cells using these transcription factors has not been shown to date. Here, we show that these transcription factors can be used to directly generate induced EpiSCs (iEpiSCs) under EpiSC culture conditions. iEpiSCs resemble EpiSCs in morphology, gene expression pattern, epigenetic status and chimaera-forming capability. This study demonstrates that the culture environment in transcription factor-mediated reprogramming determines the cell fate of the reprogrammed cell. We therefore hypothesize that it will eventually be possible to shape the identity of a directly reprogrammed cell simply by modulating culture conditions.
Jan. 22, 2011 Additional layers of gene regulatory complexity from recently discovered microRNA mechanisms.
  In recent years microRNAs have become recognized as pervasive, versatile agents of gene regulation. Some widely embraced rules involving Watson-Crick hybridization of microRNAs with mRNAs have generated great interest as scientists envision potential RNA cargoes for gene therapy and other experimental systems. However, while researchers ardently seek simplifying principles, nature seems very uncooperative. This article reviews some small RNA mechanisms that potentially regulate genes and which are not covered by previous microRNAs characterizations. In addition, we report here results of fluorescence microscopy experiments to directly demonstrate nuclear import of small RNAs equal in length to typical mature microRNAs, implying that gene regulation at the locus of transcription might be possible.
Jan. 21, 2011 Distinct conformational states of HIV-1 gp41 are recognized by neutralizing and non-neutralizing antibodies.
  HIV-1 envelope glycoprotein gp41 undergoes large conformational changes to drive fusion of viral and target cell membranes, adopting at least three distinct conformations during the viral entry process. Neutralizing antibodies against gp41 block HIV-1 infection by targeting gp41's membrane-proximal external region in a fusion-intermediate state. Here we report biochemical and structural evidence that non-neutralizing antibodies, capable of binding with high affinity to an immunodominant segment adjacent to the neutralizing epitopes in the membrane-proximal region, recognize a gp41 conformation that exists only when membrane fusion is complete. We propose that these non-neutralizing antibodies are induced in HIV-1-infected individuals by gp41 in a triggered, postfusion form and contribute to production of ineffective humoral responses. These results have important implications for gp41-based vaccine design.
Jan. 20, 2011 CMR for characterization of the myocardium in acute coronary syndromes.
  The utility of cardiac magnetic resonance imaging (CMR) as a diagnostic technique is well established. CMR enables tissue characterization, distinction between myocardial scar tissue and viable tissue, and evaluation of myocardial perfusion and contractile function. To date, CMR has been mostly applied in the assessment of stable disease; however, a role for CMR in the acute setting is also emerging. An accurate appraisal of the myocardium with CMR in the first hours after the onset of chest pain could provide supporting information to standard diagnostic tools, such as electrocardiography and measurement of blood biomarkers, which could help guide the selection of appropriate treatment. The aims of this integrated approach include positive identification of an ischemic syndrome, estimation of downstream areas at risk of damage, evaluation of epicardial artery patency and small vessel integrity, quantification of infarct size, and determination of myocardial function. This Review critically evaluates both established and emerging CMR techniques, and relates the imaging findings to the underlying pathophysiological processes in acute coronary syndromes. A more thorough understanding of CMR techniques will clarify their potential clinical applications and limitations, and assess the practicality of CMR in the setting of acute coronary syndromes, where early intervention is crucial to save myocardium at risk of irreversible injury.
Jan. 19, 2011 216025Alternans and arrhythmias: from cell to heart.
  The goal of systems biology is to relate events at the molecular level to more integrated scales from organelle to cell, tissue, and living organism. Here, we review how normal and abnormal excitation-contraction coupling properties emerge from the protein scale, where behaviors are dominated by randomness, to the cell and tissue scales, where heart has to beat with reliable regularity for a lifetime. Beginning with the fundamental unit of excitation-contraction coupling, the couplon where L-type Ca channels in the sarcolemmal membrane adjoin ryanodine receptors in the sarcoplasmic reticulum membrane, we show how a network of couplons with 3 basic properties (random activation, refractoriness, and recruitment) produces the classic physiological properties of excitation-contraction coupling and, under pathophysiological conditions, leads to Ca alternans and Ca waves. Moving to the tissue scale, we discuss how cellular Ca alternans and Ca waves promote both reentrant and focal arrhythmias in the heart. Throughout, we emphasize the qualitatively novel properties that emerge at each new scale of integration.
Jan. 18, 2011 High density lipoprotein: it's not just about lipid transport anymore.
  Plasma levels of high density lipoprotein cholesterol (HDL-C) have long been associated with protection against cardiovascular disease (CVD) in large populations. However, HDL-C has been significantly less useful for predicting CVD risk in individual patients. This has ignited a new debate on the merits of measuring HDL quantity versus quality in terms of protective potential. In addition, numerous recent studies have begun to uncover HDL functions that vary surprisingly from traditional lipid transport roles. In this paper, we review recent findings that point to important functions for HDL that go well beyond lipid transport. These discoveries suggest that HDL might be a platform that mediates protection from a host of disease states ranging from CVD to diabetes to infectious disease.
Jan. 17, 2011 Oncogenic activation of NF-kappaB.
  Recent genetic evidence has established a pathogenetic role for NF-kappaB signaling in cancer. NF-kappaB signaling is engaged transiently when normal B lymphocytes respond to antigens, but lymphomas derived from these cells accumulate genetic lesions that constitutively activate NF-kappaB signaling. Many genetic aberrations in lymphomas alter CARD11, MALT1, or BCL10, which constitute a signaling complex that is intermediate between the B-cell receptor and IkappaB kinase. The activated B-cell-like subtype of diffuse large B-cell lymphoma activates NF-kappaB by a variety of mechanisms including oncogenic mutations in CARD11 and a chronic active form of B-cell receptor signaling. Normal plasma cells activate NF-kappaB in response to ligands in the bone marrow microenvironment, but their malignant counterpart, multiple myeloma, sustains a variety of genetic hits that stabilize the kinase NIK, leading to constitutive activation of the classical and alternative NF-kappaB pathways. Various oncogenic abnormalities in epithelial cancers, including mutant K-ras, engage unconventional IkappaB kinases to activate NF-kappaB. Inhibition of constitutive NF-kappaB signaling in each of these cancer types induces apoptosis, providing a rationale for the development of NF-kappaB pathway inhibitors for the treatment of cancer.
Jan. 16, 2011 Multimodality imaging in diabetic heart disease.
  Diabetic heart disease is currently defined as left ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Its underlying etiology is likely to be multifactorial, acting synergistically together to cause myocardial dysfunction. Multimodality cardiac imaging, such as echocardiography, nuclear, computed tomography, and magnetic resonance imaging, can provide invaluable insight into different aspects of the disease process, from imaging at the cellular level for altered myocardial metabolism to microvascular and endothelial dysfunction, autonomic neuropathy, coronary atherosclerosis, and finally, interstitial fibrosis with scar formation. Furthermore, cardiac imaging is pivotal in diagnosing diabetic heart disease. Thus, the aim of the present review is to illustrate the role of multimodality cardiac imaging in elucidating the underlying pathophysiologic mechanisms of diabetic heart disease.
Jan. 15, 2011 Use of Diuretics in Patients with Hypertension
  Thiazide diuretics became available in the late 1950s and were the first effective oral antihypertensive agents with an acceptable side-effect profile. A half-century later, thiazides remain important medications for the treatment of hypertension.
Jan. 14, 2011 The tumor suppressor p53: from structures to drug discovery
  Even 30 years after its discovery, the tumor suppressor protein p53 is still somewhat of an enigma. p53's intimate and multifaceted role in the cell cycle is mirrored in its equally complex structural biology that is being unraveled only slowly. Here, we discuss key structural aspects of p53 function and its inactivation by oncogenic mutations. Concerted action of folded and intrinsically disordered domains of the highly dynamic p53 protein provides binding promiscuity and specificity, allowing p53 to process a myriad of cellular signals to maintain the integrity of the human genome. Importantly, progress in elucidating the structural biology of p53 and its partner proteins has opened various avenues for structure-guided rescue of p53 function in tumors. These emerging anticancer strategies include targeting mutant-specific lesions on the surface of destabilized cancer mutants with small molecules and selective inhibition of p53's degradative pathways.
Jan. 13, 2011 Neuroscience in the era of functional genomics and systems biology
  Advances in genetics and genomics have fuelled a revolution in discovery-based, or hypothesis-generating, research that provides a powerful complement to the more directly hypothesis-driven molecular, cellular and systems neuroscience. Genetic and functional genomic studies have already yielded important insights into neuronal diversity and function, as well as disease. One of the most exciting and challenging frontiers in neuroscience involves harnessing the power of large-scale genetic, genomic and phenotypic data sets, and the development of tools for data integration and mining. Methods for network analysis and systems biology offer the promise of integrating these multiple levels of data, connecting molecular pathways to nervous system function.
Jan. 12, 2011 Clinical proteomics of myeloid leukemia.
  Myeloid leukemias are a heterogeneous group of diseases originating from bone marrow myeloid progenitor cells. Patients with myeloid leukemias can achieve long-term survival through targeted therapy, cure after intensive chemotherapy or short-term survival because of highly chemoresistant disease. Therefore, despite the development of advanced molecular diagnostics, there is an unmet need for efficient therapy that reflects the advanced diagnostics. Although the molecular design of therapeutic agents is aimed at interacting with specific proteins identified through molecular diagnostics, the majority of therapeutic agents act on multiple protein targets. Ongoing studies on the leukemic cell proteome will probably identify a large number of new biomarkers, and the prediction of response to therapy through these markers is an interesting avenue for future personalized medicine. Mass spectrometric protein detection is a fundamental technique in clinical proteomics, and selected tools are presented, including stable isotope labeling with amino acids in cell culture (SILAC), isobaric tags for relative and absolute quantification (iTRAQ) and multiple reaction monitoring (MRM), as well as single cell determination. We suggest that protein analysis will play not only a supplementary, but also a prominent role in future molecular diagnostics, and we outline how accurate knowledge of the molecular therapeutic targets can be used to monitor therapy response.
Jan. 11, 2011 Percutaneous transcatheter aortic valve implantation: past accomplishments, present achievements and applications, future perspectives.
  Surgical aortic valve replacement remains the gold standard for the treatment of severe, symptomatic aortic stenosis. However, percutaneous treatments are challenging this paradigm in high-risk surgical patients. Technological developments have been rapid in the field of percutaneous aortic valve intervention. Two devices have been approved for general use in Europe: the Edwards SAPIEN valve (Edwards Lifesciences, Irvine, CA) and the CoreValve ReValving((R)) System (CoreValve ReValving((R)) Technology Medtronic Inc., Minneapolis, MN), with 15 potential new designs for percutaneous aortic valves in development around the world. Both systems can be delivered via the transfemoral, transapical and the axillary/subclavian routes, depending upon patient characteristics, anatomy, and the device available to the operator. Careful selection of appropriate patients is essential to ensure a safe procedure. This necessitates a multidisciplinary approach, with multiple imaging modalities used to fully delineate the peripheral vasculature, aortic anatomy and the valve itself. It is important to remember, however, that just because we can treat aortic valve disease percutaneously, it does not mean that we necessarily should. The gold standard treatment for aortic stenosis remains thoracotomy and surgical replacement of the valve; to this end it is essential that surgeons play a central role in the decision-making processes for transcatheter aortic valve implantation and that they embrace this new and exciting technology, which promises to dramatically change the way their high-risk aortic valve patients are managed over the course of the next 10 years.
Jan. 10, 2011 Identification of cholesterol-regulating genes by targeted RNAi screening.
  Elevated plasma cholesterol levels are considered responsible for excess cardiovascular morbidity and mortality. Cholesterol in plasma is tightly controlled by cholesterol within cells. Here, we developed and applied an integrative functional genomics strategy that allows systematic identification of regulators of cellular cholesterol levels. Candidate genes were identified by genome-wide gene-expression profiling of sterol-depleted cells and systematic literature queries. The role of these genes in cholesterol regulation was then tested by targeted siRNA knockdown experiments quantifying cellular cholesterol levels and the efficiency of low-density lipoprotein (LDL) uptake. With this strategy, 20 genes were identified as functional regulators of cellular cholesterol homeostasis. Of these, we describe TMEM97 as SREBP target gene that under sterol-depleted conditions localizes to endo-/lysosomal compartments and binds to LDL cholesterol transport-regulating protein Niemann-Pick C1 (NPC1). Taken together, TMEM97 and other factors described here are promising to yield further insights into how cells control cholesterol levels.
Jan. 9, 2011 Robust functional vascular network formation in vivo by cooperation of adipose progenitor and endothelial cells.
  Rapid induction and maintenance of blood flow through new vascular networks is essential for successfully treating ischemic tissues and maintaining function of engineered neo-organs. We have previously shown that human endothelial progenitor cells (EPCs) form functioning vessels in mice, but these are limited in number and persistence; and also that human adipose stromal cells (ASCs) are multipotent cells with pericytic properties which can stabilize vascular assembly in vitro. In this study, we tested whether ASCs would cooperate with EPCs to coassemble vessels in in vivo implants. Collagen implants containing EPCs, ASCs, or a 4:1 mixture of both were placed subcutaneously into NOD/SCID mice. After a range of time periods, constructs were explanted and evaluated with regard to vascular network assembly and cell fate; and heterotypic cell interactions were explored by targeted molecular perturbations. The density and complexity of vascular networks formed by the synergistic dual-cell system was many-fold higher than found in implants containing either ASCs or EPCs alone. Coimplantation of ASCs and EPCs with either pancreatic islets or adipocytes produced neoorgans populated by these parenchymal cells, as well as by chimeric human vessels conducting flow. This study is the first to demonstrate prompt and consistent assembly of a vascular network by human ASCs and endothelial cells and vascularization by these cells of parenchymal cells in implants. Mixture of these 2 readily available, nontransformed human cell types provides a practical approach to tissue engineering, therapeutic revascularization, and in vivo studies of human vasculogenesis.
Jan. 8, 2011 Astroglial networks: a step further in neuroglial and gliovascular interactions.
  Dynamic aspects of interactions between astrocytes, neurons and the vasculature have recently been in the neuroscience spotlight. It has emerged that not only neurons but also astrocytes are organized into networks. Whereas neuronal networks exchange information through electrical and chemical synapses, astrocytes are interconnected through gap junction channels that are regulated by extra- and intracellular signals and allow exchange of information. This intercellular communication between glia has implications for neuroglial and gliovascular interactions and hence has added another level of complexity to our understanding of brain function.
Jan. 7, 2011 Clinical pharmacology and pharmacogenetics in a genomics era: the DMET platform.
  While no genome-wide pharmacogenetics study has yet been published, the field of pharmacogenetics is moving towards exploratory, large-scale analyses of the interaction between genetic variation and drug treatment. The Drug Metabolizing Enzymes and Transporters (DMET) platform offers a standardized set of 1936 variants in 225 genes related to drug absorption, distribution, metabolism and elimination that is useful to scan the genome for previously unknown associations between variation in absorption, distribution, metabolism and elimination genes and pharmacokinetic and pharmacodynamic outcomes of drug treatment. The purpose of this review is to put the DMET platform into context within the current study designs that have been used in pharmacogenetics, and to explore the role that DMET has played - and will play - in future pharmacogenetics studies.
Jan. 6, 2011 Network organization of the human autophagy system
  Autophagy, the process by which proteins and organelles are sequestered in autophagosomal vesicles and delivered to the lysosome/vacuole for degradation, provides a primary route for turnover of stable and defective cellular proteins. Defects in this system are linked with numerous human diseases. Although conserved protein kinase, lipid kinase and ubiquitin-like protein conjugation subnetworks controlling autophagosome formation and cargo recruitment have been defined, our understanding of the global organization of this system is limited. Here we report a proteomic analysis of the autophagy interaction network in human cells under conditions of ongoing (basal) autophagy, revealing a network of 751 interactions among 409 candidate interacting proteins with extensive connectivity among subnetworks. Many new autophagy interaction network components have roles in vesicle trafficking, protein or lipid phosphorylation and protein ubiquitination, and affect autophagosome number or flux when depleted by RNA interference. The six ATG8 orthologues in humans (MAP1LC3/GABARAP proteins) interact with a cohort of 67 proteins, with extensive binding partner overlap between family members, and frequent involvement of a conserved surface on ATG8 proteins known to interact with LC3-interacting regions in partner proteins. These studies provide a global view of the mammalian autophagy interaction landscape and a resource for mechanistic analysis of this critical protein homeostasis pathway.
Jan. 5, 2011 Interaction networks for systems biology
  Cellular functions are almost always the result of the coordinated action of several proteins, interacting in protein complexes, pathways or networks. Progress made in devising suitable tools for analysis of protein-protein interactions, have recently made it possible to chart interaction networks on a large-scale. The aim of this review is to provide a short overview of the most promising contributions of interaction networks to human biology, structural biology and human genetics.
Jan. 4, 2011 TNF-alpha and neuropathic pain--a review.
  Tumor necrosis factor alpha (TNF-alpha) was discovered more than a century ago, and its known roles have extended from within the immune system to include a neuro-inflammatory domain in the nervous system. Neuropathic pain is a recognized type of pathological pain where nociceptive responses persist beyond the resolution of damage to the nerve or its surrounding tissue. Very often, neuropathic pain is disproportionately enhanced in intensity (hyperalgesia) or altered in modality (hyperpathia or allodynia) in relation to the stimuli. At time of this writing, there is as yet no common consensus about the etiology of neuropathic pain - possible mechanisms can be categorized into peripheral sensitization and central sensitization of the nervous system in response to the nociceptive stimuli. Animal models of neuropathic pain based on various types of nerve injuries (peripheral versus spinal nerve, ligation versus chronic constrictive injury) have persistently implicated a pivotal role for TNF-alpha at both peripheral and central levels of sensitization. Despite a lack of success in clinical trials of anti-TNF-alpha therapy in alleviating the sciatic type of neuropathic pain, the intricate link of TNF-alpha with other neuro-inflammatory signaling systems (e.g., chemokines and p38 MAPK) has indeed inspired a systems approach perspective for future drug development in treating neuropathic pain.
Jan. 3, 2011 Eukaryotic chromosome DNA replication: where, when, and how?
  DNA replication is central to cell proliferation. Studies in the past six decades since the proposal of a semiconservative mode of DNA replication have confirmed the high degree of conservation of the basic machinery of DNA replication from prokaryotes to eukaryotes. However, the need for replication of a substantially longer segment of DNA in coordination with various internal and external signals in eukaryotic cells has led to more complex and versatile regulatory strategies. The replication program in higher eukaryotes is under a dynamic and plastic regulation within a single cell, or within the cell population, or during development. We review here various regulatory mechanisms that control the replication program in eukaryotes and discuss future directions in this dynamic field.
Jan. 2, 2011 The Future of Pharmacological Therapy for Heart Failure
  Current pharmacological therapy for heart failure (HF) is based on improved understanding of the pathophysiological mechanisms of HF progression. In particular, inhibition of key activated neurohormonal systems (eg, the renin-angiotensin-aldosterone system) and the sympathetic nervous system has been the cornerstone of drug therapy for this condition. However, despite these major advances, many HF patients still only marginally respond to these therapies. Novel therapeutic approaches have been tested. Several recent phase III studies have failed, however, despite intriguing pathophysiological concepts and promising pilot data. In other studies, significant benefits have been observed in certain subgroups only, suggesting the need for a more tailored approach to individual risk and comorbidity. This review will focus on recent and potential future pharmacological HF therapies and where drug treatment may be in the next few years. In discussing future pharmacological therapy for HF, 3 key strategies will be considered: (1) optimization of conventional therapies, (2) a focus on new drug development within areas not yet adequately represented by major clinical data and (3) new drugs affecting novel therapeutic targets.
Jan. 1, 2011 Carbohydrate engineeeeeeee