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Search Results: 1 - 10 of 215465 matches for " Scott L. Diamond "
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Steady-State Kinetic Modeling Constrains Cellular Resting States and Dynamic Behavior
Jeremy E. Purvis,Ravi Radhakrishnan,Scott L. Diamond
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000298
Abstract: A defining characteristic of living cells is the ability to respond dynamically to external stimuli while maintaining homeostasis under resting conditions. Capturing both of these features in a single kinetic model is difficult because the model must be able to reproduce both behaviors using the same set of molecular components. Here, we show how combining small, well-defined steady-state networks provides an efficient means of constructing large-scale kinetic models that exhibit realistic resting and dynamic behaviors. By requiring each kinetic module to be homeostatic (at steady state under resting conditions), the method proceeds by (i) computing steady-state solutions to a system of ordinary differential equations for each module, (ii) applying principal component analysis to each set of solutions to capture the steady-state solution space of each module network, and (iii) combining optimal search directions from all modules to form a global steady-state space that is searched for accurate simulation of the time-dependent behavior of the whole system upon perturbation. Importantly, this stepwise approach retains the nonlinear rate expressions that govern each reaction in the system and enforces constraints on the range of allowable concentration states for the full-scale model. These constraints not only reduce the computational cost of fitting experimental time-series data but can also provide insight into limitations on system concentrations and architecture. To demonstrate application of the method, we show how small kinetic perturbations in a modular model of platelet P2Y1 signaling can cause widespread compensatory effects on cellular resting states.
Systems Biology of Coagulation Initiation: Kinetics of Thrombin Generation in Resting and Activated Human Blood
Manash S. Chatterjee,William S. Denney,Huiyan Jing,Scott L. Diamond
PLOS Computational Biology , 2010, DOI: 10.1371/journal.pcbi.1000950
Abstract: Blood function defines bleeding and clotting risks and dictates approaches for clinical intervention. Independent of adding exogenous tissue factor (TF), human blood treated in vitro with corn trypsin inhibitor (CTI, to block Factor XIIa) will generate thrombin after an initiation time (Ti) of 1 to 2 hours (depending on donor), while activation of platelets with the GPVI-activator convulxin reduces Ti to ~20 minutes. Since current kinetic models fail to generate thrombin in the absence of added TF, we implemented a Platelet-Plasma ODE model accounting for: the Hockin-Mann protease reaction network, thrombin-dependent display of platelet phosphatidylserine, VIIa function on activated platelets, XIIa and XIa generation and function, competitive thrombin substrates (fluorogenic detector and fibrinogen), and thrombin consumption during fibrin polymerization. The kinetic model consisting of 76 ordinary differential equations (76 species, 57 reactions, 105 kinetic parameters) predicted the clotting of resting and convulxin-activated human blood as well as predicted Ti of human blood under 50 different initial conditions that titrated increasing levels of TF, Xa, Va, XIa, IXa, and VIIa. Experiments with combined anti-XI and anti-XII antibodies prevented thrombin production, demonstrating that a leak of XIIa past saturating amounts of CTI (and not “blood-borne TF” alone) was responsible for in vitro initiation without added TF. Clotting was not blocked by antibodies used individually against TF, VII/VIIa, P-selectin, GPIb, protein disulfide isomerase, cathepsin G, nor blocked by the ribosome inhibitor puromycin, the Clk1 kinase inhibitor Tg003, or inhibited VIIa (VIIai). This is the first model to predict the observed behavior of CTI-treated human blood, either resting or stimulated with platelet activators. CTI-treated human blood will clot in vitro due to the combined activity of XIIa and XIa, a process enhanced by platelet activators and which proceeds in the absence of any evidence for kinetically significant blood borne tissue factor.
Drug Discovery for Duchenne Muscular Dystrophy via Utrophin Promoter Activation Screening
Catherine Moorwood, Olga Lozynska, Neha Suri, Andrew D. Napper, Scott L. Diamond, Tejvir S. Khurana
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0026169
Abstract: Background Duchenne muscular dystrophy (DMD) is a devastating muscle wasting disease caused by mutations in dystrophin, a muscle cytoskeletal protein. Utrophin is a homologue of dystrophin that can functionally compensate for its absence when expressed at increased levels in the myofibre, as shown by studies in dystrophin-deficient mice. Utrophin upregulation is therefore a promising therapeutic approach for DMD. The use of a small, drug-like molecule to achieve utrophin upregulation offers obvious advantages in terms of delivery and bioavailability. Furthermore, much of the time and expense involved in the development of a new drug can be eliminated by screening molecules that are already approved for clinical use. Methodology/Principal Findings We developed and validated a cell-based, high-throughput screening assay for utrophin promoter activation, and used it to screen the Prestwick Chemical Library of marketed drugs and natural compounds. Initial screening produced 20 hit molecules, 14 of which exhibited dose-dependent activation of the utrophin promoter and were confirmed as hits. Independent validation demonstrated that one of these compounds, nabumetone, is able to upregulate endogenous utrophin mRNA and protein, in C2C12 muscle cells. Conclusions/Significance We have developed a cell-based, high-throughput screening utrophin promoter assay. Using this assay, we identified and validated a utrophin promoter-activating drug, nabumetone, for which pharmacokinetics and safety in humans are already well described, and which represents a lead compound for utrophin upregulation as a therapy for DMD.
Identification of Novel Inhibitors of Dietary Lipid Absorption Using Zebrafish
Justin D. Clifton,Edinson Lucumi,Michael C. Myers,Andrew Napper,Kotaro Hama,Steven A. Farber,Amos B. Smith III,Donna M. Huryn,Scott L. Diamond,Michael Pack
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0012386
Abstract: Pharmacological inhibition of dietary lipid absorption induces favorable changes in serum lipoprotein levels in patients that are at risk for cardiovascular disease and is considered an adjuvant or alternative treatment with HMG-CoA reductase inhibitors (statins). Here we demonstrate the feasibility of identifying novel inhibitors of intestinal lipid absorption using the zebrafish system. A pilot screen of an unbiased chemical library identified novel compounds that inhibited processing of fluorescent lipid analogues in live zebrafish larvae. Secondary assays identified those compounds suitable for testing in mammals and provided insight into mechanism of action, which for several compounds could be distinguished from ezetimibe, a drug used to inhibit cholesterol absorption in humans that broadly inhibited lipid absorption in zebrafish larvae. These findings support the utility of zebrafish screening assays to identify novel compounds that target complex physiological processes.
Multiwavelength Observations of Radio-quiet Quasars with Weak Emission Lines
Richard M. Plotkin,Scott F. Anderson,W. N. Brandt,Aleksandar M. Diamond-Stanic,Xiaohui Fan,Chelsea L. MacLeod,Donald P. Schneider,Ohad Shemmer
Physics , 2010, DOI: 10.1088/0004-637X/721/1/562
Abstract: We present radio and X-ray observations, as well as optical light curves, for a subset of 26 BL Lac candidates from the Sloan Digital Sky Survey (SDSS) lacking strong radio emission and with z<2.2. Half of these 26 objects are shown to be stars, galaxies, or absorbed quasars. We conclude that the other 13 objects are Active Galactic Nuclei (AGN) with abnormally weak emission features; ten of those 13 are definitively radio-quiet, and, for those with available optical light curves, their level of optical flux variability is consistent with radio-quiet quasars. We cannot exclude the possibility that some of these 13 AGN lie on the extremely radio-faint tail of the BL Lac distribution, but our study generally supports the notion that all BL Lac objects are radio-loud. These radio-quiet AGN appear to have intrinsically weak or absent broad emission line regions, and, based on their X-ray properties, we argue that some are low-redshift analogs to weak line quasars (WLQs). SDSS BL Lac searches are so far the only systematic surveys of the SDSS database capable of recovering such exotic low-redshift WLQs. There are 71 more z<2.2 radio-quiet BL Lac candidates already identified in the SDSS not considered here, and many of those might be best unified with WLQs as well. Future studies combining low- and high-redshift WLQ samples will yield new insight on our understanding of the structure and formation of AGN broad emission line regions.
Lethal Antibody Enhancement of Dengue Disease in Mice Is Prevented by Fc Modification
Scott J. Balsitis equal contributor,Katherine L. Williams equal contributor,Ruben Lachica,Diana Flores,Jennifer L. Kyle,Erin Mehlhop,Syd Johnson,Michael S. Diamond,P. Robert Beatty,Eva Harris
PLOS Pathogens , 2010, DOI: 10.1371/journal.ppat.1000790
Abstract: Immunity to one of the four dengue virus (DV) serotypes can increase disease severity in humans upon subsequent infection with another DV serotype. Serotype cross-reactive antibodies facilitate DV infection of myeloid cells in vitro by promoting virus entry via Fcγ receptors (FcγR), a process known as antibody-dependent enhancement (ADE). However, despite decades of investigation, no in vivo model for antibody enhancement of dengue disease severity has been described. Analogous to human infants who receive anti-DV antibodies by transplacental transfer and develop severe dengue disease during primary infection, we show here that passive administration of anti-DV antibodies is sufficient to enhance DV infection and disease in mice using both mouse-adapted and clinical DV isolates. Antibody-enhanced lethal disease featured many of the hallmarks of severe dengue disease in humans, including thrombocytopenia, vascular leakage, elevated serum cytokine levels, and increased systemic viral burden in serum and tissue phagocytes. Passive transfer of a high dose of serotype-specific antibodies eliminated viremia, but lower doses of these antibodies or cross-reactive polyclonal or monoclonal antibodies all enhanced disease in vivo even when antibody levels were neutralizing in vitro. In contrast, a genetically engineered antibody variant (E60-N297Q) that cannot bind FcγR exhibited prophylactic and therapeutic efficacy against ADE-induced lethal challenge. These observations provide insight into the pathogenesis of antibody-enhanced dengue disease and identify a novel strategy for the design of therapeutic antibodies against dengue.
A Simple and Computationally Efficient Approach to Multifactor Dimensionality Reduction Analysis of Gene-Gene Interactions for Quantitative Traits
Jiang Gui, Jason H. Moore, Scott M. Williams, Peter Andrews, Hans L. Hillege, Pim van der Harst, Gerjan Navis, Wiek H. Van Gilst, Folkert W. Asselbergs, Diane Gilbert-Diamond
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066545
Abstract: We present an extension of the two-class multifactor dimensionality reduction (MDR) algorithm that enables detection and characterization of epistatic SNP-SNP interactions in the context of a quantitative trait. The proposed Quantitative MDR (QMDR) method handles continuous data by modifying MDR’s constructive induction algorithm to use a T-test. QMDR replaces the balanced accuracy metric with a T-test statistic as the score to determine the best interaction model. We used a simulation to identify the empirical distribution of QMDR’s testing score. We then applied QMDR to genetic data from the ongoing prospective Prevention of Renal and Vascular End-Stage Disease (PREVEND) study.
Teatro Citadel Edmonton – Canadá
Diamond, -,Myers, -,Wilkín, R. L.
Informes de la Construccion , 1979,
Abstract: The name of this theatre comes from its being built on the site of an old Salvation Army Citadel in Edmonton, province of Alberta. This is a complex containing three theatres with 700, 300 and 250 seats respectively, plus meeting rooms, shops, restaurant, rehearsal rooms, etc. and includes all ancillary facilities normally required. An existing three-level underground car park is used. The construction uses concrete, brickwork, Steel and glass, and the effect is clear and diaphanous with a beautiful aspect highly functional at the same time. Debe su nombre a estar situado en el emplazamiento de una antigua edificación del Ejército de Salvación, en Edmonton, provincia de Alberta. Se compone de tres teatros, de 700, 300 y 250 butacas respectivamente, además de salas de reuniones, tiendas, restaurante, salas de ensayos, etc. incluyéndose en el complejo todos los servicios auxiliares de este tipo de instalaciones. Se utiliza un aparcamiento subterráneo, existente, de tres plantas. La construcción es a base de hormigón, ladrillo, acero y cristal, habiéndose logrado un complejo transparente, de grata fisonomía y gran funcionalidad.
Effects of Spatial Pattern Scale of Brain Activity on the Sensitivity of DOT, fMRI, EEG and MEG
Katherine L. Perdue, Solomon Gilbert Diamond
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083299
Abstract: The objective of this work is to quantify how patterns of cortical activity at different spatial scales are measured by noninvasive functional neuroimaging sensors. We simulated cortical activation patterns at nine different spatial scales in a realistic head model and propagated this activity to magnetoencephalography (MEG), electroencephalography (EEG), diffuse optical tomography (DOT), and functional magnetic resonance imaging (fMRI) sensors in arrangements that are typically used in functional neuroimaging studies. We estimated contrast transfer functions (CTF), correlation distances in sensor space, and the minimum resolvable spatial scale of cortical activity for each modality. We found that CTF decreases as the spatial extent of cortical activity decreases, and that correlations between nearby sensors depend on the spatial extent of cortical activity. For cortical activity on the intermediate spatial scale of 6.7 cm2, the correlation distances (r>0.5) were 1.0 cm for fMRI, 2.0 cm for DOT, 12.8 for EEG, 9.5 cm for MEG magnetometers and 9.7 cm for MEG gradiometers. The resolvable spatial pattern scale was found to be 1.43 cm2 for MEG magnetometers, 0.88 cm2 for MEG gradiometers, 376 cm2 for EEG, 0.75 cm2 for DOT, and 0.072 cm2 for fMRI. These findings show that sensitivity to cortical activity varies substantially as a function of spatial scale within and between the different imaging modalities. This information should be taken into account when interpreting neuroimaging data and when choosing the number of nodes for network analyses in sensor space.
Late-time near-infrared observations of SN 2005df
Tiara Diamond,Peter Hoeflich,Christopher L. Gerardy
Physics , 2014, DOI: 10.1088/0004-637X/806/1/107
Abstract: We present late-time ($200-400$ days) near-infrared spectral evolution for the Type Ia supernova SN 2005df. The spectra show numerous strong emission features of [CoII], [CoIII], and [FeII] throughout the $0.8-1.8$\mu m region. As the spectrum ages, the cobalt features fade as would be expected from the decay of $^{56}$Co to $^{56}$Fe. We show that the strong and isolated [FeII] emission line at $1.644$\mu m provides a unique tool to analyze near-infrared spectra of Type Ia supernovae. Normalization of spectra to this line allows separation of features produced by stable versus unstable isotopes of iron group elements. We develop a new method of determining the initial central density, $\rho_c$, and the magnetic field, $B$, of the white dwarf using the width of the $1.644$\mu m line. The line width is sensitive because of electron capture in the early stages of burning, which increases as a function of density. The sensitivity of the line width to $B$ increase with time and the effects of the magnetic field shift towards later times with decreasing $\rho_c$. The initial central density for SN 2005df is measured as $\rho_c=0.9(\pm0.2)$ (in $10^9$g/cm$^3$), which corresponds to a white dwarf close to the Chandrasekhar mass ($\rm M_{Ch}$) with $\rm M_{WD}=1.313(\pm0.034)$M$_{\odot}$ and systematic error less than $0.04$M$_{\odot}$. Within $\rm M_{Ch}$ explosions, however, the central density found for SN 2005df is very low for a H-accretor, possibly suggesting a helium star companion or a tidally-disrupted white dwarf companion. As an alternative, we suggest mixing of the central region. We find some support for high initial magnetic fields of strength $10^6$G for SN 2005df, however, $0$G cannot be ruled out because of noise in the spectra combined with low $\rho_c$.
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