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Finnerty C.C.,Shriners Hospitals for Children | Finnerty C.C.,Institute for Translational science | Finnerty C.C.,University of Texas Medical Branch | Herndon D.N.,Shriners Hospitals for Children
Expert Opinion on Pharmacotherapy | Year: 2012

Introduction: The worldwide occurrence of burn injuries remains high despite efforts to reduce injury incidence through public awareness campaigns and improvements in living conditions. In 2004, almost 11 million people experienced burns severe enough to warrant medical treatment. Advances over the past several decades in aggressive resuscitation, nutrition, excision and grafting have reduced morbidity and mortality. Incorporation of pharmacotherapeutics into treatment regimens may further reduce complications of severe burn injuries. Areas covered: Severe burn injuries, as well as other forms of stress and trauma, trigger a hypermetabolic response that, if left untreated, impedes recovery. In the past two decades, use of anabolic agents, β-adrenergic receptor antagonists and anti-hyperglycemic agents has successfully counteracted post-burn morbidities including catabolism, the catecholamine-mediated response and insulin resistance. Here, the authors review the most up-to-date information on currently used pharmacotherapies in the treatment of these sequelae of severe burns and the insights that have expanded the understanding of the pathophysiology of severe burns. Expert opinion: Existing drugs offer promising advances in the care of burn injuries. Continued gains in the understanding of the molecular mechanisms driving the hypermetabolic response will enable the application of additional existing drugs to be broadened to further attenuate the hypermetabolic response. © Informa UK, Ltd.

PubMed | Sealy Center for Molecular Medicine, Biomolecular Resource Facility, University of Pittsburgh, University of Texas Medical Branch and Institute for Translational science
Type: | Journal: Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology | Year: 2015

Dengue virus (DENV) infection is a significant risk to over a third of the human population that causes a wide spectrum of illness, ranging from sub-clinical disease to intermediate syndrome of vascular complications called dengue fever complicated (DFC) and severe, dengue hemorrhagic fever (DHF). Methods for discriminating outcomes will impact clinical trials and understanding disease pathophysiology.We integrated a proteomics discovery pipeline with a heuristics approach to develop a molecular classifier to identify an intermediate phenotype of DENV-3 infectious outcome.121 differentially expressed proteins were identified in plasma from DHF vs dengue fever (DF), and informative candidates were selected using nonparametric statistics. These were combined with markers that measure complement activation, acute phase response, cellular leak, granulocyte differentiation and viral load. From this, we applied quantitative proteomics to select a 15 member panel of proteins that accurately predicted DF, DHF, and DFC using a random forest classifier. The classifier primarily relied on acute phase (A2M), complement (CFD), platelet counts and cellular leak (TPM4) to produce an 86% accuracy of prediction with an area under the receiver operating curve of >0.9 for DHF and DFC vs DF.Integrating discovery and heuristic approaches to sample distinct pathophysiological processes is a powerful approach in infectious disease. Early detection of intermediate outcomes of DENV-3 will speed clinical trials evaluating vaccines or drug interventions.

PubMed | Washington University in St. Louis, Graduate School for Biomedical science, Institute for Translational science, University of Texas Medical Branch and 4 more.
Type: Journal Article | Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology | Year: 2016

Recent data shows that fibroblast growth factor 14 (FGF14) binds to and controls the function of the voltage-gated sodium (Nav) channel with phenotypic outcomes on neuronal excitability. Mutations in the FGF14 gene in humans have been associated with brain disorders that are partially recapitulated in Fgf14(-/-) mice. Thus, signaling pathways that modulate the FGF14:Nav channel interaction may be important therapeutic targets. Bioluminescence-based screening of small molecule modulators of the FGF14:Nav1.6 complex identified 4,5,6,7 -: tetrabromobenzotriazole (TBB), a potent casein kinase 2 (CK2) inhibitor, as a strong suppressor of FGF14:Nav1.6 interaction. Inhibition of CK2 through TBB reduces the interaction of FGF14 with Nav1.6 and Nav1.2 channels. Mass spectrometry confirmed direct phosphorylation of FGF14 by CK2 at S228 and S230, and mutation to alanine at these sites modified FGF14 modulation of Nav1.6-mediated currents. In 1 d in vitro hippocampal neurons, TBB induced a reduction in FGF14 expression, a decrease in transient Na(+) current amplitude, and a hyperpolarizing shift in the voltage dependence of Nav channel steady-state inactivation. In mature neurons, TBB reduces the axodendritic polarity of FGF14. In cornu ammonis area 1 hippocampal slices from wild-type mice, TBB impairs neuronal excitability by increasing action potential threshold and lowering firing frequency. Importantly, these changes in excitability are recapitulated in Fgf14(-/-) mice, and deletion of Fgf14 occludes TBB-dependent phenotypes observed in wild-type mice. These results suggest that a CK2-FGF14 axis may regulate Nav channels and neuronal excitability.-Hsu, W.-C. J., Scala, F., Nenov, M. N., Wildburger, N. C., Elferink, H., Singh, A. K., Chesson, C. B., Buzhdygan, T., Sohail, M., Shavkunov, A. S., Panova, N. I., Nilsson, C. L., Rudra, J. S., Lichti, C. F., Laezza, F. CK2 activity is required for the interaction of FGF14 with voltage-gated sodium channels and neuronal excitability.

PubMed | CONICET, UTMB, University of Texas Medical Branch and Institute for Translational science
Type: | Journal: International journal of proteomics | Year: 2016

Nitric oxide (NO) protects the heart against ischemic injury; however, NO- and superoxide-dependent S-nitrosylation (S-NO) of cysteines can affect function of target proteins and play a role in disease outcome. We employed 2D-GE with thiol-labeling FL-maleimide dye and MALDI-TOF MS/MS to capture the quantitative changes in abundance and S-NO proteome of HF patients (versus healthy controls, n = 30/group). We identified 93 differentially abundant (59-increased/34-decreased) and 111 S-NO-modified (63-increased/48-decreased) protein spots, respectively, in HF subjects (versus controls, fold-change |1.5|, p 0.05). Ingenuity pathway analysis of proteome datasets suggested that the pathways involved in phagocytes migration, free radical production, and cell death were activated and fatty acid metabolism was decreased in HF subjects. Multivariate adaptive regression splines modeling of datasets identified a panel of proteins that will provide >90% prediction success in classifying HF subjects. Proteomic profiling identified ATP-synthase, thrombospondin-1 (THBS1), and vinculin (VCL) as top differentially abundant and S-NO-modified proteins, and these proteins were verified by Western blotting and ELISA in different set of HF subjects. We conclude that differential abundance and S-NO modification of proteins serve as a mechanism in regulating cell viability and free radical production, and THBS1 and VCL evaluation will potentially be useful in the prediction of heart failure.

Fang L.,University of Texas Medical Branch | Choudhary S.,University of Texas Medical Branch | Choudhary S.,301 University Blvd | Zhao Y.,University of Texas Medical Branch | And 7 more authors.
Nucleic Acids Research | Year: 2014

Ataxia-telangiectasia mutated (ATM), a member of the phosphatidylinositol 3 kinase-like kinase family, is a master regulator of the double strand DNA break-repair pathway after genotoxic stress. Here, we found ATM serves as an essential regulator of TNF-induced NF-kB pathway. We observed that TNF exposure of cells rapidly induced DNA double strand breaks and activates ATM. TNF-induced ROS promote nuclear IKKγ association with ubiquitin and its complex formation with ATM for nuclear export. Activated cytoplasmic ATM is involved in the selective recruitment of the E3-ubiquitin ligase β-TrCP to phospho-IκBα proteosomal degradation. Importantly, ATM binds and activates the catalytic subunit of protein kinase A (PKAc), ribosmal S6 kinase that controls RelA Ser 276 phosphorylation. In ATM knockdown cells, TNF-induced RelA Ser 276 phosphorylation is significantly decreased. We further observed decreased binding and recruitment of the transcriptional elongation complex containing cyclin dependent kinase-9 (CDK9; a kinase necessary for triggering transcriptional elongation) to promoters of NF-κB-dependent immediate-early cytokine genes, in ATM knockdown cells. We conclude that ATM is a nuclear damage-response signal modulator of TNF-induced NF-κB activation that plays a key scaffolding role in IκBα degradation and RelA Ser 276 phosphorylation. Our study provides a mechanistic explanation of decreased innate immune response associated with A-T mutation. © 2014 The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

PubMed | Brown University, MiraVista Laboratories, Institute for Translational science, University of Florida and 7 more.
Type: Journal Article | Journal: PloS one | Year: 2015

Invasive pulmonary aspergillosis (IPA) is an opportunistic fungal infection in patients undergoing chemotherapy for hematological malignancy, hematopoietic stem cell transplant, or other forms of immunosuppression. In this group, Aspergillus infections account for the majority of deaths due to mold pathogens. Although early detection is associated with improved outcomes, current diagnostic regimens lack sensitivity and specificity. Patients undergoing chemotherapy, stem cell transplantation and lung transplantation were enrolled in a multi-site prospective observational trial. Proven and probable IPA cases and matched controls were subjected to discovery proteomics analyses using a biofluid analysis platform, fractionating plasma into reproducible protein and peptide pools. From 556 spots identified by 2D gel electrophoresis, 66 differentially expressed post-translationally modified plasma proteins were identified in the leukemic subgroup only. This protein group was rich in complement components, acute-phase reactants and coagulation factors. Low molecular weight peptides corresponding to abundant plasma proteins were identified. A candidate marker panel of host response (9 plasma proteins, 4 peptides), fungal polysaccharides (galactomannan), and cell wall components (-D glucan) were selected by statistical filtering for patients with leukemia as a primary underlying diagnosis. Quantitative measurements were developed to qualify the differential expression of the candidate host response proteins using selective reaction monitoring mass spectrometry assays, and then applied to a separate cohort of 57 patients with leukemia. In this verification cohort, a machine learning ensemble-based algorithm, generalized pathseeker (GPS) produced a greater case classification accuracy than galactomannan (GM) or host proteins alone. In conclusion, Integration of host response proteins with GM improves the diagnostic detection of probable IPA in patients undergoing treatment for hematologic malignancy. Upon further validation, early detection of probable IPA in leukemia treatment will provide opportunities for earlier interventions and interventional clinical trials.

Hernandez C.M.,University of Texas Medical Branch | Cortez I.,University of Texas Medical Branch | Gu Z.,U.S. National Institutes of Health | Colon-Saez J.O.,U.S. National Institutes of Health | And 6 more authors.
Journal of Physiology | Year: 2014

There is much interest in α7 nicotinic acetylcholine receptors (nAChRs) in CNS function since they are found throughout peripheral tissues as well as being highly expressed in brain regions implicated in attention, learning and memory. As such, the role of these receptors in many aspects of CNS function and disease is being actively investigated. To date, only one null mouse model (A7KO) is available which is non-conditional and constitutive. Since α7 nAChRs are present on neurons and glia (including astrocytes), as well as being developmentally regulated, there is an unmet need for the technical capability to control α7 nAChR gene expression. Therefore we have generated mice in which the fourth exon of the α7 nAChR gene (Chrna7) is flanked by loxP sites (B6-Chrna7LBDEx4007Ehs) which we refer to as floxed α7 nAChR conditional knockout or α7nAChRflox. We validated the chosen approach by mating α7nAChRflox with mice expressing Cre recombinase driven by the glial acidic fibrillary protein (GFAP)-Cre promoter (GFAP-A7KO) to test whether α7nAChRflox, GFAP-A7KO and appropriate littermate controls performed equally in our standard Rodent In Vivo Assessment Core battery to assess general health, locomotion, emotional and cognitive behaviours. Neither α7nAChRflox nor GFAP-A7KO exhibited significant differences from littermate controls in any of the baseline behavioural assessments we conducted, similar to the 'first generation' non-conditional A7KO mice. We also determined that α7 nAChR binding sites were absent on GFAP-positive astrocytes in hippocampal slices obtained from GFAP-A7KO offspring from α7nAChRflox and GFAP-Cre crosses. Finally, we validated that Cre recombinase (Cre)-mediated excision led to functional, cell- and tissue-specific loss of α7 nAChRs by demonstrating that choline-induced α7 nAChR currents were present in Cre-negative, but not synapsin promoter-driven Cre-positive, CA1 pyramidal neurons. Additionally, electrophysiological characterization of α7 nAChR-mediated current traces was similar in terms of amplitude and time constants of decay (during desensitization) for the α7nAChRflox and wild-type (WT) mice. Thus, we have in vivo and in vitro evidence that the Chrna7 exon 4 targeting strategy does not alter behavioural, cognitive, or electrophysiological properties compared to WT and that Cre-mediated excision is an effective approach to delete α7 nAChR expression in a cell-specific manner. © 2014 The Physiological Society.

Spratt H.,University of Texas Medical Branch | Spratt H.,Sealy Center for Molecular Medicine | Spratt H.,Institute for Translational science | Ju H.,University of Texas Medical Branch | And 3 more authors.
Methods | Year: 2013

Biological experiments in the post-genome era can generate a staggering amount of complex data that challenges experimentalists to extract meaningful information. Increasingly, the success of an appropriately controlled experiment relies on a robust data analysis pipeline. In this paper, we present a structured approach to the analysis of multidimensional data that relies on a close, two-way communication between the bioinformatician and experimentalist. A sequential approach employing data exploration (visualization, graphical and analytical study), pre-processing, feature reduction and supervised classification using machine learning is presented. This standardized approach is illustrated by an example from a proteomic data analysis that has been used to predict the risk of infectious disease outcome. Strategies for model selection and post hoc model diagnostics are presented and applied to the case illustration. We discuss some of the practical lessons we have learned applying supervised classification to multidimensional data sets, one of which is the importance of feature reduction in achieving optimal modeling performance. © 2013 Elsevier Inc.

Ju H.,University of Texas Medical Branch | Ju H.,Institute for Translational science | Brasier A.R.,Sealy Center for Molecular Medicine | Brasier A.R.,Institute for Translational science
BMC Research Notes | Year: 2013

Background: The choice of selection methods to identify important variables for binary classification modeling is critical to produce stable models that are interpretable, that generate accurate predictions and have minimum bias. This work is motivated by data on clinical and laboratory features of severe dengue infections (dengue hemorrhagic fever, DHF) obtained from 51 individuals enrolled in a prospective observational study of acute human dengue infections. Results: We carry out a comprehensive performance comparison using several classification models for DHF over the dengue data set. We compared variable selection results by Multivariate Adaptive Regression Splines, Learning Ensemble, Random Forest, Bayesian Moving Averaging, Stochastic Search Variable Selection, and Generalized Regularized Logistics Regression. Model averaging methods (bagging, boosting and ensemble learners) have higher accuracy, but the generalized regularized regression model has the highest predictive power because the linearity assumptions of candidate predictors are strongly satisfied via deviance chi-square testing procedures. Bootstrapping applications for evaluating predictive regression coefficients in regularized regression model are performed. Conclusions: Feature reduction methods introduce inherent biases and therefore are data-type dependent. We propose that these limitations can be overcome using an exhaustive approach for searching feature space. Using this approach, our results suggest that IL-10, platelet and lymphocyte counts are the major features for predicting dengue DHF on the basis of blood chemistries and cytokine measurements. © 2013 Ju and Brasier; licensee BioMed Central Ltd.

Caldwell B.J.,New York University | Caldwell B.J.,Institute for Translational science | Trew M.L.,University of Auckland | Pertsov A.M.,New York University
Circulation: Arrhythmia and Electrophysiology | Year: 2015

Background - The electric response of myocardial tissue to periodic field stimuli has attracted significant attention as the basis for low-energy antifibrillation pacing, potentially more effective than traditional single high-energy shocks. In conventional models, an electric field produces a highly nonuniform response of the myocardial wall, with discrete excitations, or hot spots (HS), occurring at cathodal tissue surfaces or large coronary vessels. We test this prediction using novel 3-dimensional tomographic optical imaging. Methods and Results - Experiments were performed in isolated coronary perfused pig ventricular wall preparations stained with near-infrared voltage-sensitive fluorescent dye DI-4-ANBDQBS. The 3-dimensional coordinates of HS were determined using alternating transillumination. To relate HS formation with myocardial structures, we used ultradeep confocal imaging (interrogation depths, >4 mm). The peak HS distribution is located deep inside the heart wall, and the depth is not significantly affected by field polarity. We did not observe the strong colocalization of HS with major coronary vessels anticipated from theory. Yet, we observed considerable lateral displacement of HS with field polarity reversal. Models that de-emphasized lateral intracellular coupling and accounted for resistive heterogeneity in the extracellular space showed similar HS distributions to the experimental observations. Conclusions - The HS distributions within the myocardial wall and the significant lateral displacements with field polarity reversal are inconsistent with standard theories of defibrillation. Extended theories based on enhanced descriptions of cellular scale electric mechanisms may be necessary. The considerable lateral displacement of HS with field polarity reversal supports the hypothesis of biphasic stimuli in low-energy antifibrillation pacing being advantageous. © 2015 American Heart Association, Inc.

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