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Search Results: 1 - 10 of 488257 matches for " Thomas A. Christensen "
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Bayesian inference of protein structure from chemical shift data
Lars A Bratholm,Anders Steen Christensen,Thomas Hamelryck,Jan H Jensen
PeerJ , 2015, DOI: 10.7287/peerj.preprints.692v1
Abstract: Protein chemical shifts are routinely used to augment molecular mechanics force fields in protein structure simulations, with weights of the chemical shift restraints determined empirically. These weights, however, might not be an optimal descriptor of a given protein structure and predictive model, and a bias is introduced which might result in incorrect structures. In the inferential structure determination framework, both the unknown structure and the disagreement between experimental and back-calculated data are formulated as a joint probability distribution, thus utilizing the full information content of the data. Here, we present the formulation of such a probability distribution where the error in chemical shift prediction is described by either a Gaussian or Cauchy distribution. The methodology is demonstrated and compared to a set of empirically weighted potentials through Markov chain Monte Carlo simulations of three small proteins (ENHD, Protein G and the SMN Tudor Domain) using the PROFASI force field and the chemical shift predictor CamShift. Using a clustering-criterion for identifying the best structure, together with the addition of a solvent exposure scoring term, the simulations suggests that sampling both the structure and the uncertainties in chemical shift prediction leads more accurate structures compared to conventional methods using empirical determined weights. The Cauchy distribution, using either sampled uncertainties or predetermined weights, did, however, result in overall better convergence to the native fold, suggesting that both types of distribution might be useful in different aspects of the protein structure prediction.
A FRET-Based High Throughput Screening Assay to Identify Inhibitors of Anthrax Protective Antigen Binding to Capillary Morphogenesis Gene 2 Protein
Michael S. Rogers, Lorna M. Cryan, Kaiane A. Habeshian, Lauren Bazinet, Thomas P. Caldwell, P. Christine Ackroyd, Kenneth A. Christensen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039911
Abstract: Anti-angiogenic therapies are effective for the treatment of cancer, a variety of ocular diseases, and have potential benefits in cardiovascular disease, arthritis, and psoriasis. We have previously shown that anthrax protective antigen (PA), a non-pathogenic component of anthrax toxin, is an inhibitor of angiogenesis, apparently as a result of interaction with the cell surface receptors capillary morphogenesis gene 2 (CMG2) protein and tumor endothelial marker 8 (TEM8). Hence, molecules that bind the anthrax toxin receptors may be effective to slow or halt pathological vascular growth. Here we describe development and testing of an effective homogeneous steady-state fluorescence resonance energy transfer (FRET) high throughput screening assay designed to identify molecules that inhibit binding of PA to CMG2. Molecules identified in the screen can serve as potential lead compounds for the development of anti-angiogenic and anti-anthrax therapies. The assay to screen for inhibitors of this protein–protein interaction is sensitive and robust, with observed Z' values as high as 0.92. Preliminary screens conducted with a library of known bioactive compounds identified tannic acid and cisplatin as inhibitors of the PA-CMG2 interaction. We have confirmed that tannic acid both binds CMG2 and has anti-endothelial properties. In contrast, cisplatin appears to inhibit PA-CMG2 interaction by binding both PA and CMG2, and observed cisplatin anti-angiogenic effects are not mediated by interaction with CMG2. This work represents the first reported high throughput screening assay targeting CMG2 to identify possible inhibitors of both angiogenesis and anthrax intoxication.
Modulating the Focus of Attention for Spoken Words at Encoding Affects Frontoparietal Activation for Incidental Verbal Memory
Thomas A. Christensen,Kyle R. Almryde,Lesley J. Fidler,Julie L. Lockwood,Sharon M. Antonucci,Elena Plante
International Journal of Biomedical Imaging , 2012, DOI: 10.1155/2012/579786
Abstract: Attention is crucial for encoding information into memory, and current dual-process models seek to explain the roles of attention in both recollection memory and incidental-perceptual memory processes. The present study combined an incidental memory paradigm with event-related functional MRI to examine the effect of attention at encoding on the subsequent neural activation associated with unintended perceptual memory for spoken words. At encoding, we systematically varied attention levels as listeners heard a list of single English nouns. We then presented these words again in the context of a recognition task and assessed the effect of modulating attention at encoding on the BOLD responses to words that were either attended strongly, weakly, or not heard previously. MRI revealed activity in right-lateralized inferior parietal and prefrontal regions, and positive BOLD signals varied with the relative level of attention present at encoding. Temporal analysis of hemodynamic responses further showed that the time course of BOLD activity was modulated differentially by unintentionally encoded words compared to novel items. Our findings largely support current models of memory consolidation and retrieval, but they also provide fresh evidence for hemispheric differences and functional subdivisions in right frontoparietal attention networks that help shape auditory episodic recall. 1. Introduction Attention is known to alter neural processing at multiple levels of both the peripheral and central nervous systems, and both auditory and visual attention have been conceptualized as operating in both “top-down” and “bottom-up” modes [1–7]. Top-down mechanisms reflect goal-based control in order to direct attention to particular targets or to sustain attention over time. In contrast, bottom-up mechanisms have traditionally been defined by the phenomenon of reflexive attentional orienting, as when attention is drawn without intent by highly salient sensory stimuli such as a sudden loud noise or flash of light. Recently, however, some investigators have more broadly considered bottom-up effects as relevant for any incoming stimuli, with the relative saliency of the stimulus influencing whether it is ultimately encoded into memory [8]. Two recent theoretical models address the question of what roles stimulus saliency might play in first successfully encoding information into memory and then later retrieving it. As discussed below, the “Embedded Processes” model and the “Attention-to-Memory” model, while similar, also highlight the potentially divergent roles that
Oxidized Calmodulin Kinase II Regulates Conduction Following Myocardial Infarction: A Computational Analysis
Matthew D. Christensen,Wen Dun,Penelope A. Boyden,Mark E. Anderson,Peter J. Mohler,Thomas J. Hund
PLOS Computational Biology , 2009, DOI: 10.1371/journal.pcbi.1000583
Abstract: Calmodulin kinase II (CaMKII) mediates critical signaling pathways responsible for divergent functions in the heart including calcium cycling, hypertrophy and apoptosis. Dysfunction in the CaMKII signaling pathway occurs in heart disease and is associated with increased susceptibility to life-threatening arrhythmia. Furthermore, CaMKII inhibition prevents cardiac arrhythmia and improves heart function following myocardial infarction. Recently, a novel mechanism for oxidative CaMKII activation was discovered in the heart. Here, we provide the first report of CaMKII oxidation state in a well-validated, large-animal model of heart disease. Specifically, we observe increased levels of oxidized CaMKII in the infarct border zone (BZ). These unexpected new data identify an alternative activation pathway for CaMKII in common cardiovascular disease. To study the role of oxidation-dependent CaMKII activation in creating a pro-arrhythmia substrate following myocardial infarction, we developed a new mathematical model of CaMKII activity including both oxidative and autophosphorylation activation pathways. Computer simulations using a multicellular mathematical model of the cardiac fiber demonstrate that enhanced CaMKII activity in the infarct BZ, due primarily to increased oxidation, is associated with reduced conduction velocity, increased effective refractory period, and increased susceptibility to formation of conduction block at the BZ margin, a prerequisite for reentry. Furthermore, our model predicts that CaMKII inhibition improves conduction and reduces refractoriness in the BZ, thereby reducing vulnerability to conduction block and reentry. These results identify a novel oxidation-dependent pathway for CaMKII activation in the infarct BZ that may be an effective therapeutic target for improving conduction and reducing heterogeneity in the infarcted heart.
Diabetics Have the Same Risk and Benefits Regarding Postoperative Amiodarone Prophylaxis for Atrial Fibrillation When Undergoing Surgery for Lung Cancer  [PDF]
Lars P. Riber, Thomas D. Christensen, Hans K. Pilegaard
Open Journal of Thoracic Surgery (OJTS) , 2013, DOI: 10.4236/ojts.2013.32012
Abstract:

Background: To evaluate if the risk for developing atrial fibrillation after lung surgery is higher for diabetics than non-diabetic patients and whether diabetic status prolongs the length of in-hospital stay. Objective: To compare the outcome of amiodarone prophylaxis in diabetics and non-diabetics. Design: Subgroup analysis within a randomized, controlled, double-blinded trial. Results: Development of atrial fibrillation was equally frequent among diabetics (18.2%) and non-diabetics (20.5%) (p = 1.00). Atrial fibrillation occurred in 7.1% of prophylactic diabetics and in 9.3% of prophylactic non-diabetics, while 37.5% non-prophylactic diabetics and 31.3% non-prophylactic non-diabetics experienced atrial fibrillation (p = 0.31). Prophylactic amiodarone was equally effective in diabetics as in non-diabetics with a relative risk of 3.5 (1.8 - 67.0) and the number need to treat of 4.4 (3.3 - 8.3) (p = 0.31). The length of in-hospital stay for diabetics was equal to non-diabetics with an average stay of 7.1 versus 8 days at Aarhus University Hospital (p =

The generation of chromosomal deletions to provide extensive coverage and subdivision of the Drosophila melanogaster genome
R Kimberley Cook, Stacey J Christensen, Jennifer A Deal, Rachel A Coburn, Megan E Deal, Jill M Gresens, Thomas C Kaufman, Kevin R Cook
Genome Biology , 2012, DOI: 10.1186/gb-2012-13-3-r21
Abstract: A large-scale resource development project at the Bloomington Drosophila Stock Center has improved the choice of deletions beyond that provided by previous projects. FLP-mediated recombination between FRT-bearing transposon insertions was used to generate deletions, because it is efficient and provides single-nucleotide resolution in planning deletion screens. The 793 deletions generated pushed coverage of the euchromatic genome to 98.4%. Gaps in coverage contain haplolethal and haplosterile genes, but the sizes of these gaps were minimized by flanking these genes as closely as possible with deletions. In improving coverage, a complete inventory of haplolethal and haplosterile genes was generated and extensive information on other haploinsufficient genes was compiled. To aid mapping experiments, a subset of deletions was organized into a Deficiency Kit to provide maximal coverage efficiently. To improve the resolution of deletion mapping, screens were planned to distribute deletion breakpoints evenly across the genome. The median chromosomal interval between breakpoints now contains only nine genes and 377 intervals contain only single genes.Drosophila melanogaster now has the most extensive genomic deletion coverage and breakpoint subdivision as well as the most comprehensive inventory of haploinsufficient genes of any multicellular organism. The improved selection of chromosomal deletion strains will be useful to nearly all Drosophila researchers.Chromosomal deletions are important to experimental genetic analysis in two fundamental ways. First, deletions fail to complement loss-of-function mutations in genes located in the chromosomal region of the deletion. This noncomplementation is the basis for using deletions to map mutations to specific chromosomal regions, to screen for new mutations in closely linked sets of genes and to assess the allelic strengths of new mutations. Second, heterozygous deletions can enhance or suppress mutant phenotypes. Reducing the co
A Growth Curve Model with Fractional Polynomials for Analysing Incomplete Time-Course Data in Microarray Gene Expression Studies
Qihua Tan,Mads Thomassen,Jacob v. B. Hjelmborg,Anders Clemmensen,Klaus Ejner Andersen,Thomas K. Petersen,Matthew McGue,Kaare Christensen,Torben A. Kruse
Advances in Bioinformatics , 2011, DOI: 10.1155/2011/261514
Abstract: Identifying the various gene expression response patterns is a challenging issue in expression microarray time-course experiments. Due to heterogeneity in the regulatory reaction among thousands of genes tested, it is impossible to manually characterize a parametric form for each of the time-course pattern in a gene by gene manner. We introduce a growth curve model with fractional polynomials to automatically capture the various time-dependent expression patterns and meanwhile efficiently handle missing values due to incomplete observations. For each gene, our procedure compares the performances among fractional polynomial models with power terms from a set of fixed values that offer a wide range of curve shapes and suggests a best fitting model. After a limited simulation study, the model has been applied to our human in vivo irritated epidermis data with missing observations to investigate time-dependent transcriptional responses to a chemical irritant. Our method was able to identify the various nonlinear time-course expression trajectories. The integration of growth curves with fractional polynomials provides a flexible way to model different time-course patterns together with model selection and significant gene identification strategies that can be applied in microarray-based time-course gene expression experiments with missing observations. 1. Introduction The time course experiment is an important experimental design that permeates throughout biomedical research. With the recent popularity of high throughput microarray-based gene expression analysis, the time-course design has been applied to explore global transcriptional responses to treatment or to biochemical stimulations during in vivo or in vitro experiments. Analysing the time-course microarray gene expression data is a new challenge in bioinformatics and biostatistics [1–6]. Different from ordinary time-course studies that focus on one or a limited number of outcome variables, the array-based time-course experiment measures expression levels for thousands of genes simultaneously [7]. This complicates the model fitting process because it is impossible to inspect the observed and the fitted time-course patterns for determining a proper parametric form for the model (e.g., the order of a power polynomial), for each of the thousands of genes measured on the arrays. Model selection can be tedious given the various response patterns for different genes which cannot be predefined. Besides the above characteristics in an array-based experiment, time-course gene expression data are also featured
Pneumococcal Serotypes and Mortality following Invasive Pneumococcal Disease: A Population-Based Cohort Study
Zitta B. Harboe ,Reimar W. Thomsen,Anders Riis,Palle Valentiner-Branth,Jens J?rgen Christensen,Lotte Lambertsen,Karen A. Krogfelt,Helle B. Konradsen,Thomas L. Benfield
PLOS Medicine , 2009, DOI: 10.1371/journal.pmed.1000081
Abstract: Background Pneumococcal disease is a leading cause of morbidity and mortality worldwide. The aim of this study was to investigate the association between specific pneumococcal serotypes and mortality from invasive pneumococcal disease (IPD). Methods and Findings In a nationwide population-based cohort study of IPD in Denmark during 1977–2007, 30-d mortality associated with pneumococcal serotypes was examined by multivariate logistic regression analysis after controlling for potential confounders. A total of 18,858 IPD patients were included. Overall 30-d mortality was 18%, and 3% in children younger than age 5 y. Age, male sex, meningitis, high comorbidity level, alcoholism, and early decade of diagnosis were significantly associated with mortality. Among individuals aged 5 y and older, serotypes 31, 11A, 35F, 17F, 3, 16F, 19F, 15B, and 10A were associated with highly increased mortality as compared with serotype 1 (all: adjusted odds ratio ≥3, p<0.001). In children younger than 5 y, associations between serotypes and mortality were different than in adults but statistical precision was limited because of low overall childhood-related mortality. Conclusions Specific pneumococcal serotypes strongly and independently affect IPD associated mortality.
Mosquito Transcriptome Profiles and Filarial Worm Susceptibility in Armigeres subalbatus
Matthew T. Aliota,Jeremy F. Fuchs,Thomas A. Rocheleau,Amanda K. Clark,Julián F. Hillyer,Cheng-Chen Chen,Bruce M. Christensen
PLOS Neglected Tropical Diseases , 2010, DOI: 10.1371/journal.pntd.0000666
Abstract: Background Armigeres subalbatus is a natural vector of the filarial worm Brugia pahangi, but it kills Brugia malayi microfilariae by melanotic encapsulation. Because B. malayi and B. pahangi are morphologically and biologically similar, comparing Ar. subalbatus-B. pahangi susceptibility and Ar. subalbatus-B. malayi refractoriness could provide significant insight into recognition mechanisms required to mount an effective anti-filarial worm immune response in the mosquito, as well as provide considerable detail into the molecular components involved in vector competence. Previously, we assessed the transcriptional response of Ar. subalbatus to B. malayi, and now we report transcriptome profiling studies of Ar. subalbatus in relation to filarial worm infection to provide information on the molecular components involved in B. pahangi susceptibility. Methodology/Principal Findings Utilizing microarrays, comparisons were made between mosquitoes exposed to B. pahangi, B. malayi, and uninfected bloodmeals. The time course chosen facilitated an examination of key events in the development of the parasite, beginning with the very start of filarial worm infection and spanning to well after parasites had developed to the infective stage in the mosquito. At 1, 3, 6, 12, 24 h post infection and 2–3, 5–6, 8–9, and 13–14 days post challenge there were 31, 75, 113, 76, 54, 5, 3, 13, and 2 detectable transcripts, respectively, with significant differences in transcript abundance (increase or decrease) as a result of parasite development. Conclusions/Significance Herein, we demonstrate that filarial worm susceptibility in a laboratory strain of the natural vector Ar. subalbatus involves many factors of both known and unknown function that most likely are associated with filarial worm penetration through the midgut, invasion into thoracic muscle cells, and maintenance of homeostasis in the hemolymph environment. The data show that there are distinct and separate transcriptional patterns associated with filarial worm susceptibility as compared to refractoriness, and that an infection response in Ar. subalbatus can differ significantly from that observed in Ae. aegypti, a common laboratory model.
Topographical Anatomical Neuropathic-Pain Guided (TANG) Mapping: A Tool Derived from a Patient Perspective to Facilitate the Transition from Spinal Cord Stimulator Trial to Potential Permanent Implantation  [PDF]
Nelson Tang, Bryt A. Christensen, Kayode A. Williams
Open Journal of Anesthesiology (OJAnes) , 2012, DOI: 10.4236/ojanes.2012.23022
Abstract: Introduction: Collecting a patient’s pain scores and the analgesic effect achieved during spinal cord stimulation (SCS) trials can be difficult, and no standard exists for doing so. We propose a topographical mapping tool that was derived from a patient’s perspective. Case: A 60-year-old man with postherpetic neuralgia (PHN) underwent a SCS trial after conservative treatment failed to relieve his pain. During the SCS trial, with the SCS off and on in five different settings, he recorded pain levels in each of the six different painful zones he identified. The data collected were transferred to a topographical and anatomical map, which helped the physicians to better understand the effects of the SCS at different settings. Ultimately, the data collected by the patient helped the physicians to implant a permanent SCS successfully. Conclusions: Patient pain diaries have been used in pain medicine for years. This particular patient’s collection of pain scores and SCS effects inspired the construction of a more standardized tool for collecting such data during SCS trials. We propose that use of our Topographical Anatomical Neuropathic-pain Guided (TANG) mapping tool will enable physicians to choose SCS lead positions more precisely than is currently possible.
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