Collaboration & Service Projects
Large-scale electron microscopy of calcium-imaged neuron populations
PIs: A. Wetzel and G. Hood, Pittsburgh Supercomputing Center Collaborators: F. Engert, Harvard University, and D. Hildebrand (Research Assistant in Molecular and Cellular Biology, Harvard University)
Advancing high-throughput thin-section scanning EM to study relationships between neuronal circuit structure and function
PIs: A. Wetzel and G. Hood, Pittsburgh Supercomputing Center Collaborators: J. Lichtman, Harvard University (Jeremy R. Knowles Professor of Molecular and Cellular Biology; Tutor in Biochemical Sciences; Santiago Ramon y Cajal Professor of Arts and Sciences) and Josh Morgan, Harvard University (post-doctoral fellow, Department of Molecular and Cellular Biology)
Leadership
James Faeder, Principal Investigator, and MMBioS Director
Jim Faeder, leader of the Network Modeling component of MMBioS, is an Associate Professor and the Vice-Chair for Educational Programs/Initiatives in the Department of Computational and Systems Biology (DCSB) in the University of Pittsburgh School of Medicine. He is also co-director of the Joint Carnegie Mellon — University of Pittsburgh Ph.D. Program in Computational Biology (CPCB) and holds a secondary appointment in the Clinical and Translational Sciences Institute (CTSI). He has co-authored more than 100 peer-reviewed publications that cumulatively have over 7,300 citations (Google Scholar, h-index=45).
His research focuses on computational modeling of cell regulatory networks, combining development of novel methodologies with applications to specific systems of biological and biomedical relevance, including the immune system and cancer. As a member of the Cell Signaling Team at Los Alamos National Laboratory he was a co-author of an early rule-based modeling tool called BioNetGen and his group currently leads development of BioNetGen and numerous related tools. He collaborates actively with experimental scientists both within the University of Pittsburgh as well as nationally and internationally. His work has been published in many high-profile journals including Science Signaling, Nature Methods, PLOS Computational Biology, and Bioinformatics. Dr. Faeder was a founding organizer of the q-bio Conference on Cellular Information Processing and is currently an Associate Editor of PLOS Computational Biology.
Administration
This figure depicts the components and the organizational structure of the Center.
MMBioS is directed by Dr. James Faeder, University of Pittsburgh Department of Computational and Systems Biology, School of Medicine.
Pittsburgh Supercomputing Center, Carnegie Mellon University and Salk Institute leaderships are assumed by Shawn Brown, Dr. Ivet Bahar (Pitt), Dr. Robert F. Murphy (CMU), and Dr. Terrence J. Sejnowski (Salk).
Training and dissemination activities are conducted under the leadership of Phillip Compeau (CMU), Joseph Ayoob (Pitt), and Rozita Laghaei (PSC).
The PIs for the Four Technology Research and Development Projects (TR&D 1-4) are, respectively, Dr. Ivet Bahar, Dr. James Faeder (Pitt) and Dr. Sejnowski, and Dr. Murphy.
These TR&D Projects are directed by eight Driving Biomedical Projects (DBP 1-8), led respectively by Dr. Susan Amara (NIMH, NIH), Dr. Mary Kennedy (CalTech), Dr. Alexander Sorkin (Pitt), Dr. Christoph Wuelfing (U of Bristol, UK), Kristen Harris (University of Texas at Austin), Peter Sorger (Harvard University), Daniel Larson (National Cancer Institute Center for Cancer Research, NIH), and Dr. R. Clay Reid (Allen Brain Institute).
MMBioS members are involved in 29 Collaboration and Service Projects (C&S 1-29).
External Advisory Board
The External Advisory Board is composed of national experts in relevant fields of structural biology, cellular modeling, computational neuroscience, and biomedical imaging. They advise MMBioS on operations, provide critiques of the TR&D efforts, and offer valuable input to selecting and prioritizing collaborative projects and workhops.
Scott Acton, PhD
Program Director, Division of Computing and Communication Foundations
National Science Foundation
Professor, Department of Biomedical Engineering
University of Virginia
Stacey Finley, PhD
Gordon S. Marshall Early Career Chair
Associate Professor of Biomedical Engineering
University of Southern California
Les Loew, PhD
Boehringer Ingelheim Chair in Cell Sciences Professor of Cell Biology
Professor of Computer Science and Engineering
Director, R. D. Berlin Center for Cell Analysis and Modeling
University of Connecticut Health Center
Zaida (Zan) Luthey-Schulten, PhD
William H. and Janet G. Lycan Professor of Chemistry
Professor - Center for Biophysics and Quantitative Biology
University of Illinois at Urbana-Champaign
Martin Meier-Schellersheim, PhD
Chief, Computational Biology Section, Laboratory of Systems Biology
National Institute of Allergy and Infectious Diseases, NIH
Linda Petzold, PhD
Distinguished Professor in the Department of Mechanical Engineering and the Department of Computer Science (Chair 2003-2007)
Director of the Computational Science and Engineering Graduate Emphasis at the University of California Santa Barbara
Member of the US National Academy of Engineering (NAE), and a Fellow of ACM, ASME, SIAM, and AAAS
Badrinath "Badri" Roysam, PhD
Professor and Chair of Electrical and Computer Engineering
University of Houston
Ex officio members
Peter Strick, PhD
Distinguished Professor & Chair of Neurobiology
Director, Systems Neuroscience Institute
Co-Director, Center for Neuroscience
Co-Director, Center for the Neural Basis of Cognition
Professor, Departments of Neurological Surgery, Physical Medicine & Rehabiliation and Psychiatry
University of Pittsburgh
Previous EAB Members
Mark Ellisman, PhD
Director, National Center for Microscopy and Imaging Research (NCMIR)
Professor, Neurosciences and Bioengineering
Director, Center for Research in Biological Systems (CRBS)
University of California, San Diego (UCSD)
Nathan Urban, PhD
Provost
Lehigh University of Pennsylvania
Harel Weinstein, DSc
Maxwell M. Upson Professor of Physiology and Biophysics
Chairman, Department of Physiology and Biophysics
Director, Institute for Computational Biomedicine
Chair, Graduate Program in Physiology, Biophysics and Systems Biology
Weill Cornell Medical College of Cornell University (WCMC)
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Research Highlights
The Bahar (TR&D1) and Sorkin (DBP3) labs published an article in the Journal of Biological Chemistry, selected as one of JBC's "Editors' Picks. Our results demonstrate a direct coupling between conformational dynamics of DAT, functional activity of the transporter and its oligomerization leading to endocytosis. The high specificity of such coupling for DAT makes the TM4-9 hub a new target for pharmacological modulation of DAT activity and subcellular localization. (Read more)
Differences in the intrinsic spatial dynamics of the chromatin contribute to cell differentiation
Comparison with RNA-seq expression data reveals a strong overlap between highly expressed genes and those distinguished by high mobilities in the present study, in support of the role of the intrinsic spatial dynamics of chromatin as a determinant of cell differentiation. (Read more)
Nanoscale co-organization and coactivation of AMPAR, NMDAR, and mGluR at excitatory synapses
Work by TR&D2 Investigators and collaborators provide insights into the nanometer scale organization of postsynaptic glutamate receptors using a combination of dual-color superresolution imaging, electrophysiology, and computational modeling. (Read more)
Parallel Tempering with Lasso for model reduction in systems biology
TR&D3 Investigators and collaborators develop PTLasso, a Bayesian model reduction approach that combines Parallel Tempering with Lasso regularization, to automatically extract minimal subsets of detailed models that are sufficient to explain experimental data. On both synthetic and real biological data, PTLasso is an effective method to isolate distinct parts of a larger signaling model that are sufficient for specific data. (Read more)
Image-derived models of cell organization changes during differentiation and drug treatments
Our work on modeling PC12 cells undergoing differentiation into neuron-like morphologies (under C&SP11, completed) has been published in Molecular Biology of the Cell. We have also made the large dataset of 3D images collected in that study available through Dryad. (Read more)
Monoamine transporters: structure, intrinsic dynamics and allosteric regulation
T&RD1 investigators Mary Cheng and Ivet Bahar published an invited review article in Nature Structural & Molecular Biology, addressing recent progress in the elucidation of the structural dynamics of MATs and their conformational landscape and transitions, as well as allosteric regulation mechanisms. (Read more)
Trimerization of dopamine transporter triggered by AIM-100 binding
The Bahar (TR&D1) and Sorkin (DBP3) labs explored the trimerization of dopamine transporter (DAT) triggered by a furopyrimidine, AIM-100, using a combination of computational and biochemical methods, and single-molecule live-cell imaging assays. (Read more)
Pre-post synaptic alignment through neuroligin-1 tunes synaptic transmission efficiency
TR&D2 investigators and collaborators describe organizing role of neuroligin-1 to align post-synaptic AMPA Receptors with pre-synaptic release sites into trans-synaptic “nano-columns” to enhance signaling.(Read more)
Inferring the Assembly Network of Influenza Virus
In an article in PLoS Computational Biology, MMBioS TR&D4 members Xiongto Ruan and Bob Murphy collaborated with Seema Lakdawala to address this question of the assembly network of the Influenza virus.(Read more)
Our findings highlight an important mechanism by which proteins genetically implicated in Parkinson’s disease (PD; PINK1) and frontotemporal dementia (FTD; VCP) interact to support the health and maintenance of neuronal arbors.(Read more)
Improved methods for modeling cell shape
In a recent paper in Bioinformatics, Xiongtao Ruan and Bob Murphy of TR&D4 addressed the question of how best to model cell and nuclear shape.(Read more)
New tool to predict pathogenicity of missense variants based on structural dynamics: RHAPSODY
We demonstrated that the analysis of a protein’s intrinsic dynamics can be successfully used to improve the prediction of the effect of point mutations on a protein functionality. This method employs ANM/GNM tools (Read more)
New method for investigating chromatin structural dynamics.
By adapting the Gaussian Network Model (GNM) protein-modeling framework, we were able to model chromatin dynamics using Hi-C data, which led to the identification of novel cross-correlated distal domains (CCDDs) that were found to also be associated with increased gene co-expression. (Read more)
Structural elements coupling anion conductance and substrate transport identified
We identified an intermediate anion channeling state (iChS) during the global transition from the outward facing (OF) to inward facing state (IFS). Our prediction was tested and validated by experimental study conducted in the Amara lab (NIMH). Critical residues and interactions were analyzed by SCAM, electrophysiology and substrate uptake experiments (Read more)
Integrating MMBioS technologies for multiscale discovery
TR&D teams driven by individual DBPs are naturally joining forces, integrating their tools to respond to the needs of the DBP, and creating integrative frameworks for combining structural and kinetic data and computing technologies at multiple scales. (Read more)
Large scale visualization of rule-based models.
Signaling in living cells is mediated through a complex network of chemical interactions. Current predictive models of signal pathways have hundreds of reaction rules that specify chemical interactions, and a comprehensive model of a stem cell or cancer cell would be expected to have many more. Visualizations of rules and their interactions are needed to navigate, organize, communicate and analyze large signaling models. (Read more)
Integration of MCellR into MCell/CellBlender
Using spatial biochemical models of SynGAP/PSD95, MMBioS investigators were able to merge the MCellR code-base with the MCell code-base and validate its utility and correctness of this sophisticated technology now easily accessible through the MCell/CellBlender GUI. (Read more)
Causal relationships of spatial distributions of T cell signaling proteins
The idea is to identify a relationship in which a change in the concentration of one protein in one cell region consistently is associated with a change in the concentration of another protein in the same or a different region. We used the data from our Science Signaling paper reported last year to construct a model for T cells undergoing stimulation by both the T cell receptor and the costimulatory receptor. (Read more...)
BioNetGen modeling helps reveal immune system response decision
To attack or to let be is an important decision that our immune systems must make to protect our bodies from foreign invaders or protect bodily tissues from an immune attack. Using modeling and experiments, we have painted a sharper picture of how T cells make these critical decisions. (Read more)
Tools for determining the spatial relationships between different cell components
An important task for understanding how cells are organized is determining which components have spatial patterns that are related to each other.Read more
Pipeline for creation of spatiotemporal maps
Using a combination of diffeomorphic methods and improved cell segmentation, we developed a CellOrganizer pipeline for use in DPB4 to construct models of the 4D distributions of actin and 8 of its regulators during the response of T cells to antigen presentation. Read more
Multi-scale Hybrid Methodology
The hybrid methodology, coMD, that we have recently developed [1] has been recently extended to construct the energy landscape near the functional states of LeuT (Fig 1) [2]. This is the first energy landscape constructed for this NSS family member. Read more
Insights into the cooperative dynamics of AMPAR
Comparative analysis of AMPAR and NMDAR dynamics reveals striking similarities, opening the way to designing new modulators of allosteric interactions. Read more
Improved Sampling of Cell-Scale Models using the WE Strategy
The WE strategy for orchestrating a large set of parallel simulations has now been extended to spatially resolved cell-scale systems. The WESTPA implementation of WE has been used to control MCell simulations, including models built using a BioNetGen-CellOrganizer pipeline for situating complex biochemistry within spatially realistic cell models. Read more
Anatomy and Function of an Excitatory Network in the Visual Cortex
MMBioS researcher Greg Hood’s collaboration with Wei-Chung Allen Lee of Harvard University and R. Clay Reid of the Allen Institute for Brain Science concerning the reconstruction of an excitatory nerve-cell network in the mouse brain cortex at a subcellular level using the AlignTK software has been published in Nature. Read more
Molecular Mechanism of Dopamine Transport by hDAT
Dopamine transporters (DATs) control neurotransmitter dopamine (DA) homeostasis by reuptake of excess DA, assisted by sodium and chloride ions. The recent resolution of DAT structure (dDAT) from Drosophila permits us for the first time to directly view the sequence of events involved in DA reuptake in human DAT (hDAT). Read more
Synaptic Facilitation Revealed
An investigation of several mechanisms of short-term facilitation at the frog neuromuscular junction concludes that the presence of a second class of calcium sensor proteins distinct from synaptotagmin can explain known properties of facilitation. Read more
Sparse Graphical Models of Protein:Protein Interactions
DgSpi is a new method for learning and using graphical models that explicitly represent the amino acid basis for interaction specificity and extend earlier classification-oriented approaches to predict ΔG of binding. Read more
Advancing Parallel Bio-simulations
A new non-Markovian analysis can eliminate bias in estimates of long-timescale behavior, such as the mean first-passage time for the dissociation of methane molecules in explicit solvent. Read more