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Computational Electrophysiology
Rob MacLeod
ECG Imaging
Computational Biomechanics
Orly Alter
Tamara Bidone
Computational Models
Simulations of Biological Systems
Multi-Physics Models of Cancer Cells
Centers and Labs:
Center for Integrative Biomedical Computing
Muskuloskeletal Research Laboratory
Genomic Signal Processing Lab
Funded Research Projects:
FEBIO - Finite Elements for Biomechanics and Biophysics
Finite element analysis has become an indispensable tool for research and discovery in the biomedical sciences. Historically, the lack of an open software environment that was tailored to the needs of the field hampered research progress, dissemination of research and sharing of models and results. To address these issues, we developed the FEBio software suite, a FE framework designed specifically for analysis in biomechanics and biophysics, during our first funding period (2007-2011). FEBio employs mixture theory to account for the multi- constituent nature of biological tissues and fluids, unifying the classical fields of irreversible thermodynamics, solid mechanics, fluid mechanics, mass transport, chemical reactions and electrokinetics. During the second funding period (2012-2016), we implemented chemical reactions between constituents of a mixture and we broadened the target audience for FEBio by developing a plugin environment that made it easy to add features or interface other software with FEBio. During our third funding period (2016-2020), we developed a novel FE framework for simulation of compressible and incompressible CFD, extended this framework to enable analysis of FSI (Fluid-Structure Interaction) problems, and we enhanced algorithmic, analysis and numerical capabilities in FEBio by implementing efficient iterative linear solvers and preconditioners, new nonlinear solution strategies, and adaptive meshing. In this competing continuation application, we propose three aims: 1) Formulate and implement a computationally efficient damage and fatigue failure framework for fibrous tissues; 2) Extend our multiphysics algorithms to solute transport and reactions in fluid domains, and tissue growth and remodeling in fluid domains and at their interfaces with multiphasic domains; 3) Integrate the use of image data through our entire simulation pipeline, from model setup to model validation. These new capabilities will expand the applicability of FEBio to new fields of biomedical research, increasing our user base and facilitating scientific advancement.
This project will greatly expand the simulation capabilities of the FEBio software suite, which enables computer simulations in the fields of biomechanics and biophysics. This software already supports over 10,000 scientists in their research. The outcomes of the proposed research will expand scientific discovery and innovation by biomedical simulation scientists in the areas of biomechanics and biophysics.
Regulation of Cell Adhesions by Mechanical Force
This project aims to understanding how biological materials respond to mechanical force. Adhesion receptors are proteins in the plasma membrane that mediate cell binding to other cells or to the extracellular matrix. These receptors sense and transmit forces between cells and the external environment. Specifically, integrins transmit mechanical and biochemical information. This information critically guides life processes such as embryonic development, and also plays a role in diseases such as cancer, hypertension, osteoporosis and atherosclerosis. Integrins undergo drastic, long-range changes in response to biochemical signals or mechanical stresses. Exactly how integrin amino acid residues rearrange in response to force is largely unknown due to the technical challenges in observing shifts in residue positions and interactions at the single protein level. This hampers our ability to understand or modulate these processes that can lead to disease. This research will employ cell biology, computational simulations, biophysics, chemistry and material science approaches to elucidate the detailed pathways of force-dependent changes in integrins conformation and their roles in cell regulation.
The overarching objective of this research is to understand, at near-atomic level, how integrin conformation is modulated by mechanical force and how the resultant conformational transitions regulate cell behavior. The research team will develop new numerical tools to perform molecular dynamics simulations of integrins under force. These models will be used to predict mutations that stabilize or destabilize specific integrin states, which will then be tested experimentally for their effects on mechanosensing in live cells. By combining modeling with experiments, we will elucidate detailed pathways of force-dependent conformational transitions and their role in biology. This multidisciplinary approach will broaden the participation of diverse communities and underrepresented groups and positively impact engineering and material science education. Furthermore, this research may result in new approaches to design and produce biomimetic and smart materials for engineering applications.
This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
Center for Integrative Biomedical Computing Legacy Transition
Chris Johnson, Rob MacLeod, Ross Whitaker
The Center for Integrative Biomedical Computing (CIBC) has an established, twenty year record as a Biomedical Technology Research Resource (BTRR) whose focus has been technical research and development in the area of image based modeling and simulation. The resulting legacy of scientific publications, novel algorithms and computational approaches and especially a suite of software tools and data sets can continue to support a vibrant research community even as the twilight requirements of the BTRR program dictate a time limit on NIH P41 funding. However, while already in heavy use, many of the existing, open source, software tools require additional hardening, documentation, and user-interface support to reach their full potential. More important, the software engineering and infrastructure, even though they represent the highest standards available from an academic center, are not yet robust and flexible enough to sustain easy maintenance and extension by a community outside the CIBC, a key element to ensuring the continued health and growth of the impact of these tools beyond the lifetime of the BTRR. Finally, there are existing collaborators and Driving Biomedical Project (DBP) partners whose research would suffer with the pending cessation of operations of the BTRR. We propose a transition plan to achieve long term sustainability of the software and data resources that the CIBC has produced. The goal of this plan is to complete the conversion of all the technical products achieved over the lifetime of the Center into well crafted, validated computer code with all the necessary support for both users and future maintainers of the code base. We seek to convert our open-source software into something far more valuable: community supported and sustained software. The conversion will require the assistance of a professional software house that is familiar with the necessary steps and with the technical domain of our center, Kitware Inc. Kitware is a company with a long history of assisting biomedical researchers to develop highly complex software packages and libraries, including VTK, ITK, 3D Slicer, and ParaView. Members of the CIBC have collaborated with Kitware in the past so there is a proven relationship on which to pursue the proposed transition plan. This combination of the domain specific knowledge of the specific tools within the twenty years of the CIBC, along with the ability of Kitware to support and deploy software and data, will ensure a successful transition and a lasting legacy from this BTRR.
We propose a transition plan to achieve long term sustainability of the software and data resources that the Biomedical Technology Research Resource, Center for Integrative Biomedical Computing (CIBC), has produced. The goal of this plan is to complete, with the assistance of the software engineers at Kitware Inc, the conversion of all the technical products achieved over the lifetime of the CIBC into well crafted, validated computer code with all the necessary support for both users and future maintainers of the code base. We will combine domain specific knowledge of the specific tools within the twenty years of the CIBC, along with the ability of Kitware to support and deploy software and data, will ensure a successful transition and a lasting legacy from this BTRR.
Targeting Collagen Mechanical Damage Using Collagen Hybridizing Peptides
Detection of Collagen Mechanical Damage using Collagen Hybridizing Peptides. Mechanical injury to load-bearing tissues leads to many clinically significant conditions (e.g. tendinosis, rotator cuff disease) but we have limited understanding of the injury process of tissues that are damaged by mechanical stress. The overall goal of the proposed research is to gain new understanding of the biomechanics of load bearing collagenous tissues by developing the collagen hybridizing peptide (CHP) technology into a new mechanical damage detection method. CHP has been reported to bind to denatured collagen strands originating from protease activity or by mechanical damage in a manner similar to primer binding to melted DNA during PCR. We propose to substantially expand the capabilities of CHP damage detection by developing new CHPs that are smaller for faster diffusion into dense musculoskeletal tissues and exhibit accelerated binding kinetics to allow faster damage reporting. We will also develop a new CHP that only fluoresces upon binding with collagen, eliminating the need to stain and wash tissues and enabling the CHP to serve as a damage gauge in overloaded tissues. We will then develop optimized protocols for the use of the existing and new CHPs, determine the relationship between collagen fibril strain and CHP binding in musculoskeletal soft tissues, and quantitatively compare CHP targeting to other techniques. Finally, we will apply CHP targeting to elucidate the relationship between tissue level mechanical loading and mechanical damage to collagen at the molecular level. We will focus on two important musculoskeletal tissues of considerable clinical relevance: tendons and articular cartilage. Considering the wide-spread impact of collagen damage in musculoskeletal injuries and diseases, in- depth understanding of the relationships between molecular level collagen damage and mechanical overloading will provide new insights into the biomechanics of load-bearing tissues as well as help develop new diagnostics and therapies for managing musculoskeletal disorders.
Detection of Collagen Mechanical Damage using Collagen Hybridizing Peptides. The proposed work will develop new and improved peptide-based probes that can hybridize to mechanically damaged collagen with high efficiency; these probes will be used to elucidate the mechanisms of stress-induced injury in tendon and articular cartilage. Fibrous collagen is the major component of almost every load-bearing tissue, and molecular-level collagen damage is associated with permanent mechanical damage in those tissues. The outcome of this research will help manage common musculoskeletal injuries and disorders by deepening our understanding of mechanical damage in tissues and by identifying opportunities for new diagnostics and therapies.
Neovessel Guidance in Angiogenesis
Neovessel guidance in angiogenesis Vascular connectivity between adjacent vessel beds within and between tissue compartments is an essential aspect of any successful neovascularization process. To establish new connections, growing neovessels must locate other vascular elements during angiogenesis, often crossing matrix and other tissue-associated boundaries and interfaces. This is perhaps best highlighted in situations of tissue grafting (e.g. tissue free flaps) during which the vasculature of the graft must cross the graft-host tissue interface before connecting to the surrounding host circulation in order for the graft to survive. An inability for a tissue graft vasculature to connect to the host vasculature is the primary cause for tissue graft failure and necrosis. How growing neovessels traverse any tissue interface, whether part of the native tissue structure or secondary to a grafting procedure, is not known. In a series of preliminary experiments, we have determined that actively growing neovessels are unable to spontaneously cross a stroma-stroma interface during angiogenesis. Our published findings that tissue stromal biomechanics, specifically the biophysical aspects of the matrix, has a profound influence on the direction and branching of growing neovessels suggests that this interface is biomechanically incompatible with interface invasion. In addition, we have evidence that a sub-population of tissue-resident, stromal macrophages facilitates neovessel invasion of the stromal interface during angiogenesis through a VEGF-A-dependent process. Importantly, it appears that stromal cells need to migrate across the interface in order to promote interface invasion by the neovessels, suggesting that spatial gradients of VEGF-A are required. Based on these observations, we hypothesize that the graded angiogenic factor signals overcome the biomechanical barriers to directed angiogenesis caused by a stroma-stroma interface to promote interface neovascular invasion. The project will involve a combination of in vitro and computational models of angiogenesis across tissue-tissue boundaries to test this hypothesis and determine the mechanism by which stromal cells use VEGF-A signaling to regulate neovessel behavior in coordination with stroma biomechanical dynamics. These studies will provide new insights into a poorly understood aspect of vascular biology and tissue-vascular dynamics as well as create opportunities for therapeutic strategies to facilitate tissue healing, improving angiogenesis-based treatments, and tissue grafting/transplantation.
Neovessel guidance in angiogenesis Tissue repair and grafting is often compromised by poor vascular connectivity between adjacent vascular beds. This project will investigate the regulation of angiogenic neovessel invasion into adjacent tissues, a necessary aspect of vascular connectivity, by resident stromal cells. By defining the mechanisms underlying facilitation of vessel connectivity by resident stromal cells in combination with inherent tissue biomechanical dynamics, we will provide insight into novel therapeutic strategies for tissue repair and grafting/transplantation.
Multi-Tensor Decompositions for Personalized Cancer Diagnostics and Prognostics
Recurring DNA copy-number alterations (CNAs) have been recognized as a hallmark of cancer for >100 years, yet what these alterations imply about a tumor's pathogenesis and a patient's diagnosis, prognosis, and treatment remains poorly understood. This is despite the growing number of large-scale multidimensional datasets recording different aspects of a single disease, e.g., in the Cancer Genome Atlas (TCGA), and due to a fundamental need for mathematical frameworks that can create one coherent model from such multiple datasets arranged in multiple tensors of matched columns, e.g., patients, platforms, and tissues, but independent rows, e.g., probes. For example, our recent comparative modeling (by using a data-driven two-matrix spectral decomposition) of patient-matched glioblastoma (GBM) brain tumor and normal blood genomic profiles from TCGA (arranged in two matrices, of matched columns but independent rows) uncovered a previously unknown global pattern of tumor-exclusive CNAs that is correlated with, and possibly causally related to, GBM survival and response to chemotherapy. The data had been publicly available since 2008, but this signature remained unknown until we applied our comparative modeling in 2012. Survival analyses showed, and computationally validated, that the signature performs better than, and is statistically independent of, age, the best indicator of GBM survival for >50 years, and existing GBM pathology laboratory tests. A new test for GBM based upon this signature is pending an experimental re-validation at the Associated Regional and University Pathologists (ARUP) Laboratories, Inc., a nonprofit reference laboratory of the Department of Pathology at the University of Utah. In this NCI U01 project, our multidisciplinary team of researchers from the Departments of Bioengineering, Mathematics, and Pathology, the Scientific Computing and Imaging (SCI) Institute, and the Huntsman Cancer Institute (HCI) at the University of Utah, aims to (i) define, and study the properties of data- driven multi-tensor spectral decompositions; (ii) use these to model patient-, platform-, and tissue-matched but probe-independent TCGA genomic profiles, and gain biological and medical insights into the genotype- phenotype relations in lower-grade astrocytoma (LGA) brain cancer, ovarian serous cystadenocarcinoma (OV), and lung squamous cell carcinoma; and (iii) enable translation of these insights into pathology laboratory tests, by experimentally testing the computational predictions of the existing GBM model, as well as the novel LGA and OV models by using Utah samples. Ultimately, this project will bring physicians a step closer to one day being able to predict and control the progression of cell division and cancer as readily as NASA engineers plot the trajectories of spacecraft today.
Recurring DNA copy-number alterations have been recognized as a hallmark of cancer for >100 years, yet what these alterations imply about a tumor's pathogenesis and a patient's diagnosis, prognosis, and treatment remains poorly understood. In this NCI U01 project, we will (i) develop generalizations of the mathematical frameworks that underlie the theoretical description of the physical world, (ii) use these frameworks to model patient-matched datasets from the Cancer Genome Atlas, and gain biological and medical insights into the genotype-phenotype relations in cancer, and (iii) translate these insights into pathology laboratory tests. Ultimately this projct will bring physicians a step closer to one day being able to predict and control the progression of cell division and cancer as readily as NASA engineers plot the trajectories of spacecraft today.
New 3d and 4d Image-Based Clinical Measures of Atrial Structural and Functional Remodeling in Atrial Fibrillation
Joshua Cates, Shireen Youssef Elhabian
This proposal focuses on the development of new clinical measures of atrial shape for better individualized patient care of atrial fibrillation and advances the state-of-the art in computational methods for the statistical analysis of shape in clinical image data. Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults, with over 400,000 U.S. hospital admissions per year, annual costs in the U.S. of $6-7 billion, and an almost two-fold increase in the risk of mortality. We will develop and test new cardiac shape-based predictors of AF outcomes in a large patient population, including patients enrolled in the fully-funded multicenter DECAAF II clinical trial. This proposal will impact clinical science and standards of care for AF patients through (1) the development of a new MRI-based measure of dynamic cardiac shape and associated deformations over the cardiac cycle and investigation of the dynamic (4D) structural changes to the atria after catheter ablation; (2) the development of shape-based predictors of AF treatment outcomes and risk factors for stroke; and (3) shape analysis of the atria and prospective evaluation of shape-based predictive indices in the DECAAF II clinical trial population. Technological contributions of this work will impact the field of biomedical shape analysis through the development of methods for analysis of spatiotemporal (4D) anatomical shape and the development of more powerful modeling algorithms for the highly variable anatomy of the heart. This project combines the clinical experience and research infrastructure of the University of Utah's Comprehensive Arrhythmia Research and Management (CARMA) Center with the computational resources and expertise of the Scientific Computing and Imaging (SCI) Institute and leverages our unique access to a large cohort of MRI image data from AF patients enrolled in the multicenter DECAAF II clinical trial. Our team consists of an accomplished mix of computer scientists, electrophysiologists, and MRI physicists.
The goals of this proposal are to develop non-invasive image-based measures of atrial shape (geometry) and function that are clinically useful in planning patient treatment and managing risk of adverse outcomes such as stroke. Atrial fibrillation affects many millions of people in the United States, incurs annual costs of $6-7 billion, and is associated with significant mortality and morbidity.
Lab-to-Lab Training and Dissemination for the Febio Software Suite
Finite element analysis has become an indispensable tool for research and discovery in the biomedical sciences. Historically, the lack of a software environment that was tailored to the needs of the field hampered research progress, dissemination of research and sharing of models and results. Investigators previously relied on commercial software, but these packages were not geared toward biological applications, were difficult to verify, and precluded the easy addition, extension and sharing of new features. To address these issues, we developed the FEBio software suite, a FE framework designed specifically for analysis in biomechanics and biophysics. FEBio employs mixture theory to account for the multi-constituent nature of soft and hard tissues, unifying the classical fields of irreversible thermodynamics, solid mechanics, fluid mechanics, mass transport, chemical reactions and electrokinetics. Despite the popularity of the FEBio software suite, we have never been able to fully address the needs of our user base in terms of dissemination and training. The overall aim of this project is to develop an integrated software environment for FEBio to deliver new approaches for digital training and dissemination to our user community. This will be accomplished through the following specific aims: 1) Create a unified graphical software environment that encompasses the entire FEBio analysis pipeline. 2) Develop a model sharing environment for FEbio. 3) Develop digital training materials and virtual training courses to serve and expand the FEBio community. We will partner with laboratories that already use FEBio to evaluate these advancements in training and dissemination. These new mechanisms for training and dissemination will improve the accessibility of FEBio's broad simulation capabilities, creating a larger, more collaborative user group that spans a greater range of technical disciplines.
This project will develop lab-to-user training and dissemination tools for the FEBio software suite. This software supports nearly 10,000 scientists in the fields of biomechanics, biophysics and biomedical engineering in general. The materials developed under this project will support the training of the next generation of biomedical simulation scientists in the areas of biomechanics and biophysics.
Novel Characterization and Detection Techniques for Acute Myocardial Ischemia
Brian Zenger
The most common reason for a patient to visit the emergency department is chest pain caused by myocardial ischemia. Myocardial ischemia develops from inadequate perfusion of myocardial tissue and indicates the presence of surprising range of conditions, including coronary artery disease, coronary microvascular dysfunction, Takotsubo cardiomyopathy, and coronary artery dissection, and other potentially fatal cardiac diseases. Current noninvasive tests to detect ischemia may be limited by an incomplete understanding of the mecha- nisms used to induce the stress (exercise or pharmacological agents) or the limited diagnostic data acquired to visualize ischemia (12-lead electrocardiogram or ultrasound). These limitations increase the risk for failed detection of deadly cardiac diseases and explain the unsatisfactory accuracy of current diagnostic and monitor- ing approaches. The goal of this project is to leverage recent experimental findings and breakthroughs about the onset and progression of ischemia as the basis for a comprehensive re-evaluation of acute myocardial ischemia. We will develop and use experimental models and computer simulations to devise better techniques to detect acute myocardial ischemia and localize it within the ventricles. We will build on our experience with our novel large-animal experimental models of ischemia and electrocardiographic imaging (ECGI) techniques to measure and characterize the electrical changes that arise during acute myocardial ischemia created from various types of ischemic stress. We will use these measurements to characterize different types of cardiac stress and implement novel ECGI techniques to detect and localize ischemic sources within the heart.
Myocardial ischemia arises under conditions of inadequate blood supply to the heart and is associated with a surprisingly broad range of conditions, such as coronary artery disease, ischemic cardiomyopathy, or coronary artery dissection. The most common symptom (chest pain) is also the most frequent reason for visits to the emergency department of hospitals. The goal of this project is to create and validate, through controlled experimental preparations and computer modeling approaches, a painless, inexpensive, and noninvasive detection system based on the electrocardiogram to localize regions of myocardial ischemia within the heart.
Integration of Uncertainty Quantification with SCIRun Bioelectric Field Simulation Pipeline
This project harnesses mature and modern techniques for uncertainty quantification (UQ) from the computational science and mathematics communities and incorporates them into the established biomedical simulation software framework SCIRun. Just as bioelectric simulation models have become increasingly accurate at representing physical processes and geometry, so also has it become increasingly important to understand the uncertainty stemming from ignorance about precise values of model parameters. To our knowledge, success of this project represents one of the first developments of folding in modern UQ techniques into widely used, freely available software pipelines for simulation of bioelectric fields in heart and brain applications. Successful incorporation of established and proven UQ tools into SCIRun will substantially increase the utility of simulation based biomedical predictions in medical practice. Although there is a need in the research community for such tools, the number and nature of users makes commercial development very unlikely. There are no commercial tools specifically for bioelectric field modeling and while some industry uses these tools, their high intellectual cost and limited market keep them well below the threshold for commercial software.
This project harnesses mature and modern techniques that can quantify statistical uncertainty in biomedical simulations by integrating these techniques into the well-established biomedical modeling software framework, SCIRun. Biomedical simulation has become increasingly accurate at representing functions of the body, both in health and disease, however such simulations rarely include any estimates of the uncertainty stemming from ignorance about precise values of model parameters. Our proposal represents one of the first to integrate modern methods capable of quantifying such uncertainty into widely used, freely available software pipelines for simulation of bioelectric fields from the heart and brain.
Publications in Biomedical Computing:
Prediction of Femoral Head Coverage from Articulated Statistical Shape Models of Patients with Developmental Dysplasia of the Hip
P. R. Atkins, P. Agrawal, J. D. Mozingo, K. Uemura, K. Tokunaga, C. L. Peters, S. Y. Elhabian, R. T. Whitaker, A. E. Anderson. In Journal of Orthopaedic Research, Wiley, 2021.
DOI: 10.1002/jor.25227
Developmental dysplasia of the hip (DDH) is commonly described as reduced femoral head coverage due to anterolateral acetabular deficiency. Although reduced coverage is the defining trait of DDH, more subtle and localized anatomic features of the joint are also thought to contribute to symptom development and degeneration. These features are challenging to identify using conventional approaches. Herein, we assessed the morphology of the full femur and hemi-pelvis using an articulated statistical shape model (SSM). The model determined the morphological and pose-based variations associated with DDH in a population of Japanese females and established which of these variations predict coverage. Computed tomography images of 83 hips from 47 patients were segmented for input into a correspondence-based SSM. The dominant modes of variation in the model initially represented scale and pose. After removal of these factors through individual bone alignment, femoral version and neck-shaft angle, pelvic curvature, and acetabular version dominated the observed variation. Femoral head oblateness and prominence of the acetabular rim and various muscle attachment sites of the femur and hemi-pelvis were found to predict 3D CT-based coverage measurements (R2=0.5-0.7 for the full bones, R2=0.9 for the joint).
Uncertainty Quantification in Brain Stimulation using UncertainSCI
J. Tate, S. Rampersad, C. Charlebois, Z. Liu, J. Bergquist, D. White, L. Rupp, D. Brooks, A. Narayan, R. MacLeod. In Brain Stimulation: Basic, Translational, and Clinical Research in Neuromodulation, Vol. 14, No. 6, Elsevier, pp. 1659-1660. 2021.
Predicting the effects of brain stimulation with computer models presents many challenges, including estimating the possible error from the propagation of uncertain input parameters through the model. Quantification and control of these errors through uncertainty quantification (UQ) provide statistics on the likely impact of parameter variation on solution accuracy, including total variance and sensitivity associated to each parameter. While the need and importance of UQ in clinical modeling is generally accepted, tools for implementing UQ techniques remain limited or inaccessible for many researchers.
Combining endocardial mapping and electrocardiographic imaging (ECGI) for improving PVC localization: A feasibility study
W. W. Good, B. Zenger, J. A. Bergquist, L. C. Rupp, K. Gillett, N. Angel, D. Chou, G. Plank, R. S. MacLeod. In Journal of Electrocardiology, 2021.
DOI: https://doi.org/10.1016/j.jelectrocard.2021.08.013
Accurate reconstruction of cardiac activation wavefronts is crucial for clinical diagnosis, management, and treatment of cardiac arrhythmias. Furthermore, reconstruction of activation profiles within the intramural myocardium has long been impossible because electrical mapping was only performed on the endocardial surface. Recent advancements in electrocardiographic imaging (ECGI) have made endocardial and epicardial activation mapping possible. We propose a novel approach to use both endocardial and epicardial mapping in a combined approach to reconstruct intramural activation times.
To implement and validate a combined epicardial/endocardial intramural activation time reconstruction technique.
We used 11 simulations of ventricular activation paced from sites throughout myocardial wall and extracted endocardial and epicardial activation maps at approximate clinical resolution. From these maps, we interpolated the activation times through the myocardium using thin-plate-spline radial basis functions. We evaluated activation time reconstruction accuracy using root-mean-squared error (RMSE) of activation times and the percent of nodes within 1 ms of the ground truth.
Reconstructed intramural activation times showed an RMSE and percentage of nodes within 1 ms of the ground truth simulations of 3 ms and 70%, respectively. In the worst case, the RMSE and percentage of nodes were 4 ms and 60%, respectively.
We showed that a simple, yet effective combination of clinical endocardial and epicardial activation maps can accurately reconstruct intramural wavefronts. Furthermore, we showed that this approach provided robust reconstructions across multiple intramural stimulation sites.
A Nonparametric Approach for Estimating Three-Dimensional Fiber Orientation Distribution Functions (ODFs) in Fibrous Materials
A. Rauff, L.H. Timmins, R.T. Whitaker, J.A. Weiss. In IEEE Transactions on Medical Imaging, 2021.
DOI: 10.1109/TMI.2021.3115716
Many biological tissues contain an underlying fibrous microstructure that is optimized to suit a physiological function. The fiber architecture dictates physical characteristics such as stiffness, diffusivity, and electrical conduction. Abnormal deviations of fiber architecture are often associated with disease. Thus, it is useful to characterize fiber network organization from image data in order to better understand pathological mechanisms. We devised a method to quantify distributions of fiber orientations based on the Fourier transform and the Qball algorithm from diffusion MRI. The Fourier transform was used to decompose images into directional components, while the Qball algorithm efficiently converted the directional data from the frequency domain to the orientation domain. The representation in the orientation domain does not require any particular functional representation, and thus the method is nonparametric. The algorithm was verified to demonstrate its reliability and used on datasets from microscopy to show its applicability. This method increases the ability to extract information of microstructural fiber organization from experimental data that will enhance our understanding of structure-function relationships and enable accurate representation of material anisotropy in biological tissues.
Integrin-Based Mechanosensing through Conformational Deformation
T.P. Driscoll, T.C. Bidone, S.J. Ahn, A. Yu, A. Groisman, G.A. Voth, M.A. Schwartz. In Biophysical Journal, 2021.
DOI: https://doi.org/10.1016/j.bpj.2021.09.010
Conversion of integrins from low to high affinity states, termed activation, is important in biological processes including immunity, hemostasis, angiogenesis and embryonic development. Integrin activation is regulated by large-scale conformational transitions from closed, low affinity states to open, high affinity states. While it has been suggested that substrate stiffness shifts the conformational equilibrium of integrin and governs its unbinding, here we address the role of integrin conformational activation in cellular mechanosensing. Comparison of WT vs activating mutants of integrin αVβ3 show that activating mutants shift cell spreading, FAK activation, traction stress and force on talin toward high stiffness values at lower stiffness. Although all activated integrin mutants showed equivalent binding affinity for soluble ligands, the β3 S243E mutant showed the strongest shift in mechanical responses. To understand this behavior, we used coarse-grained computational models derived from molecular level information. The models predicted that wild type integrin αVβ3 displaces under force, and that activating mutations shift the required force toward lower values, with S243E showing the strongest effect. Cellular stiffness sensing thus correlates with computed effects of force on integrin conformation. Together, these data identify a role for force-induced integrin conformational deformation in cellular mechanosensing.
Reducing Line-of-block Artifacts in Cardiac Activation Maps Estimated Using ECG Imaging: A Comparison of Source Models and Estimation Methods
A.S. Rababah, L.R. Bear, Y.S. Dogrusoz, W. Good, J. Bergquist, J. Stoks, R. MacLeod, K. Rjoob, M. Jennings, J. Mclaughlin, D. D. Finlay. In Computers in Biology and Medicine, Vol. 136, pp. 104666. 2021.
Electrocardiographic imaging is an imaging modality that has been introduced recently to help in visualizing the electrical activity of the heart and consequently guide the ablation therapy for ventricular arrhythmias. One of the main challenges of this modality is that the electrocardiographic signals recorded at the torso surface are contaminated with noise from different sources. Low amplitude leads are more affected by noise due to their low peak-to-peak amplitude. In this paper, we have studied 6 datasets from two torso tank experiments (Bordeaux and Utah experiments) to investigate the impact of removing or interpolating these low amplitude leads on the inverse reconstruction of cardiac electrical activity. Body surface potential maps used were calculated by using the full set of recorded leads, removing 1, 6, 11, 16, or 21 low amplitude leads, or interpolating 1, 6, 11, 16, or 21 low amplitude leads using one of the three interpolation methods – Laplacian interpolation, hybrid interpolation, or the inverse-forward interpolation. The epicardial potential maps and activation time maps were computed from these body surface potential maps and compared with those recorded directly from the heart surface in the torso tank experiments. There was no significant change in the potential maps and activation time maps after the removal of up to 11 low amplitude leads. Laplacian interpolation and hybrid interpolation improved the inverse reconstruction in some datasets and worsened it in the rest. The inverse forward interpolation of low amplitude leads improved it in two out of 6 datasets and at least remained the same in the other datasets. It was noticed that after doing the inverse-forward interpolation, the selected lambda value was closer to the optimum lambda value that gives the inverse solution best correlated with the recorded one.
Transient recovery of epicardial and torso ST-segment ischemic signals during cardiac stress tests: A possible physiological mechanism
B. Zenger, W. W. Good, J. A. Bergquist, L. C. Rupp, M. Perez, G. J. Stoddard, V. Sharma, R. S. MacLeod. In Journal of Electrocardiology, Churchill Livingstone, 2021.
Acute myocardial ischemia has several characteristic ECG findings, including clinically detectable ST-segment deviations. However, the sensitivity and specificity of diagnosis based on ST-segment changes are low. Furthermore, ST-segment deviations have been shown to be transient and spontaneously recover without any indication the ischemic event has subsided.
Assess the transient recovery of ST-segment deviations on remote recording electrodes during a partial occlusion cardiac stress test and compare them to intramyocardial ST-segment deviations.
We used a previously validated porcineBZ experimental model of acute myocardial ischemia with controllable ischemic load and simultaneous electrical measurements within the heart wall, on the epicardial surface, and on the torso surface. Simulated cardiac stress tests were induced by occluding a coronary artery while simultaneously pacing rapidly or infusing dobutamine to stimulate cardiac function. Postexperimental imaging created anatomical models for data visualization and quantification. Markers of ischemia were identified as deviations in the potentials measured at 40% of the ST-segment. Intramural cardiac conduction speed was also determined using the inverse gradient method. We assessed changes in intramyocardial ischemic volume proportion, conduction speed, clinical presence of ischemia on remote recording arrays, and regional changes to intramyocardial ischemia. We defined the peak deviation response time as the time interval after onset of ischemia at which maximum ST-segment deviation was achieved, and ST-recovery time was the interval when ST deviation returned to below thresholded of ST elevation.
In both epicardial and torso recordings, the peak ST-segment deviation response time was 4.9±1.1 min and the ST-recovery time was approximately 7.9±2.5 min, both well before the termination of the ischemic stress. At peak response time, conduction speed was reduced by 50% and returned to near baseline at ST-recovery. The overall ischemic volume proportion initially increased, on average, to 37% at peak response time; however, it recovered only to 30% at the ST-recovery time. By contrast, the subepicardial region of the myocardial wall showed 40% ischemic volume at peak response time and recovered much more strongly to 25% as epicardial ST-segment deviations returned to baseline.
Our data show that remote ischemic signal recovery correlates with a recovery of the subepicardial myocardium, while subendocardial ischemic development persists.
Deep Adaptive Electrocardiographic Imaging with Generative Forward Model for Error Reduction,
X. Jiang, J. C. Font, J. A. Bergquist, B. Zenger, W. W. Good, D. H. Brooks, R. S. MacLeod, L. Wang. In Functional Imaging and Modeling of the Heart: 11th International Conference, In Functional Imaging and Modeling of the Heart: 11th International Conference, Vol. 12738, Springer Nature, pp. 471. 2021.
Accuracy of estimating the heart's electrical activity with Electrocardiographic Imaging (ECGI) is challenging due to using an error-prone physics-based model (forward model). While getting better results than the traditional numerical methods following the underlying physics, modern deep learning approaches ignore the physics behind the electrical propagation in the body and do not allow the use of patientspecific geometry. We introduce a deep-learning-based ECGI framework capable of understanding the underlying physics, aware of geometry, and adjustable to patient-specific data. Using a variational autoencoder (VAE), we uncover the forward model's parameter space, and when solving the inverse problem, these parameters will be optimized to reduce the errors in the forward model. In both simulation and real data experiments, we demonstrated the ability of the presented framework to provide accurate reconstruction of the heart's electrical potentials and localization of the earliest activation sites.
Uncertainty Quantification of the Effects of Segmentation Variability in ECGI,
J. D. Tate, W. W. Good, N. Zemzemi, M. Boonstra, P. van Dam, D. H. Brooks, A. Narayan, R. S. MacLeod. In Functional Imaging and Modeling of the Heart, Springer International Publishing, pp. 515--522. 2021.
DOI: 10.1007/978-3-030-78710-3_49
Despite advances in many of the techniques used in Electrocardiographic Imaging (ECGI), uncertainty remains insufficiently quantified for many aspects of the pipeline. The effect of geometric uncertainty, particularly due to segmentation variability, may be the least explored to date. We use statistical shape modeling and uncertainty quantification (UQ) to compute the effect of segmentation variability on ECGI solutions. The shape model was made with Shapeworks from nine segmentations of the same patient and incorporated into an ECGI pipeline. We computed uncertainty of the pericardial potentials and local activation times (LATs) using polynomial chaos expansion (PCE) implemented in UncertainSCI. Uncertainty in pericardial potentials from segmentation variation mirrored areas of high variability in the shape model, near the base of the heart and the right ventricular outflow tract, and that ECGI was less sensitive to uncertainty in the posterior region of the heart. Subsequently LAT calculations could vary dramatically due to segmentation variability, with a standard deviation as high as 126ms, yet mainly in regions with low conduction velocity. Our shape modeling and UQ pipeline presented possible uncertainty in ECGI due to segmentation variability and can be used by researchers to reduce said uncertainty or mitigate its effects. The demonstrated use of statistical shape modeling and UQ can also be extended to other types of modeling pipelines.
The Electrocardiographic Forward Problem: A Benchmark Study
J. A. Bergquist, W. W. Good, B. Zenger, J. D. Tate, L. C. Rupp, R. S. MacLeod. In Computers in Biology and Medicine, Vol. 134, Pergamon, pp. 104476. 2021.
DOI: https://doi.org/10.1016/j.compbiomed.2021.104476
Electrocardiographic forward problems are crucial components for noninvasive electrocardiographic imaging (ECGI) that compute torso potentials from cardiac source measurements. Forward problems have few sources of error as they are physically well posed and supported by mature numerical and computational techniques. However, the residual errors reported from experimental validation studies between forward computed and measured torso signals remain surprisingly high.
To test the hypothesis that incomplete cardiac source sampling, especially above the atrioventricular (AV) plane is a major contributor to forward solution errors.
We used a modified Langendorff preparation suspended in a human-shaped electrolytic torso-tank and a novel pericardiac-cage recording array to thoroughly sample the cardiac potentials. With this carefully controlled experimental preparation, we minimized possible sources of error, including geometric error and torso inhomogeneities. We progressively removed recorded signals from above the atrioventricular plane to determine how the forward-computed torso-tank potentials were affected by incomplete source sampling.
We studied 240 beats total recorded from three different activation sequence types (sinus, and posterior and anterior left-ventricular free-wall pacing) in each of two experiments. With complete sampling by the cage electrodes, all correlation metrics between computed and measured torso-tank potentials were above 0.93 (maximum 0.99). The mean root-mean-squared error across all beat types was also low, less than or equal to 0.10 mV. A precipitous drop in forward solution accuracy was observed when we included only cage measurements below the AV plane.
First, our forward computed potentials using complete cardiac source measurements set a benchmark for similar studies. Second, this study validates the importance of complete cardiac source sampling above the AV plane to produce accurate forward computed torso potentials. Testing ECGI systems and techniques with these more complete and highly accurate datasets will improve inverse techniques and noninvasive detection of cardiac electrical abnormalities.
Proceedings of the Eighth Annual Deep Brain Stimulation Think Tank: Advances in Optogenetics, Ethical Issues Affecting DBS Research, Neuromodulatory Approaches for Depression, Adaptive Neurostimulation, and Emerging DBS Technologies
V. Vedam-Mai, K. Deisseroth, J. Giordano, G. Lazaro-Munoz, W. Chiong, N. Suthana, J. Langevin, J. Gill, W. Goodman, N. R. Provenza, C. H. Halpern, R. S. Shivacharan, T. N. Cunningham, S. A. Sheth, N. Pouratian, K. W. Scangos, H. S. Mayberg, A. Horn, K. A. Johnson, C. R. Butson, R. Gilron, C. de Hemptinne, R. Wilt, M. Yaroshinsky, S. Little, P. Starr, G. Worrell, P. Shirvalkar, E. Chang, J. Volkmann, M. Muthuraman, S. Groppa, A. A. Kühn, L. Li, M. Johnson, K. J. Otto, R. Raike, S. Goetz, C. Wu, P. Silburn, B. Cheeran, Y. J. Pathak, M. Malekmohammadi, A. Gunduz, J. K. Wong, S. Cernera, A. W. Shukla, A. Ramirez-Zamora, W. Deeb, A. Patterson, K. D. Foote, M. S. Okun. In Frontiers in Human Neuroscience, Vol. 15, pp. 169. 2021.
DOI: 10.3389/fnhum.2021.644593
We estimate that 208,000 deep brain stimulation (DBS) devices have been implanted to address neurological and neuropsychiatric disorders worldwide. DBS Think Tank presenters pooled data and determined that DBS expanded in its scope and has been applied to multiple brain disorders in an effort to modulate neural circuitry. The DBS Think Tank was founded in 2012 providing a space where clinicians, engineers, researchers from industry and academia discuss current and emerging DBS technologies and logistical and ethical issues facing the field. The emphasis is on cutting edge research and collaboration aimed to advance the DBS field. The Eighth Annual DBS Think Tank was held virtually on September 1 and 2, 2020 (Zoom Video Communications) due to restrictions related to the COVID-19 pandemic. The meeting focused on advances in: (1) optogenetics as a tool for comprehending neurobiology of diseases and on optogenetically-inspired DBS, (2) cutting edge of emerging DBS technologies, (3) ethical issues affecting DBS research and access to care, (4) neuromodulatory approaches for depression, (5) advancing novel hardware, software and imaging methodologies, (6) use of neurophysiological signals in adaptive neurostimulation, and (7) use of more advanced technologies to improve DBS clinical outcomes. There were 178 attendees who participated in a DBS Think Tank survey, which revealed the expansion of DBS into several indications such as obesity, post-traumatic stress disorder, addiction and Alzheimer's disease. This proceedings summarizes the advances discussed at the Eighth Annual DBS Think Tank.
Identification of Deep Brain Stimulation Targets for Neuropathic Pain After Spinal Cord Injury Using Localized Increases in White Matter Fiber Cross‐Section
S. R. Black, A. Janson, M. Mahan, J. Anderson, C. R. Butson. In Neuromodulation: Technology at the Neural Interface, John Wiley & Sons, Inc., 2021.
The spinal cord injury (SCI) patient population is overwhelmingly affected by neuropathic pain (NP), a secondary condition for which therapeutic options are limited and have a low degree of efficacy. The objective of this study was to identify novel deep brain stimulation (DBS) targets that may theoretically benefit those with NP in the SCI patient population. We hypothesize that localized changes in white matter identified in SCI subjects with NP compared to those without NP could be used to develop an evidence‐based approach to DBS target identification.
To classify localized neurostructural changes associated with NP in the SCI population, we compared white matter fiber density (FD) and cross‐section (FC) between SCI subjects with NP (N = 17) and SCI subjects without NP (N = 15) using diffusion‐weighted magnetic resonance imaging (MRI). We then identified theoretical target locations for DBS using fiber bundles connected to significantly altered regions of white matter. Finally, we used computational models of DBS to determine if our theoretical target locations could be used to feasibly activate our fiber bundles of interest.
We identified significant increases in FC in the splenium of the corpus callosum in pain subjects when compared to controls. We then isolated five fiber bundles that were directly connected to the affected region of white matter. Our models were able to predict that our fiber bundles of interest can be feasibly activated with DBS at reasonable stimulation amplitudes and with clinically relevant implantation approaches.
Altogether, we identified neuroarchitectural changes associated with NP in the SCI cohort and implemented a novel, evidence‐driven target selection approach for DBS to guide future research in neuromodulation treatment of NP after SCI.
3D Model of Cell Migration and Proliferation in a Tissue Scaffold,
S. H. Campbell, T. Bidone. In Biophysical Journal, Vol. 120, No. 3, Elsevier, pp. 265a. 2021.
Tissue scaffolds restore tissue functionality without the limitations of transplants. However, successful tissue growth depends on the interplay between scaffold properties and cell activities. It has been previously reported that scaffold porosity and Young's modulus affect cell migration and tissue generation. However, how the geometrical and mechanical properties of a scaffold exactly interplay with cell processes remain poorly understood and are essential for successful tissue growth. We developed a 3D computational model that simulates cell migration and proliferation on a scaffold. The model generates an adjustable 3D porous scaffold environment with a defined pore size and Young modulus. Cells are treated as explicit spherical particles comparable in size to bone-marrow cells and are initially seeded randomly throughout the scaffold. Cells can create adhesions, proliferate, and independently migrate across pores in a random walk. Cell adhesions during migration follow the molecular-clutch mechanism, where traction force from the cells against the scaffold stiffness reinforces adhesions lifetime up to a threshold. We used the model to test how variations in cell proliferation rate, scaffold Young's modulus, and porosity affect cell migration speed. At a low proliferation rate (1 x 10−7 s−1), the spread of cell speeds is larger than at a high replication rate (1 x 10−6 s−1). A biphasic relation between Young's modulus and cell speed is also observed reflecting the molecular-clutch mechanism at the level of individual adhesions. These observations are consistent with previous reports regarding fibroblast migration on collagen-glycosaminoglycan scaffolds. Additionally, our model shows that similar cell diameters and pore diameter induces a crowding effect decreasing cell speed. The results from our study provide important insights about biophysical mechanisms that govern cell motility on scaffolds with different properties for tissue engineering applications.
Prestin Generates Instantaneous Force in Outer Hair Cell Membranes,
J. Sandhu, T. Bidone, R. D. Rabbitt. In Biophysical Journal, Vol. 120, No. 3, 2021.
Hearing occurs from sound reaching the inner ear cochlea, where electromotile Outer Hair Cells (OHCs) amplify vibrations by elongating and contracting rapidly in response to auditory frequency changes in membrane potential. OHCs can generate force cycle-by-cycle at frequencies exceeding 50kHz, but precisely how this is achieved is unclear. Electromotility requires expression of the transmembrane protein, prestin, which facilitates the electromechanical conversion through action of the Coulomb force acting on the anion Cl- bound at the core of the protein. However, recent experimental data suggests the charge displacement is too slow to support sound amplification at auditory frequencies. As a consequence, prestin electromechanics remain unclear at the molecular level. We hypothesize that prestin instantaneously transmits stress to the membrane, which subsequently drives charge displacement, membrane deformation, and OHC shape changes. To test the hypothesis, we examined the conformational dynamics of prestin and its effects on the motion of lipids under: (1) isometric conditions and (2) constant force conditions in order to mimic different regimes of membrane loading. All-atom molecular dynamics simulations of the prestin dimer embedded in POPC membranes were run and the trajectories analyzed. We discovered that under isometric conditions, the presence of a chloride ion in the electric field increased residue fluctuations. This trend was not observed under constant force conditions, supporting the idea that isometric conditions cause instantaneous force to be generated in the membrane. The analysis allowed us to identify the molecular mechanisms by which prestin allows electromechanical amplification by OHCs in the cochlea.
Computational Model of E-cadherin Clustering under Cortical Tension,
Y. Chen, C. McNabb, T. Bidone. In Biophysical Journal, Vol. 120, No. 3, Elsevier, pp. 236a. 2021.
E-cadherins are adhesion proteins that play a critical role in the formation of cell-cell junctions for several physiological processes, including tissue development and homeostasis. The formation of E-cadherin clusters involves extracellular trans-and cis-associations between cadherin ectodomains and stabilization through intracellular coupling with the contractile actomyosin cortex. The dynamic remodeling of cell-cell junctions largely depends on cortical tension, but previous modeling frameworks did not incorporate this effect. In order to gain insights into the effects of cortical tension on the dynamic properties of E-cadherin clusters, here we developed a computational model based on Brownian dynamics. The model considers individual cadherins as explicit point particles undergoing cycles of lateral diffusion on two parallel surfaces that mimic the membrane of neighboring cells. E-cadherins transit between …
Area Available for Atrial Fibrillation to Propagate Is an Important Determinant of Recurrence After Ablation,
R. Kamali, J. Kump, E. Ghafoori, M. Lange, N. Hu, T. J. Bunch, D. J. Dosdall, R. S. Macleod, R. Ranjan. In JACC: Clinical Electrophysiology, Elsevier, 2021.
This study sought to evaluate atrial fibrillation (AF) ablation outcomes based on scar patterns and contiguous area available for AF wavefronts to propagate.
Electrocardiographic imaging for atrial fibrillation: a perspective from computer models and animal experiments to clinical value
J. Salinet, R. Molero, F. S. Schlindwein, J. Karel, M. Rodrigo, J. L. Rojo-Álvarez, O. Berenfeld, A. M. Climent, B. Zenger, F. Vanheusden, J. G. S. Paredes, R. MacLeod, F. Atienza, M. S. Guillem, M. Cluitmans, P. Bonizzi. In Frontiers in Physiology, Vol. 12, Frontiers Media, April, 2021.
DOI: 10.3389/fphys.2021.653013
Salinet et al. Electrocardiographic Imaging for Atrial Fibrillation treatment guidance (for example, localization of AF triggers and sustaining mechanisms), and we discuss the technological requirements and validation. We address experimental and clinical results, limitations, and future challenges for fruitful application of ECGI for AF understanding and management. We pay attention to existing techniques and clinical application, to computer models and (animal or human) experiments, to challenges of methodological and clinical validation. The overall objective of the study is to provide a consensus on valuable directions that ECGI research may take to provide future improvements in AF characterization and treatment guidance.
Estimation and validation of cardiac conduction velocity and wavefront reconstruction using epicardial and volumetric data
W. W. Good, K. Gillette, B. Zenger, J. Bergquist, L. C. Rupp, J. D. Tate, D. Anderson, M. Gsell, G. Plank, R. S. Macleod. In IEEE Transactions on Biomedical Engineering, IEEE, 2021.
DOI: 10.1109/TBME.2021.3069792
Objective: In this study, we have used whole heart simulations parameterized with large animal experiments to validate three techniques (two from the literature and one novel) for estimating epicardial and volumetric conduction velocity (CV). Methods: We used an eikonal-based simulation model to generate ground truth activation sequences with prescribed CVs. Using the sampling density achieved experimentally we examined the accuracy with which we could reconstruct the wavefront, and then examined the robustness of three CV estimation techniques to reconstruction related error. We examined a triangulation-based, inverse-gradient-based, and streamline-based techniques for estimating CV cross the surface and within the volume of the heart. Results: The reconstructed activation times agreed closely with simulated values, with 50-70% of the volumetric nodes and 97-99% of the epicardial nodes were within 1 ms of the ground truth. We found close agreement between the CVs calculated using reconstructed versus ground truth activation times, with differences in the median estimated CV on the order of 3-5% volumetrically and 1-2% superficially, regardless of what technique was used. Conclusion: Our results indicate that the wavefront reconstruction and CV estimation techniques are accurate, allowing us to examine changes in propagation induced by experimental interventions such as acute ischemia, ectopic pacing, or drugs. Significance: We implemented, validated, and compared the performance of a number of CV estimation techniques. The CV estimation techniques implemented in this study produce accurate, high-resolution CV fields that can be used to study propagation in the heart experimentally and clinically.
Quantifying the spatiotemporal influence of acute myocardial ischemia on volumetric conduction velocity
W. W. Good, B. Zenger, J. A. Bergquist, L. C. Rupp, K. K. Gillette, M. A.F. Gsell, G. Plank, R. S. MacLeod. In Journal of Electrocardiology, Vol. 66, Churchill Livingstone, pp. 86-94. 2021.
Acute myocardial ischemia occurs when coronary perfusion to the heart is inadequate, which can perturb the highly organized electrical activation of the heart and can result in adverse cardiac events including sudden cardiac death. Ischemia is known to influence the ST and repolarization phases of the ECG, but it also has a marked effect on propagation (QRS); however, studies investigating propagation during ischemia have been limited.
We estimated conduction velocity (CV) and ischemic stress prior to and throughout 20 episodes of experimentally induced ischemia in order to quantify the progression and correlation of volumetric conduction changes during ischemia. To estimate volumetric CV, we 1) reconstructed the activation wavefront; 2) calculated the elementwise gradient to approximate propagation direction; and 3) estimated conduction speed (CS) with an inverse-gradient technique.
We found that acute ischemia induces significant conduction slowing, reducing the global median speed by 20 cm/s. We observed a biphasic response in CS (acceleration then deceleration) early in some ischemic episodes. Furthermore, we noted a high temporal correlation between ST-segment changes and CS slowing; however, when comparing these changes over space, we found only moderate correlation (corr. = 0.60).
This study is the first to report volumetric CS changes (acceleration and slowing) during episodes of acute ischemia in the whole heart. We showed that while CS changes progress in a similar time course to ischemic stress (measured by ST-segment shifts), the spatial overlap is complex and variable, showing extreme conduction slowing both in and around regions experiencing severe ischemia.
Structural connectivity predicts clinical outcomes of deep brain stimulation for Tourette syndrome
K. A. Johnson, G. Duffley, D. Nesterovich Anderson, J. L. Ostrem, M. Welter, J. C. Baldermann, J. Kuhn, D. Huys, V. Visser-Vandewalle, T. Foltynie, L. Zrinzo, M. Hariz, A. F. G. Leentjens, A. Y. Mogilner, M. H. Pourfar, L. Almeida, A. Gunduz, K. D. Foote, M. S. Okun, C. R. Butson. In Brain, July, 2020.
DOI: 10.1093/brain/awaa188
Deep brain stimulation may be an effective therapy for select cases of severe, treatment-refractory Tourette syndrome; however, patient responses are variable, and there are no reliable methods to predict clinical outcomes. The objectives of this retrospective study were to identify the stimulation-dependent structural networks associated with improvements in tics and comorbid obsessive-compulsive behaviour, compare the networks across surgical targets, and determine if connectivity could be used to predict clinical outcomes. Volumes of tissue activated for a large multisite cohort of patients (n = 66) implanted bilaterally in globus pallidus internus (n = 34) or centromedial thalamus (n = 32) were used to generate probabilistic tractography to form a normative structural connectome. The tractography maps were used to identify networks that were correlated with improvement in tics or comorbid obsessive-compulsive behaviour and to predict clinical outcomes across the cohort. The correlated networks were then used to generate 'reverse' tractography to parcellate the total volume of stimulation across all patients to identify local regions to target or avoid. The results showed that for globus pallidus internus, connectivity to limbic networks, associative networks, caudate, thalamus, and cerebellum was positively correlated with improvement in tics; the model predicted clinical improvement scores (P = 0.003) and was robust to cross-validation. Regions near the anteromedial pallidum exhibited higher connectivity to the positively correlated networks than posteroventral pallidum, and volume of tissue activated overlap with this map was significantly correlated with tic improvement (P < 0.017). For centromedial thalamus, connectivity to sensorimotor networks, parietal-temporal-occipital networks, putamen, and cerebellum was positively correlated with tic improvement; the model predicted clinical improvement scores (P = 0.012) and was robust to cross-validation. Regions in the anterior/lateral centromedial thalamus exhibited higher connectivity to the positively correlated networks, but volume of tissue activated overlap with this map did not predict improvement (P > 0.23). For obsessive-compulsive behaviour, both targets showed that connectivity to the prefrontal cortex, orbitofrontal cortex, and cingulate cortex was positively correlated with improvement; however, only the centromedial thalamus maps predicted clinical outcomes across the cohort (P = 0.034), but the model was not robust to cross-validation. Collectively, the results demonstrate that the structural connectivity of the site of stimulation are likely important for mediating symptom improvement, and the networks involved in tic improvement may differ across surgical targets. These networks provide important insight on potential mechanisms and could be used to guide lead placement and stimulation parameter selection, as well as refine targets for neuromodulation therapies for Tourette syndrome.


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This Microsemi Whitepaper details these 5 risks, and what you can do to remediate them.
Implementing an NTP Server in your datacenter is one of the most cost-effective ways to increase the reliability, performance, and security of your network for many years to come.
For more details, visit https://sync.empowerednetworks.com.


Have you ever taken a photo film to labs to wash and wonder, how is this process going on? In this article, we will join the 'mysterious game', learn every step in the process of turning a film into digital images.
The film's 'itinerary' starts from the lab's photo booth, after it has spent many days in your film camera to capture the photos you feel most proud of.
The first step is to remove the end of the film from the container with a special tool. This process is not easy, as there are many movies that will bend the end of the film in the process of filming the film into the carrying case. At this time, the inner films are still very light-sensitive, so the washing engineers will have to be careful not to take them out, and use a device called 'mobile darkroom'.
The film will then be inserted into the cutter to cut the end of the film into a rectangle.
After being cut, the film is glued to a special adhesive tape, which will not melt during the washing process. Normally, there will be 2 sheets of film with adhesive tape on both sides to ensure the film does not fall off during washing. The tape also has small holes to be able to hook the gyroscope to film through the coating machine in the following steps.
One of the most important thing is not to make customers' films mistaken for each other, so engineers will add a small sticker with a separate serial number, making it easier to pay the film.
And now the film is ready for washing.
The engineer will put the face with the tape of the film on the machine, need to put the hand under the film so that they do not fall to the floor. When the film has entered the machine, we will close the cover to make sure there is no light inside.
One of the worst things that can happen during the film washing process is power outage. If the power goes out, the film will be clogged inside the machine, between chemical tanks, and we will have to manually open the phone to get them out. The Fujifilm machine that we use today has a manual film roll mechanism, so during the power wash process, the engineers can take the film safely.
Before the opening day, labs will perform a color calibration step for the device. They will print a film to test, then use a density meter to measure the color to see if it is correct, otherwise it will have to be calibrated.


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Prince Fans Gear Up For The Purple Rain
There's no debating that Prince was an icon in the realms of both music and fashion and that's why everyone should be clicking to get their tickets to the 'My Name is Prince' retrospective at The O2, London.
The exhibition opens on 27th October 2017 and will run for 21 days reflecting the singer's residency in 2007 at the venue.
Flashy, provocative and always over the top, Prince dislodged himself from the essential masculine moorings. He was not only one of the most formidable and remarkable musicians of his generation, but also a taste-maker within fashion. This is evident, even this season with numerous brands taking inspiration by his transgressive power and hypnotic charge for autumn/winter 2017. Prada, Balenciaga and Dolce & Gabbana have drawn on the Purple One's unequivocal style in their latest women's and menswear collections.
The retrospective will feature hundreds of artefacts that will be making their debut outside of Prince's private estate of Paisley Park, Minneapolis.
Highlight items include Prince's orange cloud guitar made for his 2007 Super Bowl halftime performance, his raspberry beret and the famous cloud suit from 1985.
My Name is Prince is on from 27th October 2017 until 7th January at The O2.
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The estimation of debris-flow volume is a fundamental task for the design of any hazard mitigation intervention in a mountain channel. The estimation may be carried out before the occurrence of a debris flow through methodologies aimed at assessing the debris potential in the basin. It can be carried out through instrumentation deployed along the torrent (stage sensors, geophones, etc.). Finally, volume estimation may be performed after the occurrence of the phenomenon, surveying the deposits left in the channel, in a possible retention basin or on the fan. The surveys can be carried out through a conventional topographic survey, through a terrestrial laser scanner (TLS), by photogrammetric techniques, etc. Each method delivers approximated results, due to different reasons. A systematic comparison of the results of these different estimation procedures, carried out simultaneously in the same catchment, might help to better understand their advantages and limitations, to improve their output and to validate and standardize the respective methodologies. An European Territorial Cooperation project, named SedAlp, has been recently funded by the Alpine Space programme. An important focus of the project is on methods and data collection on sediment transport. In this context, one of the activities that is taking place in a pilot area consists in the comparison of the different methods and procedures for debris-flow volume estimation.


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- Prev Article Prof. Hu publishes new book on Taiwan - Next Article
August 14, 2017 Share
Congratulations to Wagner College government & politics associate professor Shuahua Hu upon the publication of his new book, "Foreign Policies Toward Taiwan," which will be formally launched on Aug. 18 by Routledge, the world's leading academic publisher in the humanities and social sciences.
"The issue of Taiwan is the single most difficult factor in the relationship between China and the United States," says Routledge on the book's website. "Any cross-straits conflict between China and Taiwan is likely not only to pit the world's two leading powers against each other, but also to suck in many other countries.
"This book provides a comprehensive analysis of other countries' foreign policies towards Taiwan. It considers the position of the United States and key regional powers including Japan and South and North Korea, examines the attitude of Russia and other countries which support China on this issue, and discusses the surprising policies of some smaller countries, which have recognized Taiwan's independence. The book also relates the overall picture to various international relations theories."
A substantial preview of the book is available on Google Books.
Professor Hu's areas of specialization include comparative and international politics in East Asia. His current research project examines the policies of major powers, such as China, the US, Japan, and Russia, toward Taiwan. He is the author of "Explaining Chinese Democratization" (Praeger, 2000) and has published numerous articles on comparative and international politics in Asia. Previously, he was a research fellow at the Institute of World Economy and Politics at the Chinese Academy of Social Sciences and a research assistant at the Washington-based U.S. Institute of Peace. He joined the faculty of Wagner College in the Fall 2001 semester.
Shaohua Hu earned his Ph.D. from American University, and his bachelor's and master's degrees from Peking University.
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Fall 2022 Dean's List
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Nursing completion ceremonies, photos & video
January 25, 2023 Fall 2022 Dean's List Wagner College announces undergraduate honor rolls for fall 2022 semester
January 3, 2023 Winter Break 2023 Campus services schedule — what's open, and when, on the Wagner College campus thru Jan. 29
December 20, 2022 Nursing completion ceremonies, photos & video Here are the videos, and links to the still photos, from the Evelyn L. Spiro School of Nursing completion ceremonies in December 2022
November 22, 2022 New exhibition by Gina Fuentes Walker 'On Thought & Process' runs in the Wagner College Gallery thru Feb. 3; gallery reception Dec. 13
November 16, 2022 2022 Faculty Awards Dinner Congratulations to all the award winners, and to those celebrating career milestones, who were recognized at the 2022 Faculty Awards Dinner, held Tuesday evening, Nov. 15, in the Faculty Dining Room.
November 14, 2022 WCT's 'Gentleman's Guide,' Dec. 1-4 'A Gentleman's Guide to Love & Murder,' a 2013 Broadway hit, plays this weekend in the Main Hall auditorium
November 11, 2022 $25K grant funds micro-internship program Nicolais School of Business secures support from KPMG U.S. Foundation for training partnership between students and local businesses, nonprofits
November 1, 2022 Araimo listed among Staten Island Power 100 City & State N.Y. releases 2022 list of local political royalty and VIPs
October 28, 2022 Wagner students take winning stand For third year in a row, Wagner students win national competition for policy letters to elected officials
Stories from alumni around the world.
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Wagner College 2019 news coverage
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We had the opportunity to visit Pizza Express where we learnt about the ingredients used in pizzas and how to make them. We also learnt about the different food groups: carbohydrates, fats, proteins, vitamins, minerals and dairy. We had the opportunity to ask a nurse lots of our questions about nutrition and staying healthy. The children spent a morning cooking a range of different dishes (and tasting them too). Linked to geography, we discovered which foods are grown in the UK and which are grown in other parts of the world.


Little Venice is home to several well-known 'institutions' such as the Canal Cafe Theatre which has launched some of the best comedians around the UK and the world including Miranda Hart and Last Week Tonight star, John Oliver, and also The Puppet Theatre which began staging marionette performances in a converted barge in 1982.
Whether it was named during the time Robert Browning lived in the area between 1862 to 1887, or whether it was named earlier by Lord Byron; Little Venice is a beautiful part of London surrounding three waterways; Grand Union canal, Regent's canal and the Paddington basin. Nowadays the area is known for its shops, bars and recent famous residents such as Robbie Williams, Noel Gallagher and Richard Branson.
Molly's: A cute neighbourhood restaurant offering brunches, lunches and dinner for take-away or to eat in.
The Waterway: Fabulous waterside restaurant with a huge deck for the summer and a winter log cabin pop-up happening this winter. Book now!
Pearl Liang: Hugely popular Chinese restaurant with great decor and fun staff.
If you're looking for a traditional British pub, Little Venice has you covered!
Warwick Castle: Fabulous traditional pub serving good pub grub and showing major sporting events.
The Bridge House: Another traditional British pub with craft ales, Sunday roasts. Great for a bite to eat before popping upstairs to the Canal Cafe Theatre.
Prince Alfred: Traditional pub with snob windows and a quiz night.
Whilst it's not known for its major shopping, Little Venice has some independent fantastic offerings.
The Winery: Formerly a Victorian pharmacy, The Winery now offers a great selection of wines & informal wine-tasting evenings.
The canal is the place to start if you want to stretch your legs in the fresh air. From Little Venice you can walk along the canal to Regents Park, London Zoo, Camden Town and beyond. Explore the 197 hectares of Regents Park at your leisure - the London Zoo pass is worth buying if you're going to go regularly.


text:
Glass Chamber Players
Schoenberg/Glass
Music by Philip Glass and Arnold Schoenberg
Wendy Sutter, Artistic Director
Orange Mountain Music 0069
1. Verklaerte Nacht 30:19
2. String Sextet – Movement I 4:41
3. String Sextet – Movement II 5:52
4. String Sextet – Movement III 10:29
5. String Sextet – Movement IV 3:12
The Glass Chamber Players were created spontaneously with its initial investment by Wendy Sutter, Philip Glass, and Richard Guérin. The group is a collection of virtuosi who have a breadth of classical repertoire and were chosen each for his/her particular talent and passion for music.
Despite Philip Glass' wide-ranging career of over 50 years, in recent times the composer had not been focusing on chamber music with his last string quartet, no.5, dating from back in 1991. However beginning in 2007 with his solo cello suite, Songs & Poems, composed for cellist and GCP Artistic Director Wendy Sutter, he began composing a series of chamber works including his 2008 Four Movements for Two Pianos, Sonata for Violin and Piano written for GCP member Maria Bachmann in 2009, and a large suite for solo violin written for GCP member Tim Fain in 2010.
"Here kid, listen to this…"
Philip Glass was born in pre-WWII Baltimore Maryland in 1937. The composer frequently tells the story of how his father Ben Glass, who had an auto-mechanic shop in the 1930s, frequently worked on people's cars, which led to fixing the car radios, then Ben got rid of the cars in favor of a store that sold and repaired radios. As a sideline to the radio business Ben Glass would sell some records as a small part of the business. It grew to be a big part of the business finally becoming a proper record store.
Much has been made about Philip Glass' sense as a businessman. Growing up in this American entrepreneurial environment, the young Philip would learn his first lessons in the music business. He would see people hand a five-dollar bill to his father and his father would hand them a record. "There's nothing wrong with that." Glass would later say. This was his first exposure to what for many is a complicated relationship of art and commerce in America. For a composer who would eventually take part in changing the course of music history, it's difficult to disregard the practical business sense which was ingrained in him from day one while working in his father's record shop.
In another story, Glass would tell of the "return privilege" which was part of the record industry in which retailers were allowed to return a certain percentage of the records if they were damaged. In order to exercise this privilege, Philip and his brother Marty would go down into the basement and break the records that had not sold. This was the first job that Philip Glass ever held in the music industry.
Such an action was a logical answer to a problem: what to do with the records that didn't sell? Being a very practical guy, as we saw with the evolution of his businesses, Ben Glass had another idea. He would take the records home and listen to them to try to find out why people weren't buying them. It just so happens that the music which was not selling was classical and 20th century chamber music by composers like Schoenberg, Shostakovich, and Bartok. It was in this way that the Glass home record collection of 78s grew and that a very big part of Philip Glass' artistic sensibilities were first cultivated. The soundtrack of Philip Glass' youth had been created.
It is important to the history of music is that Philip Glass spent time as a young person at home with his father listening to chamber music records. Ben Glass was not an educated musician, but he was a music lover in best sense. In the process of listening to these records to "find out what was wrong with them," he became a sophisticated listener and developed a taste for chamber music. Father Glass would bring Philip in to the room and simply say to the future composer, "Here kid, listen to this." Years later, after his father's death, Glass composed his first concert-work as a mature composer, his Violin Concerto No.1 in 1987. He composed it as a piece that he hoped his father would have liked in the tradition of the great concertos by such composers as Mendelssohn, Sibelius, and Tchaikovsky concertos.
We see that during Philip Glass' formation as a composer, chamber music of the kind which is presented on this record, had always been a part of his musical identity. After graduating from the University of Chicago, while working at Bethlehem Steel, and during years of study at Juilliard, and with Nadia Boulanger in France, with Albert Fine in New York, with Darius Milhaud in Aspen, Glass composed chamber music constantly. This was 'early' music that Glass categorizes as music of a "generic modernist American sort after Copland/Harris/Schuman." But it's important to see that he was composing these chamber pieces from his first essays as a teenager through his mid-twenties until he found his mature voice as a composer. These juvenilia were among the up to 75 pieces while at Juilliard (over about a five year period, as Glass was not initially accepted as a composition student at the school) and another 20 or so pieces while working in the Pittsburgh School system through the Ford Foundation for two years. Examples of pieces of this time are String Quartet, Sonatino Nos. 1 and 2, Arioso Nos. 1 and 2, Serenade for Flute, "Contrasts" for violin, winds, brass and percussion.
Glass' mature language as a composer was not fully developed until his return from France in the mid-1960s after studying with the pedagogue par excellence Nadia Boulanger (and of course Glass' other hugely important encounter with Ravi Shankar.) As his musical language settled and matured, the Philip Glass Ensemble, a vehicle for the new music that Glass was composing, was formed essentially a chamber group. The instrumental composition of the Ensemble was partly happenstance and partly a means to a musical end; in very much the same way Schoenberg's instrumentation was for Pierrot Lunaire. The reasons for this is because the requirements of chamber music are typically more complex the virtuosic than say your ordinary Romantic symphony. Musical language aside, the Philip Glass Ensemble, even when playing its largest pieces such as Music in 12 Parts, is still in essence a chamber group (though it must be said that Glass' interest and subject matter for his music was for a very long time very far removed from the classical music concert hall.) With the present recording we hear Philip Glass' mature music in a very different, yet totally appropriate context, alongside Schoenberg's ultra-Romantic Verklarte Nacht.
There is certain elegance in Glass' advocating to place Schoenberg on this program considering how doctrinaire Schoenberg's disciples became about tonal composers. Clearly by the time of composing Verklaerte Nacht, Schoenberg was gearing up to challenge all of the rules of classic tonality and devise new ones. Glass has pursued his own challenges to conventional tonality that usually manifest in very individual polytonality. However, the choice of music for this release was unified not by conceptions and ideas about tonality, but by less controversial criteria: character and quality. This is return of sorts for Glass to the music of his youth (and the recordings of his youth) is significant. Glass has always described himself as a theater composer, yet on this recital, his Symphony No.3 for strings (originally for 19 string players, transcribed for sextet by Michael Riesman) stands as a piece of purely instrumental music and finds itself in perfect company with Schoenberg's extraordinarily dark and dense Verklaerte Nacht (Transfigured Night), which was inspired by the poem by Richard Dehmel. In Dehmel's poem, with only a few words, the reader is swooning in a sea of the complex emotions of life, and the poem's two lovers are united by love and their own courage. Schoenberg's musical complexity could not be more perfectly analogous to Dehmel's words.
Not only was the repertoire carefully considered, but the way this record was recorded was as well: it was captured live in two performances at the Baryshnikov Arts Center in Manhattan in December 2009. This 'live-recording' sound harkens back to those classic recordings of the 1930s, 40s, and 50s before the advent of serious editing. The end result is almost always thrilling in its ebullience and pathos exactly because of the emotional arc of the performance, unencumbered by the random audible page turn or occasional ambient noise. Indeed on the nights of the recordings, there was an appropriately lugubrious rainstorm outside on the New York City streets.
This type of recording gives is a snapshot of an event that happened in real time and is an actual document of these fine players performance, and brings to full-circle a journey which Philip Glass began back in Baltimore Maryland almost 70 years ago.
Richard Guérin, New York 2010
Richard Guérin, Managing Director
Album Produced by Michael Riesman, Richard Guérin, and Don Christensen
Recorded and Engineered by Michael Riesman and Dan Bora
Edited, Mixed, and Mastererd by Michael Riesman
Recorded at the Baryshnikov Arts Center, New York, December 2009
"Sextet for Strings" arranged from Glass' Symphony No.3 by Michael Riesman
Design: Steven Erdman – www.houseoflard.com
Philip Glass' music is published by Dunvagen Music Publishers
Executive Producers: Philip Glass, Kurt Munkacsi, and Don Christensen
Schoenberg – Verklaerte Nacht is published by Universal Editions
Glass – String Sextet (arr. of Symphony No.3) is published by Dunvagen Music Publishers, Inc. (ASCAP).
℗ and © 2010 by Orange Mountain Music.
iTunes/Apple Music
Symphonies Nos. 2 and 3


The Hand Spout Holder that mounts on the spa shell or Foot Rest. It holds the Hand Spout Head in place so water can be filled into the spa bowl or gel bowl accordingly. Allow 6-10 weeks for backorder or special order items. For further information, please contact sales@lexor.com or call: (888) 479 - 6916.


Rock Brothers have been selected for inclusion in C.O.C.A.'s Outdoor Sculpture Park. Opening of "Heaven & Earth" at Seattle's Carkeek Park is on June 27th from 3 to 5pm.
Executive Decision is a dining table made of salvaged ash. Hand crafted with a modern design, the uncured wood was allowed to warp when drying. The table was then altered by driving a large wedge of rough wood through the surface to create an artistic statement about the choices we make and why.
Three additional picnic tables will be placed at equal distances around the central piece. Each of the picnic tables have landscape sized boulders placed into cutouts on top of the tables. This creates an additional scale to the installation and pushes the conversatio regarding how issues, once laid on a table, can hardly be ignored.
Now showing at Rock|DeMent in Seattle's Pioneer Square.


text:
Q: Grails won't read external config file? I'm on Windows 7. Inside my Grails (2.3.6) app's Config.groovy file I have:
grails.config.locations = [
    "file:/etc/myapp/env.groovy"
]

// fizz.buzz is defined inside env.groovy
println "fizz.buzz=${fizz.buzz}"

At the root of my D:\ drive:
etc/
    myapp/
        env.groovy

When I run grails -Dgrails.env=local run-app I get the following output:
fizz.buzz=[:]

What's going on here? Why can't Grails find my env.groovy file and/or read its properties?
My permissions:

Running File('/etc/myapp/env.groovy').absolutePath in the Groovy Console, I get:
Exception thrown

groovy.lang.MissingMethodException: No signature of method: ConsoleScript2.File() is
applicable for argument types: (java.lang.String) values: [/etc/myapp/env.groovy]
Possible solutions: find(), find(groovy.lang.Closure), use([Ljava.lang.Object;),
with(groovy.lang.Closure), is(java.lang.Object), wait()

I also tried running my app and passing in the value for fizz.buzz on the command line via a switch like so:
grails -Dgrails.env=local -Dfizz.buzz="true" run-app

The result was the same. Is it possible that the configs ARE being read in, but are just not available (caching, etc.) at the time that the println is running inside Config.groovy?

redpajama_set_name: RedPajamaStackExchange


Résumé : OBJECTIVES : Following the explosion of a chemical plant in France, a study was conducted to analyse the relationship between hearing thresholds and distance from the explosion based on post- and pre-blast audiometric data, and to describe the functional symptoms and visits for hearing problems. METHODS : Audiometric tests with standard procedure of 511 workers of a company located near the explosion were proposed and conducted by the occupational medicine department after the explosion. Past occupational noise exposure, past medical history of ear problems, distance from the explosion, functional symptoms and visits for hearing problems following explosion and results of past audiometric tests if available were collected. Workers were classified as "exposed" or "less exposed" according to the distance from the explosion. Mean decibel threshold shifts for each ear were analysed by frequency with Student's t test and by multiple linear regression taking into account confounding factors. RESULTS : Of a total of 425 (83%) of the firm's workers who participated in the study, 49% had received an audiometric test before the explosion. Hearing shift between pre- and post-explosion audiograms was significantly greater for the "exposed" group than for the "less exposed" one at 2,000 and 4,000 Hz (P < 0.05, P < 0.001, respectively) and borderline at 6,000 Hz (P = 0.09) for the right ear and at 2,000 (P < 0.01), 6,000 and 8,000 Hz (P < 0.05) for the left ear. Among those of the "exposed" workers who reported any functional symptom following the explosion, 45% did not visit an ENT specialist despite these signs. CONCLUSIONS : The study demonstrated statistically significant hearing shift from 2,000 to 6,000 Hz in relation with distance from the explosion and showed that even when functional symptoms were present, people did not necessarily seek medical advice. Screening for hearing loss should be recommended for people most exposed to excess acoustic pressure, in order to offer them prevention advice.


My baby girl, Runt was crying for more than a day already. I thought she was just being a cry-baby. But at 4:00 PM on Sunday, March 16, she gave birth to 6 baby bunnies! This series is about Runt's babies: Pepper, Buttercup, Precious, Snowball, and the other two that I haven't named yet.


text:
Q: How AirTime could change the look of the Facebook permission dialog? I saw this very personalized facebook dialog installing AirTime Facebook app:

*

*How could they do that technically? (Just heavy CSS hacking?)

*Is it against the Facebook's TOS ?

A: That's just a page that launches the dialog box, not the actual dialog (it's launched in a popup when you click the button) so it's still part of their site, on a page that detects if you've allowed the Facebook permissions.


text:
The Rivière Noire (English: Black River) is a tributary of the rivière de l'Esturgeon, flowing on the south bank of the Saint Lawrence river, in the administrative region of Montérégie, in the province of Quebec, in Canada. This river flows through the following municipalities:
 Saint-Rémi, in the MRC Les Jardins-de-Napierville Regional County Municipality;
 Saint-Isidore in the MRC of Roussillon Regional County Municipality.

The valley of this river is served by the chemin du rang Saint-Régis.

The surface of the Black River (except the rapids areas) is generally frozen from mid-December to the end of March; however, safe circulation on the ice is generally done from the end of December to the beginning of March. The water level of the river varies with the seasons and the precipitation; the spring flood occurs in March or April.

Geography
The Black River has its source in an agricultural area next to the chemin du rang Sainte-Thérèse. This source is located  south-west of the village center of Saint-Rémi,  to the south-East of the center of the village of Saint-Isidore,  northeast of the mouth of the Esturgeon river.

From its source, the current of the Black river descends on  westwards in agricultural area, with a drop of . The course of the Black River passes under the bridge of Chemin Saint-Régis (route 207)

The confluence of the Black River is located at . From its mouth, the current follows on  the course of the rivière de l'Esturgeon, on  the course of the Châteauguay River, which flows onto the south bank of the Saint Lawrence River.

Toponymy
The toponym "Rivière Noire" was formalized on August 17, 1978 at the Commission de toponymie du Québec.

Notes and references

Appendices

Related articles
 Les Jardins-de-Napierville Regional County Municipality
 Roussillon Regional County Municipality
 Saint-Isidore, a municipality
 Saint-Rémi, a municipality
 Châteauguay River
 Rivière de l'Esturgeon
 St. Lawrence River
 List of rivers of Quebec

External links

Rivers of Montérégie
Roussillon Regional County Municipality

redpajama_set_name: RedPajamaWikipedia