39 results on '"Wood III, William"'
Search Results
2. Transcriptional changes in the rat brain induced by repetitive transcranial magnetic stimulation.
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Weiler, Marina, Stieger, Kevin C., Shroff, Kavisha, Klein, Jessie P., Wood III, William H., Yongqing Zhang, Chandrasekaran, Prabha, Lehrmann, Elin, Camandola, Simonetta, Long, Jeffrey M., Mattson, Mark P., Becker, Kevin G., and Rapp, Peter R.
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TRANSCRANIAL magnetic stimulation ,CENTRAL nervous system physiology ,GENE expression ,ION channels - Abstract
Introduction: Transcranial Magnetic Stimulation (TMS) is a noninvasive technique that uses pulsed magnetic fields to affect the physiology of the brain and central nervous system. Repetitive TMS (rTMS) has been used to study and treat several neurological conditions, but its complex molecular basis is largely unexplored. Methods: Utilizing three experimental rat models (in vitro, ex vivo, and in vivo) and employing genome-wide microarray analysis, our study reveals the extensive impact of rTMS treatment on gene expression patterns. Results: These effects are observed across various stimulation protocols, in diverse tissues, and are influenced by time and age. Notably, rTMS-induced alterations in gene expression span a wide range of biological pathways, such as glutamatergic, GABAergic, and anti-inflammatory pathways, ion channels, myelination, mitochondrial energetics, multiple neuron-and synapse-specific genes. Discussion: This comprehensive transcriptional analysis induced by rTMS stimulation serves as a foundational characterization for subsequent experimental investigations and the exploration of potential clinical applications. [ABSTRACT FROM AUTHOR]
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- 2023
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3. Molecular characterization of the transition to mid-life in Caenorhabditis elegans
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Eckley, D. Mark, Rahimi, Salim, Mantilla, Sandra, Orlov, Nikita V., Coletta, Christopher E., Wilson, Mark A., Iser, Wendy B., Delaney, John D., Zhang, Yongqing, Wood, III, William, Becker, Kevin G., Wolkow, Catherine A., and Goldberg, Ilya G.
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- 2013
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4. Design information retrieval: a thesauri-based approach for reuse of informal design information
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Yang, Maria C., Wood, III, William H., and Cutkosky, Mark R.
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- 2005
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5. Gene expression and pathway analysis of ovarian cancer cells selected for resistance to cisplatin, paclitaxel, or doxorubicin
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Sherman-Baust Cheryl A, Becker Kevin G, Wood III William H, Zhang Yongqing, and Morin Patrice J
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Gynecology and obstetrics ,RG1-991 - Abstract
Abstract Background Resistance to current chemotherapeutic agents is a major cause of therapy failure in ovarian cancer patients, but the exact mechanisms leading to the development of drug resistance remain unclear. Methods To better understand mechanisms of drug resistance, and possibly identify novel targets for therapy, we generated a series of drug resistant ovarian cancer cell lines through repeated exposure to three chemotherapeutic drugs (cisplatin, doxorubicin, or paclitaxel), and identified changes in gene expression patterns using Illumina whole-genome expression microarrays. Validation of selected genes was performed by RT-PCR and immunoblotting. Pathway enrichment analysis using the KEGG, GO, and Reactome databases was performed to identify pathways that may be important in each drug resistance phenotype. Results A total of 845 genes (p < 0.01) were found altered in at least one drug resistance phenotype when compared to the parental, drug sensitive cell line. Focusing on each resistance phenotype individually, we identified 460, 366, and 337 genes significantly altered in cells resistant to cisplatin, doxorubicin, and paclitaxel, respectively. Of the 845 genes found altered, only 62 genes were simultaneously altered in all three resistance phenotypes. Using pathway analysis, we found many pathways enriched for each resistance phenotype, but some dominant pathways emerged. The dominant pathways included signaling from the cell surface and cell movement for cisplatin resistance, proteasome regulation and steroid biosynthesis for doxorubicin resistance, and control of translation and oxidative stress for paclitaxel resistance. Conclusions Ovarian cancer cells develop drug resistance through different pathways depending on the drug used in the generation of chemoresistance. A better understanding of these mechanisms may lead to the development of novel strategies to circumvent the problem of drug resistance.
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- 2011
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6. The association between poverty and gene expression within peripheral blood mononuclear cells in a diverse Baltimore City cohort.
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Arnold, Nicole S., Noren Hooten, Nicole, Zhang, Yongqing, Lehrmann, Elin, Wood III, William, Camejo Nunez, Wendy, Thorpe, Roland J., Evans, Michele K., and Dluzen, Douglas F.
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BLOOD cells ,GENE expression ,POVERTY ,TOLL-like receptors ,GENE ontology ,ENDOCYTOSIS - Abstract
Socioeconomic status (SES), living in poverty, and other social determinants of health contribute to health disparities in the United States. African American (AA) men living below poverty in Baltimore City have a higher incidence of mortality when compared to either white males or AA females living below poverty. Previous studies in our laboratory and elsewhere suggest that environmental conditions are associated with differential gene expression (DGE) patterns in peripheral blood mononuclear cells (PBMCs). DGE have also been associated with hypertension and cardiovascular disease (CVD) and correlate with race and sex. However, no studies have investigated how poverty status associates with DGE between male and female AAs and whites living in Baltimore City. We examined DGE in 52 AA and white participants of the Healthy Aging in Neighborhoods of Diversity across the Life Span (HANDLS) cohort, who were living above or below 125% of the 2004 federal poverty line at time of sample collection. We performed a microarray to assess DGE patterns in PBMCs from these participants. AA males and females living in poverty had the most genes differentially-expressed compared with above poverty controls. Gene ontology (GO) analysis identified unique and overlapping pathways related to the endosome, single-stranded RNA binding, long-chain fatty-acyl-CoA biosynthesis, toll-like receptor signaling, and others within AA males and females living in poverty and compared with their above poverty controls. We performed RT-qPCR to validate top differentially-expressed genes in AA males. We found that KLF6, DUSP2, RBM34, and CD19 are expressed at significantly lower levels in AA males in poverty and KCTD12 is higher compared to above poverty controls. This study serves as an additional link to better understand the gene expression response in peripheral blood mononuclear cells in those living in poverty. [ABSTRACT FROM AUTHOR]
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- 2020
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7. Monoclonal Antibody to Marinobufagenin Downregulates TGFβ Profibrotic Signaling in Left Ventricle and Kidney and Reduces Tissue Remodeling in Salt-Sensitive Hypertension.
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Yongqing Zhang, Wen Wei, Shilova, Victoria, Petrashevskaya, Natalia N., Zernetkina, Valentina I., Grigorova, Yulia N., Marshall, Courtney A., Fenner, Rachel C., Lehrmann, Elin, Wood III, William H., Becker, Kevin G., Lakatta, Edward G., Bagrov, Alexei Y., Fedorova, Olga V., Zhang, Yongqing, Wei, Wen, and Wood, William H 3rd
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- 2019
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8. Variation in human chromosome 21 ribosomal RNA genes characterized by TAR cloning and long-read sequencing
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Kim, Jung-Hyun, primary, Dilthey, Alexander T, additional, Nagaraja, Ramaiah, additional, Lee, Hee-Sheung, additional, Koren, Sergey, additional, Dudekula, Dawood, additional, Wood III, William H, additional, Piao, Yulan, additional, Ogurtsov, Aleksey Y, additional, Utani, Koichi, additional, Noskov, Vladimir N, additional, Shabalina, Svetlana A, additional, Schlessinger, David, additional, Phillippy, Adam M, additional, and Larionov, Vladimir, additional
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- 2018
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9. Misregulation of the IgH Locus in Thymocytes.
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Kumari, Gita, Gerasimova, Tatiana, Du, Hansen, De, Supriyo, Wood III, William H., Becker, Kevin G., and Sen, Ranjan
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Functional antigen receptor genes are assembled by somatic rearrangements that are largely lymphocyte lineage specific. The immunoglobulin heavy chain (IgH) gene locus is unique amongst the seven antigen receptor loci in undergoing partial gene rearrangements in the wrong lineage. Here we demonstrate that breakdown of lineage-specificity is associated with inappropriate activation of the Eμ enhancer during T cell development by a different constellation of transcription factors than those used in developing B cells. This is reflected in reduced enhancer-induced epigenetic changes, eRNAs, formation of the RAG1/2-rich recombination center, attenuated chromatin looping and markedly different utilization of D
H gene segments in CD4+ CD8+ (DP) thymocytes. Additionally, CTCF-dependent VH locus compaction is disrupted in DP cells despite comparable transcription factor binding in both lineages. These observations identify multiple mechanisms that contribute to lineage-specific antigen receptor gene assembly. [ABSTRACT FROM AUTHOR]- Published
- 2018
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10. miR-570 interacts with mitochondrial ATPase subunit g (ATP5L) encoding mRNA in stored platelets
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Dahiya, Neetu, primary, Sarachana, Tewarit, additional, Kulkarni, Sandhya, additional, Wood III, William H., additional, Zhang, Yongqing, additional, Becker, Kevin G., additional, Wang, Bi-Dar, additional, and Atreya, Chintamani D., additional
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- 2016
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11. Extracellular RNA profiles with human age.
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Dluzen, Douglas F., Noren Hooten, Nicole, De, Supriyo, Wood III, William H., Zhang, Yongqing, Becker, Kevin G., Zonderman, Alan B., Tanaka, Toshiko, Ferrucci, Luigi, and Evans, Michele K.
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RNA ,BIOMARKERS ,SERUM ,AGING ,RNA sequencing - Abstract
Summary: Circulating extracellular RNAs (exRNAs) are potential biomarkers of disease. We thus hypothesized that age‐related changes in exRNAs can identify age‐related processes. We profiled both large and small RNAs in human serum to investigate changes associated with normal aging. exRNA was sequenced in 13 young (30–32 years) and 10 old (80–85 years) African American women to identify all RNA transcripts present in serum. We identified age‐related differences in several RNA biotypes, including mitochondrial transfer RNAs, mitochondrial ribosomal RNA, and unprocessed pseudogenes. Age‐related differences in unique RNA transcripts were further validated in an expanded cohort. Pathway analysis revealed that EIF2 signaling, oxidative phosphorylation, and mitochondrial dysfunction were among the top pathways shared between young and old. Protein interaction networks revealed distinct clusters of functionally‐related protein‐coding genes in both age groups. These data provide timely and relevant insight into the exRNA repertoire in serum and its change with aging. [ABSTRACT FROM AUTHOR]
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- 2018
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12. miR-570 interacts with mitochondrial ATPase subunit g (ATP5L) encoding mRNA in stored platelets.
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Dahiya, Neetu, Sarachana, Tewarit, Kulkarni, Sandhya, Wood III, William H., Zhang, Yongqing, Becker, Kevin G., Wang, Bi-Dar, and Atreya, Chintamani D.
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MICRORNA ,ADENOSINE triphosphatase ,MITOCHONDRIAL physiology ,MESSENGER RNA ,BLOOD platelets - Abstract
Loss of platelet quality during ex vivo storage is a major concern in the transfusion medicine field and it has been known that platelet mitochondrial dysfunction is associated with storage time. In the last decade, small noncoding RNAs also known as microRNAs (miRNAs) have been reported to regulate key cellular processes through their target sequence interactions with selected mRNAs. In this study, we focused on understanding the mechanisms of platelet mitochondrial dysfunction during storage through miRNA regulation of mRNAs. RNA was isolated from day 0, day 5, and day 9 of stored human leukocyte-depleted platelets and subjected to differential miRNA and mRNA profiling. The miRNA profiling identified several miRNAs at low levels including a set of 12 different miR-548 family members (miR-548a-3p, miR-548aa, miR-548x, miR-548ac, miR-548c-3p, miR-603, miR-548aj, miR-548ae, miR-548z, miR-548u, miR-548al, and miR-570-3p). The mRNA profiling identified, among many, the mitochondrial ATP synthase subunit g (ATP5L) mRNA at high levels during storage. Target Scan algorithm for potential targets of miR-570-3p also identified ATP5L as one of its targets. We further identified two target sites for miR-570-3p in the 3′ untranslated region (3′UTR) of ATP5L mRNA. While ATP5L is a subunit of F0ATPase complex, its function is not established yet. Overexpression of miR-570-3p in platelets resulted in reduced levels of ATP5L mRNA and concomitant ATP loss. These experimental results provide first-time insights into the miRNA–mRNA interactions underlying mitochondrial dysfunction in ex vivo stored platelets and warrants further investigation. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Possible angiogenic roles for claudin-4 in ovarian cancer
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Li, Jianghong, primary, Chigurupati, Srinivasulu, additional, Agarwal, Rachana, additional, Mughal, Mohamed R., additional, Mattson, Mark P., additional, Becker, Kevin G., additional, Wood, III, William H., additional, Zhang, Yongqing, additional, and Morin, Patrice J., additional
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- 2009
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14. Long-Term Artificial Sweetener Acesulfame Potassium Treatment Alters Neurometabolic Functions in C57BL/6J Mice.
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Cong, Wei-na, Wang, Rui, Cai, Huan, Daimon, Caitlin M., Scheibye-Knudsen, Morten, Bohr, Vilhelm A., Turkin, Rebecca, Wood III, William H., Becker, Kevin G., Moaddel, Ruin, Maudsley, Stuart, and Martin, Bronwen
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NONNUTRITIVE sweeteners ,ACESULFAME-K ,BRAIN metabolism ,LABORATORY mice ,OBESITY ,DISEASE prevalence ,CELLULAR signal transduction - Abstract
With the prevalence of obesity, artificial, non-nutritive sweeteners have been widely used as dietary supplements that provide sweet taste without excessive caloric load. In order to better understand the overall actions of artificial sweeteners, especially when they are chronically used, we investigated the peripheral and central nervous system effects of protracted exposure to a widely used artificial sweetener, acesulfame K (ACK). We found that extended ACK exposure (40 weeks) in normal C57BL/6J mice demonstrated a moderate and limited influence on metabolic homeostasis, including altering fasting insulin and leptin levels, pancreatic islet size and lipid levels, without affecting insulin sensitivity and bodyweight. Interestingly, impaired cognitive memory functions (evaluated by Morris Water Maze and Novel Objective Preference tests) were found in ACK-treated C57BL/6J mice, while no differences in motor function and anxiety levels were detected. The generation of an ACK-induced neurological phenotype was associated with metabolic dysregulation (glycolysis inhibition and functional ATP depletion) and neurosynaptic abnormalities (dysregulation of TrkB-mediated BDNF and Akt/Erk-mediated cell growth/survival pathway) in hippocampal neurons. Our data suggest that chronic use of ACK could affect cognitive functions, potentially via altering neuro-metabolic functions in male C57BL/6J mice. [ABSTRACT FROM AUTHOR]
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- 2013
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15. Non-Steroidal Anti-inflammatory Drugs Decrease E2F1 Expression and Inhibit Cell Growth in Ovarian Cancer Cells.
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Valle, Blanca L., D'Souza, Theresa, Becker, Kevin G., Wood III, William H., Zhang, Yongqing, Wersto, Robert P., and Morin, Patrice J.
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NONSTEROIDAL anti-inflammatory agents ,GENE expression ,CANCER cell growth ,OVARIAN cancer prevention ,EPIDEMIOLOGY of cancer ,CANCER invasiveness ,APOPTOSIS - Abstract
Epidemiological studies have shown that the regular use of non-steroidal anti-inflammatory (NSAIDs) drugs is associated with a reduced risk of various cancers. In addition, in vitro and experiments in mouse models have demonstrated that NSAIDs decrease tumor initiation and/or progression of several cancers. However, there are limited preclinical studies investigating the effects of NSAIDs in ovarian cancer. Here, we have studied the effects of two NSAIDs, diclofenac and indomethacin, in ovarian cancer cell lines and in a xenograft mouse model. Diclofenac and indomethacin treatment decreased cell growth by inducing cell cycle arrest and apoptosis. In addition, diclofenac and indomethacin reduced tumor volume in a xenograft model of ovarian cancer. To identify possible molecular pathways mediating the effects of NSAID treatment in ovarian cancer, we performed microarray analysis of ovarian cancer cells treated with indomethacin or diclofenac. Interestingly, several of the genes found downregulated following diclofenac or indomethacin treatment are transcriptional target genes of E2F1. E2F1 was downregulated at the mRNA and protein level upon treatment with diclofenac and indomethacin, and overexpression of E2F1 rescued cells from the growth inhibitory effects of diclofenac and indomethacin. In conclusion, NSAIDs diclofenac and indomethacin exert an anti-proliferative effect in ovarian cancer in vitro and in vivo and the effects of NSAIDs may be mediated, in part, by downregulation of E2F1. [ABSTRACT FROM AUTHOR]
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- 2013
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16. SENSOR SYSTEMS FOR AN ON-LINE DIAGNOSTIC EXPERT SYSTEM IN FOSSIL POWER PLANTS
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Kim, Young-Jin, primary, Wood III, William H., additional, and Agogino, Alice M., additional
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- 1992
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17. Krüppel-like factor 4 (KLF4) directly regulates proliferation in thymocyte development and IL-17 expression during Th17 differentiation.
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Jie An, Golech, Susanne, Klaewsongkram, Jettanong, Yongqing Zhang, Subedi, Kalpana, Huston, Gail E., Wood III, William H., Wersto, Robert P., Becker, Kevin G., Swain, Susan L., and Nanping Weng
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Krüppel-like factor 4 (KLF4), a transcription factor, plays a key role in the pluripotency of stem cells. We sought to determine the function of KLF4 in T-cell development and differentiation by using T-cell-specific Klf4-knockout (KO) mice. We found that KLF4 was highly expressed in thymocytes and mature T cells and was rapidly down-regulated in mature T cells after activation. In Klf4-KO mice, we observed a modest reduction of thymocytes (27%) due to the reduced proliferation of double-negative (DN) thymocytes. We demonstrated that a direct repression of Cdkn1b by KLF4 was a cause of decreased DN proliferation. During in vitro T-cell differentiation, we observed significant reduction of IL-17-expressing CD4
4 T cells (Th17; 24%) but not in other types of Th differentiation. The reduction of Th17 cells resulted in a significant attenuation of the severity (35%) of experimental autoimmune encephalomyelitis in vivo in Klf4-KO mice as compared with the Klf4 wild-type littermates. Finally, we demonstrated that KLF4 directly binds to the promoter of Il17a and positively regulates its expression. In summary, these findings identify KLF4 as a critical regulator in T-cell development and Th17 differentiation. [ABSTRACT FROM AUTHOR]- Published
- 2011
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18. CHD5, a Brain-Specific Paralog of Mi2 Chromatin Remodeling Enzymes, Regulates Expression of Neuronal Genes.
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Potts, Rebecca Casaday, Zhang, Peisu, Wurster, Andrea L., Precht, Patricia, Mughal, Mohamed R., Wood III, William H., Zhang, Yonqing, Becker, Kevin G., Mattson, Mark P., and Pazin, Michael J.
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CONGENITAL heart disease ,CHROMATIN ,VENTRICULAR remodeling ,GENE expression ,NEUROBLASTOMA ,TUMOR suppressor genes ,MESSENGER RNA ,DNA microarrays - Abstract
CHD5 is frequently deleted in neuroblastoma and is a tumor suppressor gene. However, little is known about the role of CHD5 other than it is homologous to chromatin remodeling ATPases. We found CHD5 mRNA was restricted to the brain; by contrast, most remodeling ATPases were broadly expressed. CHD5 protein isolated from mouse brain was associated with HDAC2, p66ß, MTA3 and RbAp46 in a megadalton complex. CHD5 protein was detected in several rat brain regions and appeared to be enriched in neurons. CHD5 protein was predominantly nuclear in primary rat neurons and brain sections. Microarray analysis revealed genes that were upregulated and downregulated when CHD5 was depleted from primary neurons. CHD5 depletion altered expression of neuronal genes, transcription factors, and brain-specific subunits of the SWI/ SNF remodeling enzyme. Expression of gene sets linked to aging and Alzheimer's disease were strongly altered by CHD5 depletion from primary neurons. Chromatin immunoprecipitation revealed CHD5 bound to these genes, suggesting the regulation was direct. Together, these results indicate that CHD5 protein is found in a NuRD-like multi-protein complex. CHD5 expression is restricted to the brain, unlike the closely related family members CHD3 and CHD4. CHD5 regulates expression of neuronal genes, cell cycle genes and remodeling genes. CHD5 is linked to regulation of genes implicated in aging and Alzheimer's disease. [ABSTRACT FROM AUTHOR]
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- 2011
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19. Claudin-7 Is Frequently Overexpressed in Ovarian Cancer and Promotes Invasion.
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Dahiya, Neetu, Becker, Kevin G., Wood, III, William H., Yongqing Zhang, and Morin, Patrice J.
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CLAUDINS ,TIGHT junctions ,OVARIAN cancer ,CANCER invasiveness ,ENDOMETRIAL cancer ,SMALL interfering RNA ,DNA microarrays ,IMMUNOBLOTTING ,GENE expression - Abstract
Background: Claudins are tight junction proteins that are involved in tight junction formation and function. Previous studies have shown that claudin-7 is frequently upregulated in epithelial ovarian cancer (EOC) along with claudin-3 and claudin-4. Here, we investigate in detail the expression patterns of claudin-7, as well as its possible functions in EOC. Methodology/Principal Findings: A total of 95 ovarian tissue samples (7 normal ovarian tissues, 65 serous carcinomas, 11 clear cell carcinomas, 8 endometrioid carcinomas and 4 mucinous carcinomas) were studied for claudin-7 expression. In realtime RT-PCR analysis, the gene for claudin-7, CLDN7, was found to be upregulated in all the tumor tissue samples studied. Similarly, immunohistochemical analysis and western blotting showed that claudin-7 protein was significantly overexpressed in the vast majority of EOCs. Small interfering RNA-mediated knockdown of claudin-7 in ovarian cancer cells led to significant changes in gene expression as measured by microarrays and validated by RT-PCR and immunoblotting. Analyses of the genes differentially expressed revealed that the genes altered in response to claudin-7 knockdown were associated with pathways implicated in various molecular and cellular functions such as cell cycle, cellular growth and proliferation, cell death, development, and cell movement. Through functional experiments in vitro, we found that both migration and invasion were altered in cells where CLDN7 had been knocked down or overexpressed. Interestingly, claudin-7 expression was associated with a net increase in invasion, but also with a decrease in migration. Conclusion/Significance: Our work shows that claudin-7 is significantly upregulated in EOC and that it may be functionally involved in ovarian carcinoma invasion. CLDN7 may therefore represent potential marker for ovarian cancer detection and a target for therapy. [ABSTRACT FROM AUTHOR]
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- 2011
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20. Fine Mapping of Five Loci Associated with Low-Density Lipoprotein Cholesterol Detects Variants That Double the Explained Heritability.
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Sanna, Serena, Bingshan Li, Mulas, Antonella, Sidore, Carlo, Kang, Hyun M., Jackson, Anne U., Piras, Maria Grazia, Usala, Gianluca, Maninchedda, Giuseppe, Sassu, Alessandro, Serra, Fabrizio, Palmas, Maria Antonietta, Wood III, William H., Njølstad, Inger, Laakso, Markku, Hveem, Kristian, Tuomilehto, Jaakko, Lakka, Timo A., Rauramaa, Rainer, and Boehnke, Michael
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LOCUS (Genetics) ,LOW density lipoproteins ,GENE mapping ,CHOLESTEROL ,HERITABILITY ,GENETIC polymorphisms ,NORWEGIANS ,DISEASES - Abstract
Complex trait genome-wide association studies (GWAS) provide an efficient strategy for evaluating large numbers of common variants in large numbers of individuals and for identifying trait-associated variants. Nevertheless, GWAS often leave much of the trait heritability unexplained. We hypothesized that some of this unexplained heritability might be due to common and rare variants that reside in GWAS identified loci but lack appropriate proxies in modern genotyping arrays. To assess this hypothesis, we re-examined 7 genes (APOE, APOC1, APOC2, SORT1, LDLR, APOB, and PCSK9) in 5 loci associated with low-density lipoprotein cholesterol (LDL-C) in multiple GWAS. For each gene, we first catalogued genetic variation by re-sequencing 256 Sardinian individuals with extreme LDL-C values. Next, we genotyped variants identified by us and by the 1000 Genomes Project (totaling 3,277 SNPs) in 5,524 volunteers. We found that in one locus (PCSK9) the GWAS signal could be explained by a previously described low-frequency variant and that in three loci (PCSK9, APOE, and LDLR) there were additional variants independently associated with LDL-C, including a novel and rare LDLR variant that seems specific to Sardinians. Overall, this more detailed assessment of SNP variation in these loci increased estimates of the heritability of LDL-C accounted for by these genes from 3.1% to 6.5%. All association signals and the heritability estimates were successfully confirmed in a sample of ,10,000 Finnish and Norwegian individuals. Our results thus suggest that focusing on variants accessible via GWAS can lead to clear underestimates of the trait heritability explained by a set of loci. Further, our results suggest that, as prelude to large-scale sequencing efforts, targeted re-sequencing efforts paired with large-scale genotyping will increase estimates of complex trait heritability explained by known loci. [ABSTRACT FROM AUTHOR]
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- 2011
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21. Amitriptyline-Mediated Cognitive Enhancement in Aged 36Tg Alzheimer's Disease Mice Is Associated with Neurogenesis and Neurotrophic Activity.
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Chadwick, Wayne, Mitchell, Nick, Caroll, Jenna, Yu Zhou, Park, Sung-Soo, Wang, Liyun, Becker, Kevin G., Zhang, Yongqing, Lehrmann, Elin, Wood III, William H., Martin, Bronwen, and Maudsley, Stuart
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AMITRIPTYLINE ,ALZHEIMER'S disease treatment ,LABORATORY mice ,DEVELOPMENTAL neurobiology ,AMYLOID beta-protein ,ANTIDEPRESSANTS ,TRANSGENIC mice ,MEMORY ,NEUROTROPHINS ,THERAPEUTICS - Abstract
Approximately 35 million people worldwide suffer from Alzheimer's disease (AD). Existing therapeutics, while moderately effective, are currently unable to stem the widespread rise in AD prevalence. AD is associated with an increase in amyloid beta (Ab) oligomers and hyperphosphorylated tau, along with cognitive impairment and neurodegeneration. Several antidepressants have shown promise in improving cognition and alleviating oxidative stress in AD but have failed as longterm therapeutics. In this study, amitriptyline, an FDA-approved tricyclic antidepressant, was administered orally to aged and cognitively impaired transgenic AD mice (3*TgAD). After amitriptyline treatment, cognitive behavior testing demonstrated that there was a significant improvement in both long- and short-term memory retention. Amitriptyline treatment also caused a significant potentiation of non-toxic Ab monomer with a concomitant decrease in cytotoxic dimer Ab load, compared to vehicle-treated 3*TgAD controls. In addition, amitriptyline administration caused a significant increase in dentate gyrus neurogenesis as well as increases in expression of neurosynaptic marker proteins. Amitriptyline treatment resulted in increases in hippocampal brain-derived neurotrophic factor protein as well as increased tyrosine phosphorylation of its cognate receptor (TrkB). These results indicate that amitriptyline has significant beneficial actions in aged and damaged AD brains and that it shows promise as a tolerable novel therapeutic for the treatment of AD. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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22. Multiple Oxygen Tension Environments Reveal Diverse Patterns of Transcriptional Regulation in Primary Astrocytes.
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Chadwick, Wayne, Boyle, John P., Yu Zhou, Wang, Liyun, Park, Sung-Soo, Martin, Bronwen, Wang, Rui, Becker, Kevin G., Wood III, William H., Zhang, Yongqing, Peers, Chris, and Maudsley, Stuart
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ASTROCYTES ,CENTRAL nervous system physiology ,PHYSIOLOGICAL transport of oxygen ,LABORATORY mice ,IMMUNOREGULATION ,HEMOSTATICS ,GENETIC transcription regulation ,CELL cycle regulation ,GENE expression - Abstract
The central nervous system normally functions at O
2 levels which would be regarded as hypoxic by most other tissues. However, most in vitro studies of neurons and astrocytes are conducted under hyperoxic conditions without consideration of O2 -dependent cellular adaptation. We analyzed the reactivity of astrocytes to 1, 4 and 9% O2 tensions compared to the cell culture standard of 20% O2 , to investigate their ability to sense and translate this O2 information to transcriptional activity. Variance of ambient O2 tension for rat astrocytes resulted in profound changes in ribosomal activity, cytoskeletal and energy-regulatory mechanisms and cytokine-related signaling. Clustering of transcriptional regulation patterns revealed four distinct response pattern groups that directionally pivoted around the 4% O2 tension, or demonstrated coherent ascending/decreasing gene expression patterns in response to diverse oxygen tensions. Immune response and cell cycle/ cancer-related signaling pathway transcriptomic subsets were significantly activated with increasing hypoxia, whilst hemostatic and cardiovascular signaling mechanisms were attenuated with increasing hypoxia. Our data indicate that variant O2 tensions induce specific and physiologically-focused transcript regulation patterns that may underpin important physiological mechanisms that connect higher neurological activity to astrocytic function and ambient oxygen environments. These strongly defined patterns demonstrate a strong bias for physiological transcript programs to pivot around the 4% O2 tension, while uni-modal programs that do not, appear more related to pathological actions. The functional interaction of these transcriptional 'programs' may serve to regulate the dynamic vascular responsivity of the central nervous system during periods of stress or heightened activity. [ABSTRACT FROM AUTHOR]- Published
- 2011
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23. Methamphetamine Induces Dopamine D1 Receptor- Dependent Endoplasmic Reticulum Stress-Related Molecular Events in the Rat Striatum.
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Jayanthi, Subramaniam, McCoy, Michael T., Beauvais, Genevieve, Ladenheim, Bruce, Gilmore, Kristi, Wood III, William, Becker, Kevin, and Cadet, Jean Lud
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PHYSIOLOGICAL effects of methamphetamine ,ADRENERGIC uptake inhibitors ,NEUROTRANSMITTER uptake inhibitors ,NEUROTRANSMITTER receptors ,DOPAMINE receptors ,GENETIC transcription ,GENETIC code - Abstract
Methamphetamine (METH) is an illicit toxic psychostimulant which is widely abused. Its toxic effects depend on the release of excessive levels of dopamine (DA) that activates striatal DA receptors. Inhibition of DA-mediated neurotransmission by the DA D1 receptor antagonist, SCH23390, protects against METH-induced neuronal apoptosis. The initial purpose of the present study was to investigate, using microarray analyses, the influence of SCH23390 on transcriptional responses in the rat striatum caused by a single METH injection at 2 and 4 hours after drug administration. We identified 545 out of a total of 22,227 genes as METH-responsive. These include genes which are involved in apoptotic pathways, endoplasmic reticulum (ER) stress, and in transcription regulation, among others. Of these, a total of 172 genes showed SCH23390-induced inhibition of METH-mediated changes. Among these SCH23390-responsive genes were several genes that are regulated during ER stress, namely ATF3, HSP27, Hmox1, HSP40, and CHOP/Gadd153. The secondary goal of the study was to investigate the role of DA D1 receptor stimulation on the expression of genes that participate in ER stress-mediated molecular events. We thus used quantitative PCR to confirm changes in the METH-responsive ER genes identified by the microarray analyses. We also measured the expression of these genes and of ATF4, ATF6, BiP/GRP78, and of GADD34 over a more extended time course. SCH23390 attenuated or blocked METH-induced increases in the expression of the majority of these genes. Western blot analysis revealed METH-induced increases in the expression of the antioxidant protein, Hmox1, which lasted for about 24 hours after the METH injection. Additionally, METH caused DA D1 receptor-dependent transit of the Hmox1 regulator protein, Nrf2, from cytosolic into nuclear fractions where the protein exerts its regulatory functions. When taken together, these findings indicate that SCH23390 can provide protection against neuronal apoptosis by inhibiting METH-mediated DA D1 receptor-mediated ER stress in the rat striatum. Our data also suggest that METH-induced toxicity might be a useful model to dissect molecular mechanisms involved in ER stress-dependent events in the rodent brain. [ABSTRACT FROM AUTHOR]
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- 2009
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- View/download PDF
24. Gonadal Transcriptome Alterations in Response to Dietary Energy Intake: Sensing the Reproductive Environment.
- Author
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Martin, Bronwen, Pearson, Michele, Brenneman, Randall, Golden, Erin, Wood III, William, Prabhu, Vinayakumar, Becker, Kevin G., Mattson, Mark P., and Maudsley, Stuart
- Subjects
TRANSCRIPTION factors ,ANIMAL nutrition ,GENES ,LABORATORY rats ,GONADS ,GONADAL sex reversal ,ANIMAL sexual behavior ,ANIMAL behavior ,DIET - Abstract
Reproductive capacity and nutritional input are tightly linked and animals' specific responses to alterations in their physical environment and food availability are crucial to ensuring sustainability of that species. We have assessed how alterations in dietary energy intake (both reductions and excess), as well as in food availability, via intermittent fasting (IF), affect the gonadal transcriptome of both male and female rats. Starting at four months of age, male and female rats were subjected to a 20% or 40% caloric restriction (CR) dietary regime, every other day feeding (IF) or a high fat-high glucose (HFG) diet for six months. The transcriptional activity of the gonadal response to these variations in dietary energy intake was assessed at the individual gene level as well as at the parametric functional level. At the individual gene level, the females showed a higher degree of coherency in gonadal gene alterations to CR than the males. The gonadal transcriptional and hormonal response to IF was also significantly different between the male and female rats. The number of genes significantly regulated by IF in male animals was almost 5 times greater than in the females. These IF males also showed the highest testosterone to estrogen ratio in their plasma. Our data show that at the level of gonadal gene responses, the male rats on the IF regime adapt to their environment in a manner that is expected to increase the probability of eventual fertilization of females that the males predict are likely to be sub-fertile due to their perception of a food deficient environment. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
25. MicroRNA Expression and Identification of Putative miRNA Targets in Ovarian Cancer.
- Author
-
Dahiya, Neetu, Sherman-Baust, Cheryl A., Tian-Li Wang, Davidson, Ben, Ie-Ming Shih, Yongqing Zhang, Wood III, William, Becker, Kevin G., and Morin, Patrice J.
- Subjects
GENE expression ,CLUSTER analysis (Statistics) ,RNA ,CANCER genetics ,OVARIAN cancer ,CANCER cells ,BIODEGRADATION ,EPITHELIUM ,OLIGONUCLEOTIDES ,GENETICS - Abstract
Background: MicroRNAs (miRNAs) represent a class of small non-coding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Emerging evidence suggests the potential involvement of altered regulation of miRNA in the pathogenesis of cancers, and these genes are thought to function as both tumor suppressors and oncogenes. Methodology/Principal Findings: Using microRNA microarrays, we identify several miRNAs aberrantly expressed in human ovarian cancer tissues and cell lines. miR-221 stands out as a highly elevated miRNA in ovarian cancer, while miR-21 and several members of the let-7 family are found downregulated. Public databases were used to reveal potential targets for the highly differentially expressed miRNAs. In order to experimentally identify transcripts whose stability may be affected by the differentially expressed miRNAs, we transfected precursor miRNAs into human cancer cell lines and used oligonucleotide microarrays to examine changes in the mRNA levels. Interestingly, there was little overlap between the predicted and the experimental targets or pathways, or between experimental targets/pathways obtained using different cell lines, highlighting the complexity of miRNA target selection. Conclusion/Significance: Our results identify several differentially expressed miRNAs in ovarian cancer and identify potential target transcripts that may be regulated by these miRNAs. These miRNAs and their targets may have important roles in the initiation and development of ovarian cancer. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
26. Conserved and Differential Effects of Dietary Energy Intake on the Hippocampal Transcriptomes of Females and Males.
- Author
-
Martin, Bronwen, Pearson, Michele, Brenneman, Randall, Golden, Erin, Keselman, Alex, Iyun, Titilola, Carlson, Olga D., Egan, Josephine M., Becker, Kevin G., Wood III, William, Prabhu, Vinayakumar, de Cabo, Rafael, Maudsley, Stuart, and Mattson, Mark P.
- Subjects
PHYSIOLOGY ,DIET ,HIPPOCAMPUS (Brain) ,ENERGY metabolism ,LOW-calorie diet ,MOLECULAR genetics ,APOPTOSIS ,GLUCOSE ,BODY weight ,LEPTIN ,INSULIN - Abstract
The level of dietary energy intake influences metabolism, reproductive function, the development of age-related diseases, and even cognitive behavior. Because males and females typically play different roles in the acquisition and allocation of energy resources, we reasoned that dietary energy intake might differentially affect the brains of males and females at the molecular level. To test this hypothesis, we performed a gene array analysis of the hippocampus in male and female rats that had been maintained for 6 months on either ad libitum (control), 20% caloric restriction (CR), 40% CR, intermittent fasting (IF) or high fat/ high glucose (HFG) diets. These diets resulted in expected changes in body weight, and circulating levels of glucose, insulin and leptin. However, the CR diets significantly increased the size of the hippocampus of females, but not males. Multiple genes were regulated coherently in response to energy restriction diets in females, but not in males. Functional physiological pathway analyses showed that the 20% CR diet down-regulated genes involved in glycolysis and mitochondrial ATP production in males, whereas these metabolic pathways were up-regulated in females. The 40% CR diet up-regulated genes involved in glycolysis, protein deacetylation, PGC-1α and mTor pathways in both sexes. IF down-regulated many genes in males including those involved in protein degradation and apoptosis, but up-regulated many genes in females including those involved in cellular energy metabolism, cell cycle regulation and protein deacetylation. Genes involved in energy metabolism, oxidative stress responses and cell death were affected by the HFG diet in both males and females. The gender-specific molecular genetic responses of hippocampal cells to variations in dietary energy intake identified in this study may mediate differential behavioral responses of males and females to differences in energy availability. [ABSTRACT FROM AUTHOR]
- Published
- 2008
- Full Text
- View/download PDF
27. AGEMAP: A Gene Expression Database for Aging in Mice.
- Author
-
Zahn, Jacob M., Poosala, Suresh, Owen, Art B., Ingram, Donald K., Lustig, Ana, Carter, Arnell, Weeraratna, Ashani T., Taub, Dennis D., Gorospe, Myriam, Mazan-Mamczarz, Krystyna, Lakatta, Edward G., Boheler, Kenneth R., Xiangru Xu, Mattson, Mark P., Falco, Geppino, Ko, Minoru S. H., Schlessinger, David, Firman, Jeffrey, Kummerfeld, Sarah K., and Wood III, William H.
- Subjects
GENE expression ,GENETICS of aging ,LABORATORY mice ,GENETIC transcription ,HOMEOSTASIS ,ELECTRON transport - Abstract
We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
28. Gene expression characteristics of CD28null memory phenotype CD8+ T cells and its implication in T-cell aging.
- Author
-
Monchou Fann, Wai Kan Chiu, Wood III, William H., Levine, Bruce L., Becker, Kevin G., and Nan-ping Weng
- Subjects
T cells ,AGING ,MEMORY ,GENE expression ,LYMPHOCYTES ,IMMUNE system - Abstract
Accumulation of CD28
null CD8+ T cells is considered as one of the hallmarks of aging in the human immune system. However, the precise changes of CD28null CD8+ T cells, compared to those of the precursor CD28+ CD8+ memory T cells, have not been determined. In this study, we present an analysis of the global gene expression profiles of CD28+ and CD28null memory phenotype CD8+ T cells. These two CD8+ T subsets exhibited an overall similar gene expression profile with only a few dozen genes that were differentially expressed. A wide range of functions, including co-stimulation, effector activity, signaling, and transcription, were possessed by these differentially expressed genes, reflecting significant functional changes of CD28null memory phenotype CD8+ T cells from their CD28+ counterparts. In addition, CD28null memory CD8+ T cells expressed several natural killer cell receptors and high levels of granzymes, perforin, and FasL, indicating an increasing capacity for cytotoxicity during memory CD8+ T-cell aging. Interestingly,in vitroculture of these two subsets with interleukin-15 showed that similar gene expression changes occurred in both subsets. Our analysis provides the gene expression portraits of CD28null memory phenotype CD8+ T cells and alteration from their CD28+ counterparts and suggests potential mechanisms of T-cell aging. [ABSTRACT FROM AUTHOR]- Published
- 2005
- Full Text
- View/download PDF
29. Global analysis of stress-regulated mRNA turnover by using cDNA arrays.
- Author
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Jinshu Fan, Xiaoling Yang, Wengong Wang, Wood III, William H., Becker, Kevin G., and Gorospe, Myriam
- Subjects
ANTISENSE DNA ,MESSENGER RNA ,GENE expression - Abstract
Examines the use of complementary DNA array technology in stress-regulated messenger RNA turnover. Determination of changes in gene expression patterns; Establishment of transcription mechanisms regulating gene expression; Preparation of total RNA.
- Published
- 2002
- Full Text
- View/download PDF
30. PREFERENCES FOR PARENT EDUCATION PROGRAMS AMONG LOW SOCIOECONOMIC STATUS, CULTURALLY DIVERSE PARENTS.
- Author
-
Wood III, William D. and Baker, Jean A.
- Subjects
- *
PARENTING education , *FAMILY life education - Abstract
Presents information on a study which examined parent preferences, behaviors and beliefs toward school-based parent education programs among low income and culturally diverse parents. Measurement of parenting beliefs and behaviors; Differences among parents in their willingness to participate in school-based parent education programs; Experimental procedure; Results and discussion.
- Published
- 1999
- Full Text
- View/download PDF
31. Engineering Courseware Content and Delivery: The NEEDS Infrastructure for Distance Independent Education.
- Author
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Wood III, William H. and Agogino, Alice M.
- Subjects
- *
ENGINEERING education , *ENGINEERING - Abstract
Focuses on the Synthesis Engineering Education Coalition's development of multimedia courseware into varied engineering curricula. Educational objectives of Synthesis for engineering education reform; Introduction of courseware to support student learning process; Development of NEEDS prototype information server for Synthesis educational community.
- Published
- 1996
- Full Text
- View/download PDF
32. Dynamic BRG1 Recruitment during T Helper Differentiation and Activation Reveals Distal Regulatory Elements.
- Author
-
De, Supriyo, Wurster, Andrea L., Precht, Patricia, Wood III, William H., Becker, Kevin G., and Pazin, Michael J.
- Subjects
T cells ,CELL differentiation ,CHROMATIN ,ENZYMES ,TRANSCRIPTION factors - Abstract
T helper cell differentiation and activation require specific transcriptional programs accompanied by changes in chromatin structure. However, little is known about the chromatin remodeling enzymes responsible. We performed genome-wide analysis to determine the general principles of BRG1 binding, followed by analysis of specific genes to determine whether these general rules were typical of key T cell genes. We found that binding of the remodeling protein BRG1 was programmed by both lineage and activation signals. BRG1 binding positively correlated with gene activity at protein-coding and microRNA (miRNA) genes. BRG1 binding was found at promoters and distal regions, including both novel and previously validated distal regulatory elements. Distal BRG1 binding correlated with expression, and novel distal sites in the Gata3 locus possessed enhancer-like activity, suggesting a general role for BRG1 in long-distance gene regulation. BRG1 recruitment to distal sites in Gata3 was impaired in cells lacking STAT6, a transcription factor that regulates lineage-specific genes. Together, these findings suggest that BRG1 interprets both differentiation and activation signals and plays a causal role in gene regulation, chromatin structure, and cell fate. Our findings suggest that BRG1 binding is a useful marker for identifying active cis-regulatory regions in protein-coding and miRNA genes. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
33. Longitudinal analysis reveals age-related changes in the T cell receptor repertoire of human T cell subsets.
- Author
-
Xiaoping Sun, Nguyen, Thomas, Achour, Achouak, Ko, Annette, Cifello, Jeffrey, Chen Ling, Sharma, Jay, Toyoko Hiroi, Yongqing Zhang, Chia, Chee W., Wood III, William, Wu, Wells W., Zukley, Linda, Je-Nie Phue, Becker, Kevin G., Rong-Fong Shen, Ferrucci, Luigi, Nan-ping Weng, Sun, Xiaoping, and Ling, Chen
- Subjects
- *
CELL receptors , *T cells - Abstract
A diverse T cell receptor (TCR) repertoire is essential for protection against a variety of pathogens, and TCR repertoire size is believed to decline with age. However, the precise size of human TCR repertoires, in both total and subsets of T cells, as well as their changes with age, are not fully characterized. We conducted a longitudinal analysis of the human blood TCRα and TCRβ repertoire of CD4+ and CD8+ T cell subsets using a unique molecular identifier-based (UMI-based) RNA-seq method. Thorough analysis of 1.9 × 108 T cells yielded the lower estimate of TCR repertoire richness in an adult at 3.8 × 108. Alterations of the TCR repertoire with age were observed in all 4 subsets of T cells. The greatest reduction was observed in naive CD8+ T cells, while the greatest clonal expansion was in memory CD8+ T cells, and the highest increased retention of TCR sequences was in memory CD8+ T cells. Our results demonstrated that age-related TCR repertoire attrition is subset specific and more profound for CD8+ than CD4+ T cells, suggesting that aging has a more profound effect on cytotoxic as opposed to helper T cell functions. This may explain the increased susceptibility of older adults to novel infections. [ABSTRACT FROM AUTHOR]
- Published
- 2022
- Full Text
- View/download PDF
34. Methamphetamine-induced gene expression profiles in the striatum of male rat pups exposed to the drug in utero
- Author
-
Noailles, Pierre-Antoine H., Becker, Kevin G., Wood III, William H., Teichberg, Diane, and Cadet, Jean-Lud
- Subjects
- *
METHAMPHETAMINE , *NEUROTOXIC agents , *BRAIN , *GENE expression - Abstract
Methamphetamine is a neurotoxic pychostimulant which affects monoaminergic and non-monoaminergic systems in the brain. Clinical studies in humans have found that exposure to methamphetamine in the developing embryo can cause significant behavioral and cognitive anomalies later in life. Exposure of animals to methamphetamine (METH) in utero can cause neurobehavioral effects that do not become apparent until young adulthood. In the present study, we sought to determine the effects of in utero METH exposure on the striata of perinatal rat pups using a recently developed 17 k cDNA microarray. We found that METH administration caused alterations in 913 genes according to strict criteria. These alterations include changes in genes that participate in signal transduction, heat shock responses and neuronal development. The majority of the changes in gene expression were more prominent at the 7-day time point. These observations suggest that in utero METH exposure might initiate molecular programs that significantly impact gene expression during the developmental period long after the last exposure to this drug. Thus, during development, METH exposure in utero might cause significant long-term changes in gene expression that might constitute, in part, some of the substrates for the behavioral and cognitive anomalies reported in the literature. [Copyright &y& Elsevier]
- Published
- 2003
- Full Text
- View/download PDF
35. Altered 3D chromatin structure permits inversional recombination at the IgH locus.
- Author
-
Xiang Qiu, Fei Ma, Mingming Zhao, Yaqiang Cao, Shipp, Lillian, Liu, Angela, Dutta, Arun, Singh, Amit, Braikia, Fatima Zohra, De, Supriyo, Wood III, William H., Becker, Kevin G., Weiqiang Zhou, Hongkai Ji, Keji Zhao, Atchison, Michael L., and Sen, Ranjan
- Subjects
- *
IMMUNOGLOBULIN genes , *GENE rearrangement , *GENE targeting , *IMMUNOGLOBULIN heavy chains , *MEDICAL sciences , *DOUBLE-strand DNA breaks - Abstract
The article discusses about the altered three-dimensional chromatin structure permits inversional recombination at the Idiopathic guttate hypomelanosis (IgH) locus. It mentions that Immunoglobulin heavy chain (IgH) genes assembled by two sequential DNA rearrangement events that are initiated by recombination activating gene products.
- Published
- 2020
- Full Text
- View/download PDF
36. AUF1 promotes let-7b loading on Argonaute 2.
- Author
-
Je-Hyun Yoon, Myung Hyun Jo, White, Elizabeth J. F., De, Supriyo, Hafner, Markus, Zucconi, Beth E., Abdelmohsen, Kotb, Martindale, Jennifer L., Xiaoling Yang, Wood III, William H., Yu Mi Shin, Ji-Joon Song, Tuschl, Thomas, Becker, Kevin G., Wilson, Gerald M., Sungchul Hohng, and Gorospe, Myriam
- Subjects
- *
ARGONAUTE proteins , *EUKARYOTIC cells , *MICRORNA , *NUCLEOPROTEINS , *GENE silencing - Abstract
Eukaryotic gene expression is tightly regulated post-transcriptionally by RNA-binding proteins (RBPs) and microRNAs. The RBP AUrich- binding factor 1 (AUF1) isoform p37 was found to have high affinity for the microRNA let-7b in vitro (Kd = ~6 nM) in cells. Ribonucleoprotein immunoprecipitation, in vitro association, and single-molecule-binding analyses revealed that AUF1 promoted let- 7b loading onto Argonaute 2 (AGO2), the catalytic component of the RNA-induced silencing complex (RISC). In turn, AGO2-let-7 triggered target mRNA decay. Our findings uncover a novel mechanism by which AUF1 binding and transfer of microRNA let-7 to AGO2 facilitates let-7-elicited gene silencing. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
37. Amitriptyline Improves Motor Function via Enhanced Neurotrophin Signaling and Mitochondrial Functions in the Murine N171-82Q Huntington Disease Model.
- Author
-
Wei-Na Cong, Chadwick, Wayne, Rui Wang, Daimon, Caitlin M., Huan Cai, Amma, Jennifer, Wood III, William H., Becker, Kevin G., Martin, Bronwen, and Maudsley, Stuart
- Subjects
- *
AMITRIPTYLINE , *NEURODEGENERATION , *ADRENERGIC uptake inhibitors , *TRINUCLEOTIDE repeats , *MICROSATELLITE repeats - Abstract
Huntington disease (HD) is a neurodegenerative disorder characterized by progressive motor impairment and cognitive alterations. HereditaryHDis primarily caused by the expansion of a CAG trinucleotide repeat in the huntingtin (Htt) gene, which results in the production of mutant huntingtin protein (mHTT) with an expanded amino-terminal polyglutamine (poly(Q)) stretch. Besides pathological mHTT aggregation, reduced brain-derived neurotrophic factor (BDNF) levels, impaired neurotrophin signaling, and compromised mitochondrial functions also contribute to the deleterious progressive etiology of HD. As a well tolerated Food and Drug Administration-approved antidepressant, amitriptyline (AMI) has shown efficacy in treating neurodegenerative murine models via potentiation of BDNF levels and amelioration of alterations in neurotrophin signaling pathways. In this study, we observed profound improvements in the motor coordination of AMI-treated N171-82Q HD model mice. The beneficial effects of AMI treatment were associated with its ability to reducemHTTaggregation, potentiation of the BDNF-TrkB signaling system, and support of mitochondrial integrity and functionality. Our study not only provides preclinical evidence for the therapeutic potency of AMI in treating HD, but it also represents an important example of the usefulness of additional pharmacogenomic profiling of pre-existing drugs for novel therapeutic effects with often intractable pathological scenarios. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
38. Growth Factor Signals in Neural Cells: COHERENT PATTERNS OF INTERACTION CONTROL MULTIPLE LEVELS OF MOLECULAR AND PHENOTYPIC RESPONSES.
- Author
-
Martin, Bronwen, Brenneman, Randall, Golden, Erin, Walent, Tom, Becker, Kevin G., Prabhu, Vinayakumar V., Wood III, William, Ladenheim, Bruce, Cadet, Jean-Lud, and Maudsley, Stuart
- Subjects
- *
NERVE growth factor , *SOMATOMEDIN , *EPIDERMAL growth factor , *TRANSCRIPTION factors , *NEUROTRANSMITTERS , *PHENOTYPES - Abstract
Individual neurons express receptors for several different growth factors that influence the survival, growth, neurotransmitter phenotype, and other properties of the cell. Although there has been considerable progress in elucidating the molecular signal transduction pathways and physiological responses of neurons and other cells to individual growth factors, little is known about if and how signals from different growth factors are integrated within a neuron. In this study, we determined the interactive effects of nerve growth factor, insulin-like growth factor 1, and epidermal growth factor on the activation status of downstream kinase cascades and transcription factors, cell survival, and neurotransmitter production in neural cells that express receptors for all three growth factors. We document considerable differences in the quality and quantity of intracellular signaling and eventual phenotypic responses that are dependent on whether cells are exposed to a single or multiple growth factors. Dual stimulations that generated the greatest antagonistic or synergistic actions, compared with a theoretically neutral summation of their two activities, yielded the largest eventual change of neuronal phenotype indicated by the ability of the cell to produce norepinephrine or resist oxidative stress. Combined activation of insulin-like growth factor 1 and epidermal growth factor receptors was particularly notable for antagonistic interactions at some levels of signal transduction and norepinephrine production, but potentiation at other levels of signaling and cytoprotection. Our findings suggest that in true physiological settings where multiple growth factors are present, activation of one receptor type may result in molecularand phenotypic responses that are different from that observed in typical experimental paradigms in which cells are exposed to only a single growth factor at a time. [ABSTRACT FROM AUTHOR]
- Published
- 2009
- Full Text
- View/download PDF
39. AGEMAP: A Gene Expression Database for Aging in Mice
- Author
-
Jacob M. Zahn, Suresh Poosala, William H. Wood, Dennis D. Taub, Art B. Owen, Jeffrey Firman, Mark P. Mattson, David Schlessinger, Ana Lustig, Edward G. Lakatta, Donald K. Ingram, Xiangru Xu, Kevin G. Becker, Minoru S.H. Ko, Sarah K. Kummerfeld, Kenneth R. Boheler, Geppino Falco, Krystyna Mazan-Mamczarz, Myriam Gorospe, Stuart K. Kim, Ashani T. Weeraratna, Arnell Carter, Alan B. Zonderman, Zahn, Jacob M., Poosala, Suresh, Owen, Art B., Ingram, Donald K., Lustig, Ana, Carter, Arnell, Weeraratna, Ashani T., Taub, Dennis D., Gorospe, Myriam, Mazan Mamczarz, Krystyna, Lakatta, Edward G., Boheler, Kenneth R., Xu, Xiangru, Mattson, Mark P., Falco, Geppino, Ko, Minoru S. H., Schlessinger, David, Firman, Jeffrey, Kummerfeld, Sarah K., Wood III, William H., Zonderman, Alan B., Kim, Stuart K., and Becker, Kevin G.
- Subjects
Cancer Research ,Aging ,lcsh:QH426-470 ,Biology ,Neural tissues ,computer.software_genre ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Genetic ,Species Specificity ,Homo (Human) ,Helminths ,Gene expression ,Databases, Genetic ,Genetics ,Helminth ,Animals ,Humans ,Gene ,Molecular Biology ,Ecology, Evolution, Behavior and Systematics ,Vascular tissue ,Genetics (clinical) ,030304 developmental biology ,Regulation of gene expression ,0303 health sciences ,Database ,Animal ,Diptera ,Gene Expression Profiling ,Genetics and Genomics ,Mus (Mouse) ,Ecology, Evolution, Behavior and Systematic ,Gene expression profiling ,lcsh:Genetics ,Gene Expression Regulation ,Organ Specificity ,Caenorhabditis ,Drosophila ,computer ,030217 neurology & neurosurgery ,Homeostasis ,Human ,Research Article ,Developmental Biology - Abstract
We present the AGEMAP (Atlas of Gene Expression in Mouse Aging Project) gene expression database, which is a resource that catalogs changes in gene expression as a function of age in mice. The AGEMAP database includes expression changes for 8,932 genes in 16 tissues as a function of age. We found great heterogeneity in the amount of transcriptional changes with age in different tissues. Some tissues displayed large transcriptional differences in old mice, suggesting that these tissues may contribute strongly to organismal decline. Other tissues showed few or no changes in expression with age, indicating strong levels of homeostasis throughout life. Based on the pattern of age-related transcriptional changes, we found that tissues could be classified into one of three aging processes: (1) a pattern common to neural tissues, (2) a pattern for vascular tissues, and (3) a pattern for steroid-responsive tissues. We observed that different tissues age in a coordinated fashion in individual mice, such that certain mice exhibit rapid aging, whereas others exhibit slow aging for multiple tissues. Finally, we compared the transcriptional profiles for aging in mice to those from humans, flies, and worms. We found that genes involved in the electron transport chain show common age regulation in all four species, indicating that these genes may be exceptionally good markers of aging. However, we saw no overall correlation of age regulation between mice and humans, suggesting that aging processes in mice and humans may be fundamentally different., Author Summary This work studies the aging process in mice using DNA microarrays to identify genes that change expression during aging. The entire set of age-regulated genes constitutes a transcriptional profile that can be used to measure ages of different individuals. Furthermore, the aging expression profile highlights genetic and metabolic pathways that change with age, providing key insights about possible molecular changes that may contribute to cell senescence and physiological decline. This aging study is massive in scope, involving gene expression measurements from 16 different tissues at four different ages. Expression data for genes of interest can be queried over the web by researchers interested in aging. Different tissues were found to have strikingly different levels of age-related change, and could be divided into three groups based on their patterns of aging: a neural group, a vascular group, and a steroid-responsive group. The electron transport chain pathway stands out because it is the only genetic pathway that shows a similar pattern of age-related change in mice, humans, worms, and flies. However, there is little overall similarity between changes in gene expression during aging of humans and mice, consistent with evolutionary theories suggesting that aging lies outside the force of natural selection.
- Published
- 2007
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