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Search Results: 1 - 10 of 227443 matches for " Thomas N. Denny "
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Caloric restriction in C57BL/6J mice mimics therapeutic fasting in humans
Lisa B Mahoney, Christine A Denny, Thomas N Seyfried
Lipids in Health and Disease , 2006, DOI: 10.1186/1476-511x-5-13
Abstract: Three groups of individually housed adult female C57BL/6J (B6) mice (n = 4/group) were fed a standard rodent chow diet either: (1) unrestricted (UR); (2) restricted for three weeks to reduce body weight by approximately 15–20% (R); or (3) restricted for three weeks and then re-fed unrestricted (ad libitum) for an additional three weeks (R-RF). Body weight and food intake were measured throughout the study, while plasma lipids and levels of glucose and ketone bodies (β-hydroxybutyrate) were measured at the termination of the study. Plasma glucose, phosphatidylcholine, cholesterol, and triglycerides were significantly lower in the R mice than in the UR mice. In contrast, plasma fatty acids and β-hydroxybutyrate were significantly higher in the R mice than in the UR mice. CR had no effect on plasma phosphatidylinositol levels. While body weight and plasma lipids of the R-RF mice returned to unrestricted levels upon re-feeding, food intake and glucose levels remained significantly lower than those prior to the initiation of CR.CR establishes a new homeostatic state in B6 mice that persists for at least three weeks following ad libitum re-feeding. Moreover, the plasma biomarker changes observed in B6 mice during CR mimic those reported in humans on very low calorie diets or during therapeutic fasting.Caloric restriction (CR) has long been recognized as a natural therapy that improves health and extends longevity in humans and rodents [1-7]. CR diminishes inflammation and oxidative stress that occurs from aging by decreasing the production of reactive oxygen species [1,8,9]. In rodents and primates, CR lowers plasma insulin, cholesterol, triglycerides, and insulin-like growth factor (IGF-1) levels, while elevating plasma high-density lipoprotein (HDL) levels [10-14]. These changes in plasma metabolites reduce risk for atherosclerosis, diabetes, and obesity [15]. Additional health benefits of CR likely result from reduced glucose levels and elevated ketone bodies (β-hydrox
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L. Heinzen,Dongliang Ge,Kenneth D. Cronin,Jessica M. Maia,Kevin V. Shianna,Willow N. Gabriel,Kathleen A. Welsh-Bohmer,Christine M. Hulette,Thomas N. Denny,David B. Goldstein
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
Nuevas evidencias de la relación antigénica entre los virus de la neuropatía epidémica y el sistema nervioso humano: Estudio de la respuesta inmune celular en pacientes con neuropatía epidémica y controles. Revisión del tema
Pedro,Más Lago; Ana Beatriz,Pérez; Luis,Sarmiento Pérez; Marité,Bello Corredor; Ivonne,ávalos Redón; Sonia,Resik Aguirre; Thomas,Denny; Gissel,García; María Guadalupe,Guzmán Tirado;
Revista Cubana de Medicina Tropical , 1998,
Abstract: a series of experiments was made at the virology department of the "pedro kourí" institute of tropical medicine aimed at obtaining new evidences on the possible antigenic relations existing between the viruses isolated from patients with epidemic neuropathy and the structures of the human nervous system. according to the results it may be finally inferred that the persistance and/or autoimmunity may be considered as mechanisms through which the studied viruses participate in the etiopathogeny of the epidemic neuropathy in cuba. for future experiments it is very important to identify the possible viral epitopes involved in the mollecular mimicry that are responsible for the probable autoimmune mechanisms or for the viral persistance.
Tissue-Specific Genetic Control of Splicing: Implications for the Study of Complex Traits
Erin L Heinzen equal contributor,Dongliang Ge equal contributor,Kenneth D Cronin,Jessica M Maia,Kevin V Shianna,Willow N Gabriel,Kathleen A Welsh-Bohmer,Christine M Hulette,Thomas N Denny,David B Goldstein
PLOS Biology , 2008, DOI: 10.1371/journal.pbio.1000001
Abstract: Numerous genome-wide screens for polymorphisms that influence gene expression have provided key insights into the genetic control of transcription. Despite this work, the relevance of specific polymorphisms to in vivo expression and splicing remains unclear. We carried out the first genome-wide screen, to our knowledge, for SNPs that associate with alternative splicing and gene expression in human primary cells, evaluating 93 autopsy-collected cortical brain tissue samples with no defined neuropsychiatric condition and 80 peripheral blood mononucleated cell samples collected from living healthy donors. We identified 23 high confidence associations with total expression and 80 with alternative splicing as reflected by expression levels of specific exons. Fewer than 50% of the implicated SNPs however show effects in both tissue types, reflecting strong evidence for distinct genetic control of splicing and expression in the two tissue types. The data generated here also suggest the possibility that splicing effects may be responsible for up to 13 out of 84 reported genome-wide significant associations with human traits. These results emphasize the importance of establishing a database of polymorphisms affecting splicing and expression in primary tissue types and suggest that splicing effects may be of more phenotypic significance than overall gene expression changes.
The Magnitude and Kinetics of the Mucosal HIV-Specific CD8+ T Lymphocyte Response and Virus RNA Load in Breast Milk
Tatenda Mahlokozera, Helen H. Kang, Nilu Goonetilleke, Andrea R. Stacey, Rachel V. Lovingood, Thomas N. Denny, Linda Kalilani, James E. G. Bunn, Steve R. Meshnick, Persephone Borrow, Norman L. Letvin, Sallie R. Permar, the Center for HIV/AIDS Vaccine Immunology
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0023735
Abstract: Background The risk of postnatal HIV transmission is associated with the magnitude of the milk virus load. While HIV-specific cellular immune responses control systemic virus load and are detectable in milk, the contribution of these responses to the control of virus load in milk is unknown. Methods We assessed the magnitude of the immunodominant GagRY11 and subdominant EnvKY9-specific CD8+ T lymphocyte response in blood and milk of 10 A*3002+, HIV-infected Malawian women throughout the period of lactation and correlated this response to milk virus RNA load and markers of breast inflammation. Results The magnitude and kinetics of the HIV-specific CD8+ T lymphocyte responses were discordant in blood and milk of the right and left breast, indicating independent regulation of these responses in each breast. However, there was no correlation between the magnitude of the HIV-specific CD8+ T lymphocyte response and the milk virus RNA load. Further, there was no correlation between the magnitude of this response and markers of breast inflammation. Conclusions The magnitude of the HIV-specific CD8+ T lymphocyte response in milk does not appear to be solely determined by the milk virus RNA load and is likely only one of the factors contributing to maintenance of low virus load in milk.
Computational Phenotype Discovery Using Unsupervised Feature Learning over Noisy, Sparse, and Irregular Clinical Data
Thomas A. Lasko, Joshua C. Denny, Mia A. Levy
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0066341
Abstract: Inferring precise phenotypic patterns from population-scale clinical data is a core computational task in the development of precision, personalized medicine. The traditional approach uses supervised learning, in which an expert designates which patterns to look for (by specifying the learning task and the class labels), and where to look for them (by specifying the input variables). While appropriate for individual tasks, this approach scales poorly and misses the patterns that we don’t think to look for. Unsupervised feature learning overcomes these limitations by identifying patterns (or features) that collectively form a compact and expressive representation of the source data, with no need for expert input or labeled examples. Its rising popularity is driven by new deep learning methods, which have produced high-profile successes on difficult standardized problems of object recognition in images. Here we introduce its use for phenotype discovery in clinical data. This use is challenging because the largest source of clinical data – Electronic Medical Records – typically contains noisy, sparse, and irregularly timed observations, rendering them poor substrates for deep learning methods. Our approach couples dirty clinical data to deep learning architecture via longitudinal probability densities inferred using Gaussian process regression. From episodic, longitudinal sequences of serum uric acid measurements in 4368 individuals we produced continuous phenotypic features that suggest multiple population subtypes, and that accurately distinguished (0.97 AUC) the uric-acid signatures of gout vs. acute leukemia despite not being optimized for the task. The unsupervised features were as accurate as gold-standard features engineered by an expert with complete knowledge of the domain, the classification task, and the class labels. Our findings demonstrate the potential for achieving computational phenotype discovery at population scale. We expect such data-driven phenotypes to expose unknown disease variants and subtypes and to provide rich targets for genetic association studies.
Elucidation of Hepatitis C Virus Transmission and Early Diversification by Single Genome Sequencing
Hui Li,Mark B. Stoddard,Shuyi Wang,Lily M. Blair,Elena E. Giorgi,Erica H. Parrish,Gerald H. Learn,Peter Hraber,Paul A. Goepfert,Michael S. Saag,Thomas N. Denny,Barton F. Haynes,Beatrice H. Hahn,Ruy M. Ribeiro,Alan S. Perelson,Bette T. Korber,Tanmoy Bhattacharya,George M. Shaw
PLOS Pathogens , 2012, DOI: 10.1371/journal.ppat.1002880
Abstract: A precise molecular identification of transmitted hepatitis C virus (HCV) genomes could illuminate key aspects of transmission biology, immunopathogenesis and natural history. We used single genome sequencing of 2,922 half or quarter genomes from plasma viral RNA to identify transmitted/founder (T/F) viruses in 17 subjects with acute community-acquired HCV infection. Sequences from 13 of 17 acute subjects, but none of 14 chronic controls, exhibited one or more discrete low diversity viral lineages. Sequences within each lineage generally revealed a star-like phylogeny of mutations that coalesced to unambiguous T/F viral genomes. Numbers of transmitted viruses leading to productive clinical infection were estimated to range from 1 to 37 or more (median = 4). Four acutely infected subjects showed a distinctly different pattern of virus diversity that deviated from a star-like phylogeny. In these cases, empirical analysis and mathematical modeling suggested high multiplicity virus transmission from individuals who themselves were acutely infected or had experienced a virus population bottleneck due to antiviral drug therapy. These results provide new quantitative and qualitative insights into HCV transmission, revealing for the first time virus-host interactions that successful vaccines or treatment interventions will need to overcome. Our findings further suggest a novel experimental strategy for identifying full-length T/F genomes for proteome-wide analyses of HCV biology and adaptation to antiviral drug or immune pressures.
Carcinogénesis gástrica
Otero Regino,William; Gómez,Martín A; Castro,Denny;
Revista Colombiana de Gastroenterologia , 2009,
Abstract: gastric cancer is second among cancers as a cause of death. more than 90% of all gastric cancers are adenocarcinomas whose principal cause is helicobacter pylori. although h. pylori is a necessary condition, it is not a sufficient condition since only 1-2% of those infected develop gastric cancer. there are multiple factors besides h. pylori infection involved in the etiology of this cancer. they include genetic factors related to the individual and environmental factors. although the ways in which h. pylori participates in this carcinogenesis are not completely clear, two different mechanisms are involved. h. pylori infection induces persistent inflammation accompanied by hyperproliferation of cells, and it causes damage to dna from free radicals in which progenitor cells from the bone marrow participate. these cells could be the "stem cells" of gastric cancer. the second path involves the direct action of proteins from h. pylori on gastric cells. among the genetic factors involved there is evidence that il-1b, tnf, il-8, and inf gama e il-10 polymorphisms, among others, induce b inflammatory responses which are associated with higher risks of gastric cancer.
Carcinogénesis gástrica Gastric carcinogenesis
William Otero Regino,Martín A Gómez,Denny Castro
Revista Colombiana de Gastroenterologia , 2009,
Abstract: El cáncer gástrico (CG) es la segunda causa de muerte por cáncer. Más del 90% de los CG son adenocarcinomas y el principal agente etiológico es H. pylori y aunque este es necesario, no es suficiente ya que solo 1-2% de los infectados desarrolla CG. Su origen es multifactorial, e involucra factores genéticos del individuo, factores medioambientales y la infección por H. pylori. Los mecanismos por los cuales H. pylori participa en la carcinogénesis no son claros pero hay dos vías involucradas: mecanismos indirectos a través de la inflamación persistente inducida por la infección, acompa ada de hiperproliferación celular, y da o del DNA por radicales libres, con participación adicional de células progenitoras de la médula ósea que sería el "stem cell" para el CG. La segunda vía involucra acciones directas de proteínas de H. pylori sobre las células gástricas. Entre los factores genéticos del huésped hay evidencia de que polimorfismos genéticos de IL-1B, TNF, IL-8, INF gama e IL-10 entre otros, inducen una fuerte respuesta inflamatoria que se asocia con mayor riesgo de CG. Gastric cancer is second among cancers as a cause of death. More than 90% of all gastric cancers are adenocarcinomas whose principal cause is Helicobacter pylori. Although H. Pylori is a necessary condition, it is not a sufficient condition since only 1-2% of those infected develop gastric cancer. There are multiple factors besides H. Pylori infection involved in the etiology of this cancer. They include genetic factors related to the individual and environmental factors. Although the ways in which H. Pylori participates in this carcinogenesis are not completely clear, two different mechanisms are involved. H. Pylori infection induces persistent inflammation accompanied by hyperproliferation of cells, and it causes damage to DNA from free radicals in which progenitor cells from the bone marrow participate. These cells could be the "stem cells" of gastric cancer. The second path involves the direct action of proteins from H. Pylori on gastric cells. Among the genetic factors involved there is evidence that IL-1B, TNF, IL-8, and INF gama e IL-10 polymorphisms, among others, induce B inflammatory responses which are associated with higher risks of gastric cancer.
Distribution of High-Risk Human Papillomavirus Genotypes among HIV-Negative Women with and without Cervical Intraepithelial Neoplasia in South Africa
Alicia C. McDonald, Lynette Denny, Chunhui Wang, Wei-Yann Tsai, Thomas C. Wright, Louise Kuhn
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044332
Abstract: Objective Large studies describing the profile of high-risk Human papillomavirus (hrHPV) genotypes among women in sub-Saharan Africa are lacking. Here we describe the prevalence and distribution of hrHPV genotypes among HIV-negative women in South Africa, with and without cervical intraepithelial neoplasia (CIN). Methods We report data on 8,050 HIV-negative women, aged 17–65 years, recruited into three sequential studies undertaken in Cape Town, South Africa. Women had no history of previous cervical cancer screening. Cervical samples were tested for hrHPV DNA using the Hybrid Capture 2 (HC2) assay and all positive samples were genotyped using a PCR-based assay (Line Blot). Women underwent colposcopy and biopsy/endocervical curettage to determine CIN status. The prevalence and distribution of specific hrHPV genotypes were examined by age and CIN status. Results Overall, 20.7% (95% CI, 19.9–21.6%) of women were hrHPV-positive by HC2, with women with CIN having the highest rates of positivity. Prevalence decreased with increasing age among women without CIN; but, a bimodal age curve was observed among women with CIN. HPV 16 and 35 were the most common hrHPV genotypes in all age and CIN groups. HPV 45 became more frequent among older women with CIN grade 2 or 3 (CIN2,3). Younger women (17–29 years) had more multiple hrHPV genotypes overall and in each cervical disease group than older women (40–65 years). Conclusion HPV 16, 35, and 45 were the leading contributors to CIN 2,3. The current HPV vaccines could significantly reduce HPV-related cervical disease; however, next generation vaccines that include HPV 35 and 45 would further reduce cervical disease in this population.
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