Integration of multi-scale biosimulation models via light-weight semantics

Currently, biosimulation researchers use a variety of computational environments and languages to model biological processes. Ideally, researchers should be able to semi- automatically merge models to more effectively build larger, multi-scale models. How- ever, current modeling methods do not capture the underlying semantics of these models sufficiently to support this type of model construction. In this paper, we both propose a general approach to solve this problem, and we provide a specific example that demon- strates the benefits of our methodology. In particular, we describe three biosimulation models: (1) a cardio-vascular fluid dynamics model, (2) a model of heart rate regulation via baroreceptor control, and (3) a sub-cellular-level model of the arteriolar smooth mus- cle. Within a light-weight ontological framework, we leverage reference ontologies to match concepts across models. The light-weight ontology then helps us combine our three models into a merged model that can answer questions beyond the scope of any single model

Diffusion Coefficients of Endogenous Cytosolic Proteins from Rabbit Skinned Muscle Fibers

AbstractEfflux time courses of endogenous cytosolic proteins were obtained from rabbit psoas muscle fibers skinned in oil and transferred to physiological salt solution. Proteins were separated by gel electrophoresis and compared to load-matched standards for quantitative analysis. A radial diffusion model incorporating the dissociation and dissipation of supramolecular complexes accounts for an initial lag and subsequent efflux of glycolytic and glycogenolytic enzymes. The model includes terms representing protein crowding, myofilament lattice hindrance, and binding to the cytomatrix. Optimization algorithms returned estimates of the apparent diffusion coefficients, D(r,t), that were very low at the onset of diffusion (∼10−10 cm2 s−1) but increased with time as cytosolic protein density, which was initially high, decreased. D(r,t) at later times ranged from 2.11 × 10−7 cm2 s−1 (parvalbumin) to 0.20 × 10−7 cm2 s−1 (phosphofructose kinase), values that are 3.6- to 12.3-fold lower than those predicted in bulk water. The low initial values are consistent with the presence of complexes in situ; the higher later values are consistent with molecular sieving and transient binding of dissociated proteins. Channeling of metabolic intermediates via enzyme complexes may enhance production of adenosine triphosphate at rates beyond that possible with randomly and/or sparsely distributed enzymes, thereby matching supply with demand

Impact of anode layer thruster plumes on satellite communications

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76372/1/AIAA-1997-3067-147.pd

Electromagnetic wave scattering experiments in Hall thruster plasma plumes

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/76740/1/AIAA-1998-3642-699.pd

Developmental Transcriptomic Analysis of the Cave-Dwelling Crustacean, Asellus aquaticus

Cave animals are a fascinating group of species often demonstrating characteristics including reduced eyes and pigmentation, metabolic efficiency, and enhanced sensory systems. Asellus aquaticus, an isopod crustacean, is an emerging model for cave biology. Cave and surface forms of this species differ in many characteristics, including eye size, pigmentation, and antennal length. Existing resources for this species include a linkage map, mapped regions responsible for eye and pigmentation traits, sequenced adult transcriptomes, and comparative embryological descriptions of the surface and cave forms. Our ultimate goal is to identify genes and mutations responsible for the differences between the cave and surface forms. To advance this goal, we decided to use a transcriptomic approach. Because many of these changes first appear during embryonic development, we sequenced embryonic transcriptomes of cave, surface, and hybrid individuals at the stage when eyes and pigment become evident in the surface form. We generated a cave, a surface, a hybrid, and an integrated transcriptome to identify differentially expressed genes in the cave and surface forms. Additionally, we identified genes with allele-specific expression in hybrid individuals. These embryonic transcriptomes are an important resource to assist in our ultimate goal of determining the genetic underpinnings of the divergence between the cave and surface forms

A computational analysis of the long-term regulation of arterial pressure

The asserted dominant role of the kidneys in the chronic regulation of blood pressure and in the etiology of hypertension has been debated since the 1970s. At the center of the theory is the observation that the acute relationships between arterial pressure and urine production—the acute pressure-diuresis and pressure-natriuresis curves—physiologically adapt to perturbations in pressure and/or changes in the rate of salt and volume intake. These adaptations, modulated by various interacting neurohumoral mechanisms, result in chronic relationships between water and salt excretion and pressure that are much steeper than the acute relationships. While the view that renal function is the dominant controller of arterial pressure has been supported by computer models of the cardiovascular system known as the “Guyton-Coleman model”, no unambiguous description of a computer model capturing chronic adaptation of acute renal function in blood pressure control has been presented. Here, such a model is developed with the goals of: 1. representing the relevant mechanisms in an identifiable mathematical model; 2. identifying model parameters using appropriate data; 3. validating model predictions in comparison to data; and 4. probing hypotheses regarding the long-term control of arterial pressure and the etiology of primary hypertension. The developed model reveals: long-term control of arterial blood pressure is primarily through the baroreflex arc and the renin-angiotensin system; and arterial stiffening provides a sufficient explanation for the etiology of primary hypertension associated with ageing. Furthermore, the model provides the first consistent explanation of the physiological response to chronic stimulation of the baroreflex

Structural insights into recognition of acetylated histone ligands by the BRPF1 bromodomain

AbstractBromodomain-PHD finger protein 1 (BRPF1) is part of the MOZ HAT complex and contains a unique combination of domains typically found in chromatin-associated factors, which include plant homeodomain (PHD) fingers, a bromodomain and a proline-tryptophan-tryptophan-proline (PWWP) domain. Bromodomains are conserved structural motifs generally known to recognize acetylated histones, and the BRPF1 bromodomain preferentially selects for H2AK5ac, H4K12ac and H3K14ac. We solved the X-ray crystal structures of the BRPF1 bromodomain in complex with the H2AK5ac and H4K12ac histone peptides. Site-directed mutagenesis on residues in the BRPF1 bromodomain-binding pocket was carried out to investigate the contribution of specific amino acids on ligand binding. Our results provide critical insights into the molecular mechanism of ligand binding by the BRPF1 bromodomain, and reveal that ordered water molecules are an essential component driving ligand recognition

Families of Quintic Calabi-Yau 3-Folds with Discrete Symmetries

At special loci in their moduli spaces, Calabi-Yau manifolds are endowed with discrete symmetries. Over the years, such spaces have been intensely studied and have found a variety of important applications. As string compactifications they are phenomenologically favored, and considerably simplify many important calculations. Mathematically, they provided the framework for the first construction of mirror manifolds, and the resulting rational curve counts. Thus, it is of significant interest to investigate such manifolds further. In this paper, we consider several unexplored loci within familiar families of Calabi-Yau hypersurfaces that have large but unexpected discrete symmetry groups. By deriving, correcting, and generalizing a technique similar to that of Candelas, de la Ossa and Rodriguez-Villegas, we find a calculationally tractable means of finding the Picard-Fuchs equations satisfied by the periods of all 3-forms in these families. To provide a modest point of comparison, we then briefly investigate the relation between the size of the symmetry group along these loci and the number of nonzero Yukawa couplings. We include an introductory exposition of the mathematics involved, intended to be accessible to physicists, in order to make the discussion self-contained.Comment: 54 pages, 3 figure

Deep phenotyping of cardiac function in heart transplant patients using cardiovascular systems models

Heart transplant patients are followed with periodic right heart catheterizations (RHCs) to identify post-transplant complications and guide treatment. Post-transplant positive outcomes are associated with a steady reduction of right ventricular and pulmonary arterial pressures, toward normal levels of right-side pressure (about 20mmHg) measured by RHC. This study shows more information about patient progression is obtained by combining standard RHC measures with mechanistic computational cardiovascular systems models. This study shows: to understand how cardiovascular system models can be used to represent a patient's cardiovascular state, and to use these models to track post-transplant recovery and outcome. To obtain reliable parameter estimates comparable within and across datasets, we use sensitivity analysis, parameter subset selection, and optimization to determine patient specific mechanistic parameter that can be reliably extracted from the RHC data. Patient-specific models are identified for ten patients from their first post-transplant RHC and longitudinal analysis is done for five patients. Results of sensitivity analysis and subset selection show we can reliably estimate seven non-measurable quantities including ventricular diastolic relaxation, systemic resistance, pulmonary venous elastance, pulmonary resistance, pulmonary arterial elastance, pulmonary valve resistance and systemic arterial elastance. Changes in parameters and predicted cardiovascular function post-transplant are used to evaluate cardiovascular state during recovery in five patients. Of these five patients, only one patient showed inconsistent trends during recovery in ventricular pressure-volume relationships and power output. At a four-year recovery time point this patient exhibited biventricular failure along with graft dysfunction while the remaining four exhibited no cardiovascular complications.Comment: 53 Pages (including supplement), 9 figures in manuscript, 9 figures in supplemen