Jun 03, 2009: NBCR Summer Institute 2009 -- Cyberinfrastructure for Personalized Medicine

The National Biomedical Computation Resource (NBCR) is pleased to present its 4th annual Summer Institute to be held Aug 3 - August 7, 2009, at the University of California, San Diego, La Jolla, CA, USA. The training program provides an overview of cyberinfrastructure for personalized medicine, and includes a computational seminar series and hands-on training sessions on the tools essential for cutting edge biomedical research and development of personalized medicine. NBCR's goal in offering this Summer Institute is to broaden the impact of these tools with transparent access to cyberinfrastructure and work closely with the biomedical community in future developments, while offering significant opportunities for networking among researchers and participants. Training Sessions Each of the following 6 topics represents one of the parallel tracks. Each participant may sign up for up to two tracks. A1. Programming Scalable Scientific Workflows A2. From Cluster to Cloud Computing B1. Molecular Electrostatics and Diffusion B2. Virtual Screening & Computer Aided Drug Design C1. Electron Tomography and Mesoscale Modeling C2. Computational Cardiac Electrophysiology and Mechanics Course Materials and Cost: For online access of training session materials, please visit the NBCR Public Wiki or after the Summer Institute for 2009 materials. The workshop is geared toward graduate students, postdocs and researchers interested in learning how to use specific tools addressed by this workshop and/or who are interested in learning how to take advantage of cyberinfrastructure for personalized medicine.

Registration fees: $400 for two tracks, $350 for one track. $100 for computational seminar series (with lunch provided) and Thursday night conference dinner Waivers: Registration fees are waived for out of town participants using UCSD campus housing and meals provisions. Students and staff from UCSD and local academic institutions may register free for the training tracks, subject to space availability. Local academic participants who present an accepted poster receive free attendance of all conference events. Scholarships There are a number of scholarships awarded each year to help defray the cost of attending the Summer Institute. Please send your CV, poster abstract, and one letter of recommendation from your Ph.D. advisor or immediate supervisor to Dr. Wilfred Li (wilfred at ucsd.edu). Scholarship recipients are required to present a scientific poster during the poster session. The best poster prize recipient will be selected by a panel of judges. Important Dates: * Scholarship application: June 30th, 2009. * Scholarship notification: July 3rd, 2009. * Local participants: July 31st, 2009. * Out of town participants: July 17th, 2009. • * Training Sessions and Computational Seminar Series: Aug 3rd-7th, 2009. Please contact Teri Simas (858.534.5034, tgraysimas@ucsd.edu) for further information _________ Links: NBCR: http://www.nbcr.net NBCR Tools: http://tools.nbcr.net NBCR Summer Institute: http://si.nbcr.net NCRR: http://www.ncrr.nih.gov

Mar 15, 2009: Subcellular anatomy of cardiac myocytes revealed through advanced 3D tomographic study

Computational biology promises to offer advanced simulations cellular environment so that more personalized care and diagnosis may be provided in real time. Heart failure is still a leading cause of death in the US and around the world. Scientists at UCSD have collaborated in a new study just published in the Journal of Cell Science that yielded detailed information on the subcellular anatomy in a mouse model of heart failure. Subcellular anatomy is considered to be important in calcium regulation, and its variation over time may hold clues to the progression of heart diseases. Hoshijima and colleagues (1) at the Neurosciences department, UCSD, used a combination of light microscopy and electron microscopy to provide a high definition image of the subcellular organelles such as junctional sarcoplasmic reticulum (jSR), T-tubules and mitochondria, and how they form an intricate membrane system inside the cell. This study could change how scientists think about these organelles, and the regulatory molecules such as ryanodine receptors (RyR), L-type calcium channels, are distributed in the cell. Such detailed geometric studies are important to the development of realistic models for computational studies that may help researchers, and eventually physicians, to better understand the progression of heart diseases. The challenge in getting accurate subcellular structures and mathematical models, known as meshes, to represent them, is huge. A major obstacle is that many of the subcellular structures have dimensions at or below the diffraction limit of the light microscopy (LM) or beyond the general view field of conventional electron microscopy (EM). Through the use of image pre-processing and tracking capabilities of software packages including GAMer (Geometry-preserving Adaptive MeshER) (2), IMOD (3), and TxBR (Transform Based Back-Projection and Bundle Adjustment) (4), the availability of these high definition images allow the reconstruction of these organelles in 3D through a process called tomographic reconstruction (Figure 1). These highly detailed 3D measurements indicated that the dyadic clefts, small intermembrance space between the T-tubules and jSR are polymorphic and occupy a much smaller volume than previously reported, almost an order of magnitude smaller. The estimated distance between nearest dyadic clefts is also an order of magnitude smaller. A possible connection between mitochondria and Ca2+ signaling is suggested with the observation of “tethers” or “bridges” between mitochondria and jSR. At the molecular level, the quantity of RyR tetramers is estimated to be about 8 for an average dyadic cleft observed in mice. The heterogeneity in RyR clusters or single units could offer explanations for the quantal nature of calcium sparks, the measurable changes of calcium concentration during cellular events. With these advanced 3D imaging data, more accurate mesoscale simulations possible to better understand the local control of calcium dynamics in cardiac myocytes. Tools from NBCR such as SMOL (5) and new software under development (6) will be able to take advantage of these advanced geometric studies. GAMer, TxBR, SMOL are all supported by funding from the National Center for Research Resources (NCRR) to the National Biomedical Computation Resource (NBCR), and are available for download from http://tools.nbcr.net.

Figure 1. The 3-D mesh models of polymorphicT-tubules (green), jSR (yellow), and mitochondria (magenta) are shown within the 2-D image of a middle slice of the tomographic volume of mouse myocardium through electron microscopy. The bar in the lower left indicates the length scale of 1μm.   _________ References: 1.         Hayashi, T., Martone, M. E., Yu, Z., Thor, A., Doi, M., Holst, M., Ellisman, M. H. & Hoshijima, M. (2009). Three-dimensional electron microscopy reveals new details of membrane systems for calcium signaling in the heart. J. Cell. Sci. 2.         Yu, Z. Y., Holst, M. J. & McCammon, J. A. (2008). High-fidelity geometric modeling for biomedical applications. Finite Elements in Analysis and Design 44, 715-723. 3.         Kremer, J. R., Mastronarde, D. N. & McIntosh, J. R. (1996). Computer visualization of three-dimensional image data using IMOD. J Struct Biol 116, 71-6. 4.         Lawrence, A., Bouwer, J. C., Perkins, G. & Ellisman, M. H. (2006). Transform-based backprojection for volume reconstruction of large format electron microscope tilt series. J Struct Biol 154, 144-67. 5.         Cheng, Y., Suen, J. K., Zhang, D., Bond, S. D., Zhang, Y., Song, Y., Baker, N. A., Bajaj, C. L., Holst, M. J. & McCammon, J. A. (2007). Finite element analysis of the time-dependent Smoluchowski equation for acetylcholinesterase reaction rate calculations. Biophys J 92, 3397-406. 6.         Lu, S., Michailova, A., Cheng, Y., Yu, Z., Kaiser, T. H., Li, W. W., Banks, R. E., Holst, M., McCammon, J. A., Hoshijima, M. & McCulloch, A. D. (2008). Multi-Scale Modeling of Ventricular Myocytes: Contributions of structural and functional heterogeneities to excitation-contraction coupling in the normal and failing rodent heart. IEEE Engineering in Medicine and Biology, 1-13. Links: NCMIR: http://ncmir.ucsd.edu NBCR: http://www.nbcr.net NBCR Tools: http://tools.nbcr.net FETK: http://www.fetk.org NCRR: http://www.ncrr.nih.gov

Feb 15, 2009: Comparative molecular dynamics yield new clues to species specificity switch of influenza virus

Hemagglutinin (HA) is an influenza viral envelope membrane protein responsible for the attachment of the virus to the human cell surface proteins with glycan receptors. The cell surface glycans are polysaccharides often terminated with a sialic acid (SIA) residue, which is crucial for HA binding. The SIA is attached to a Galactose residue through either alpha-2,3 or alpha-2,6 linkage, and this linkage difference has been hypothesized in many studies to be the determinant for species specificity. Avian influenza viruses are observed to prefer alpha-2,3 linked glycans, whereas those adapted to humans may have decreased alpha-2,3 glycan affinity, and increased alpha-2,6 glycan affinity (Figure 1). However, there are experimental data that cannot be explained by the linkage difference alone, including glycan microarray studies, as well as in vitro and in vivo assays (1). The glycan topology or shape, especially those longer than three residues, was proposed to be a critical determinant in species specificity shift (2). Xu and colleagues have published a comparative molecular dynamics study on the interaction of HA from avian and swine species with natural pentasaccharides found in breast milk, which are analogues of the avian or human glycan receptors, namely, LSTa (alpha-2,3) and LSTc (alpha-2,6) (3). The study is a first extensive computational simulation of long glycan receptors (5 residues long) with HA from different species. The crystal structural studies often do not contain the complete glycan receptors, and models of the glycans were built where necessary. The results showed that the glycan topology could vary significantly during the course of the simulation, especially when the glycans are bound to different HA’s. Consistent with experimental studies, the SIA is found to account for more than half of the binding energy between HA and glycans. However, sequence specific interactions between the HA receptor binding domain (RBD) and glycans are also observed.    Using the MM-GBSA technique (4), and considering the entropic contributions from the complex formation, the authors were able to determine the relative binding affinity between the HA’s and the avian or human receptor analogues. The development of these computational simulation systems would enable in silico studies on potential HA RBD mutations that could occur in cases of a pandemic virus, as well as the role of glycan composition, cell surface expression patterns and other modifications to the glycan itself.  Moreover, the presence of these natural glycan receptors for the influenza virus in human breast milk suggests a possible role in the protection of infants from viral infections. These studies could help guide the design of glycan based inhibitors to the influenza virus.

Figure 1. Representative conformations of pentasaccharides with alpha-2,3 (LSTa) or alpha-2,6 (LSTc) linkages in complex with hemagglutinin H5 from avian influenza virus. _________ References: 1.       Nicholls, J. M., Chan, R. W., Russell, R. J., Air, G. M. & Peiris, J. S. (2008). Evolving complexities of influenza virus and its receptors. Trends Microbiol 16, 149-57. 2.       Chandrasekaran, A., Srinivasan, A., Raman, R., Viswanathan, K., Raguram, S., Tumpey, T. M., Sasisekharan, V. & Sasisekharan, R. (2008). Glycan topology determines human adaptation of avian H5N1 virus hemagglutinin. Nat Biotechnol 26, 107-13. 3.       Xu, D., Newhouse, I., Pao, H., Amaro, R. E., McCammon, J. A., Li, W. W. & Arzberger, P. W. (2009). Distinct Glycan Topology for Avian and Human Sialo-Pentasaccharide Receptor Analogues upon Binding Different Hemagglutinins: A Molecular Dynamics Perspective. J Mol Biol, In Press. 4.       Srinivasan, J., Cheatham, T. E., 3rd, Cieplak, P., Kollman, P. A. & Case, D. A. (1998). Continuum solvent studies of the stability of DNA, RNA, and phosphoramidate-DNA helices. J Am Chem Soc 120, 9401-9409. _________ Links: NBCR: http://www.nbcr.net NBCR Tools: http://tools.nbcr.net TATRC: http://www.tatrc.org NCRR: http://www.ncrr.nih.gov

Jan 15, 2009: Continuity 6 offers new guidance for heart pacer development in patients with history of heart attack

Cardiac resynchronization therapy (CRT) is a clinically proven therapy for patients with arrhythmia (irregular heartbeats) and heart failure (decreased cardiac function). It works through surgical implantation of a device that regulates the electrical signal firing sequence to restore the normal or required heart rhythm. However, about 30% of the patients do not respond to CRT, and these patients often have prior incidences of heart attacks (blockage of coronary arteries, aka, myocardial infarction) which left tissues scars in their heart muscles. The way the scars affect patient responsiveness to CRT is complicated by the process of heart remodeling, a process in which the normal heart muscles compensate for the damaged heart muscle cells with visible changes in the size, shape and function of the heart. In a recent study published in the journal Medical Imaging Analysis (1), Kerckhoffs and colleagues analyzed the mechanism of CRT resistance in heart failure patients with left bundle branch block (LBBB), a condition caused by the poor conduction of electrical signals in the left bundle branch of the atrioventricular bundle (bundle of His) of the heart. This also leaves the Purkinje fibers in the left ventricular wall with no signal to distribute, and a delayed contraction in the left ventricle (LV) usually observed in the electrocardiogram (ECG). Using Continuity (2,3), the authors took advantage of computational models established in earlier studies (4,5), and simulated LBBB, acute simultaneous biventricular pacing (BiV) in hearts with chronic scars of different sizes, and measured a number of regional and global function indicators of the heart (Figure 1). The simulation produced functional indicators that are in agreement with experimental and clinical findings (Figure 2). It also indicated that the failing heart could benefit from BiV and the non-scared regions functions independently of scar sizes during biventricular pacing. This somewhat surprising finding indicates that the paced failing heart could function “normally” despite tissue heterogeneity. The transmural (across the heart wall) heterogeneity has been previously hypothesized to be important for a uniform contraction in the normal heart (4), and detailed mechanical models have been proposed (6). However, the simplifications made in these models and the variations observed in clinical studies suggest that patient specific modeling is critical to further understanding of the heterogeneity of patient responses to CRT, and for better heart pacing strategies.   _________ Links: Continuity: http://www.continuity.ucsd.edu NBCR: http://www.nbcr.net NBCR Tools: http://tools.nbcr.net NCRR: http://www.ncrr.nih.gov

Figure 1. Computational models of heart failure with increasingly realistic geometry and model complexity for accurate simulations. Figure 2. Continuity 6 allows simulations to be conducted for geometrically realistic models of canine heart with  LBBB or biventricular pacing in normal and heart failure conditions. Crosses indicate pacer locations. The color indicates the activation time of cardiac action potential propagation. _________ References: 1.        Kerckhoffs, R. C., McCulloch, A. D., Omens, J. H. & Mulligan, L. J. (2008). Effects of biventricular pacing and scar size in a computational model of the failing heart with left bundle branch block. Med Image Anal. 2.       Rogers, J. M. & McCulloch, A. D. (1994). A collocation--Galerkin finite element model of cardiac action potential propagation. IEEE Trans Biomed Eng 41, 743-57. 3.       Usyk, T. P. & McCulloch, A. D. (2003). Relationship between regional shortening and asynchronous electrical activation in a three-dimensional model of ventricular electromechanics. J Cardiovasc Electrophysiol 14, S196-202. 4.       Kerckhoffs, R. C. P., Bovendeerd, P. H. M., Kotte, J. C. S., Prinzen, F. W., Smits, K. & Arts, T. (2003). Homogeneity of cardiac contraction despite physiological asynchrony of depolarization: A model study. Annals of Biomedical Engineering 31, 536-547. 5.       Kerckhoffs, R. C. P., Lumens, J., Vernooy, K., Omens, J. H., Mulligan, L. J., Delhaas, T., Arts, T., McCulloch, A. D. & Prinzen, F. W. (2008). Cardiac resynchronization: Insight from experimental and computational models. Progress in Biophysics and Molecular Biology 97, 543-561. 6.       Campbell, S. G., Flaim, S. N., Leem, C. H. & McCulloch, A. D. (2008). Mechanisms of transmurally varying myocyte electromechanics in an integrated computational model. Philos Transact A Math Phys Eng Sci 366, 3361-80.

This Resource is supported by the National Institutes of Health (NIH) through a National Center for Research Resources program grant (P 41 RR08605) to researchers at the University of California, San Diego, including the San Diego Supercomputer Center (SDSC), the California Institute of Telecommunications and Information Technology (Calit2), The Center for Research in Biological Systems (CRBS), The Scripps Research Institute (TSRI), and Washington University in St. Louis (WUSTL).

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