22 results on '"Nelson, B."'
Search Results
2. Evolution of insulin at the edge of foldability and its medical implications
- Author
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Rege, Nischay K., Liu, Ming, Yang, Yanwu, Dhayalan, Balamurugan, Wickramasinghe, Nalinda P., Chen, Yen-Shan, Rahimi, Leili, Guo, Huan, Haataja, Leena, Sun, Jinhong, Ismail-Beigi, Faramarz, Phillips, Nelson B., Arvan, Peter, and Weiss, Michael A.
- Published
- 2020
3. Genetic contributions to circadian activity rhythm and sleep pattern phenotypes in pedigrees segregating for severe bipolar disorder.
- Author
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Pagani, Lucia, St Clair, Patricia A, Teshiba, Terri M, Service, Susan K, Fears, Scott C, Araya, Carmen, Araya, Xinia, Bejarano, Julio, Ramirez, Margarita, Castrillón, Gabriel, Gomez-Makhinson, Juliana, Lopez, Maria C, Montoya, Gabriel, Montoya, Claudia P, Aldana, Ileana, Navarro, Linda, Freimer, Daniel G, Safaie, Brian, Keung, Lap-Woon, Greenspan, Kiefer, Chou, Katty, Escobar, Javier I, Ospina-Duque, Jorge, Kremeyer, Barbara, Ruiz-Linares, Andres, Cantor, Rita M, Lopez-Jaramillo, Carlos, Macaya, Gabriel, Molina, Julio, Reus, Victor I, Sabatti, Chiara, Bearden, Carrie E, Takahashi, Joseph S, and Freimer, Nelson B
- Subjects
Chromosomes ,Human ,Pair 1 ,Humans ,Pedigree ,Family ,Sleep ,Bipolar Disorder ,Circadian Rhythm ,Inheritance Patterns ,Quantitative Trait ,Heritable ,Lod Score ,Phenotype ,Middle Aged ,Female ,Male ,Actigraphy ,actigraphy ,behavior ,bipolar disorder ,circadian rhythms ,endophenotypes ,Human Genome ,Serious Mental Illness ,Brain Disorders ,Mental Health ,Genetics ,Sleep Research ,2.1 Biological and endogenous factors ,Aetiology - Abstract
Abnormalities in sleep and circadian rhythms are central features of bipolar disorder (BP), often persisting between episodes. We report here, to our knowledge, the first systematic analysis of circadian rhythm activity in pedigrees segregating severe BP (BP-I). By analyzing actigraphy data obtained from members of 26 Costa Rican and Colombian pedigrees [136 euthymic (i.e., interepisode) BP-I individuals and 422 non-BP-I relatives], we delineated 73 phenotypes, of which 49 demonstrated significant heritability and 13 showed significant trait-like association with BP-I. All BP-I-associated traits related to activity level, with BP-I individuals consistently demonstrating lower activity levels than their non-BP-I relatives. We analyzed all 49 heritable phenotypes using genetic linkage analysis, with special emphasis on phenotypes judged to have the strongest impact on the biology underlying BP. We identified a locus for interdaily stability of activity, at a threshold exceeding genome-wide significance, on chromosome 12pter, a region that also showed pleiotropic linkage to two additional activity phenotypes.
- Published
- 2016
4. Fine-Scale Mapping of a Locus for Severe Bipolar Mood Disorder on Chromosome 18p11.3 in the Costa Rican Population
- Author
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McInnes, L. Alison, Service, Susan K., Reus, Victor I., Barnes, Glenn, Charlat, Olga, Jawahar, Satya, Lewitzky, Steve, Yang, Qing, Duong, Quyen, Spesny, Mitzi, Araya, Carmen, Araya, Xinia, Gallegos, Alvaro, Meza, Luis, Molina, Julio, Ramirez, Rolando, Mendez, Roxana, Silva, Sandra, Fournier, Eduardo, Batki, Steven L., Mathews, Carol A., Neylan, Thomas, Glatt, Charles E., Escamilla, Michael A., Luo, David, Gajiwala, Paresh, Song, Terry, Crook, Stephen, Nguyen, Jasmine B., Roche, Erin, Meyer, Joanne M., Leon, Pedro, Sandkuijl, Lodewijk A., Freimer, Nelson B., and Chen, Hong
- Published
- 2001
5. Brain-Derived Neurotrophic Factor Mediates Estradiol-Induced Dendritic Spine Formation in Hippocampal Neurons
- Author
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Murphy, Diane D., Cole, Nelson B., and Segal, Menahem
- Published
- 1998
6. A Complete Genome Screen for Genes Predisposing to Severe Bipolar Disorder in Two Costa Rican Pedigrees
- Author
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McInnes, L. Alison, Escamilla, Michael A., Service, Susan K., Reus, Victor I., Leon, Pedro, Silva, Sandra, Rojas, Eugenia, Spesny, Mitzi, Baharloo, Siamak, Blankenship, Kathleen, Peterson, Amy, Tyler, David, Shimayoshi, Norito, Tobey, Christa, Batki, Steven, Vinogradov, Sophia, Meza, Luis, Gallegos, Alvaro, Fournier, Eduardo, Smith, Lauren B., Barondes, Samuel H., Sandkuijl, Lodewijk A., and Freimer, Nelson B.
- Published
- 1996
7. Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome
- Author
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Olivier, Nelson B., Altman, Roger B., Noeske, Jonas, Basarab, Gregory S., Code, Erin, Ferguson, Andrew D., Gao, Ning, Huang, Jian, Juette, Manuel F., Livchak, Stephania, Miller, Matthew D., Prince, D. Bryan, Cate, Jamie H. D., Buurman, Ed T., and Blanchard, Scott C.
- Published
- 2014
8. Protective hinge in insulin opens to enable its receptor engagement
- Author
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Menting, John G., Yang, Yanwu, Chan, Shu Jin, Phillips, Nelson B., Smith, Brian J., Whittaker, Jonathan, Wickramasinghe, Nalinda P., Whittaker, Linda J., Pandyarajan, Vijay, Wan, Zhu-li, Yadav, Satya P., Carroll, Julie M., Strokes, Natalie, Roberts,, Charles T., Ismail-Beigi, Faramarz, Milewski, Wieslawa, Steiner, Donald F., Chauhan, Virander S., Ward, Colin W., Weiss, Michael A., and Lawrence, Michael C.
- Published
- 2014
- Full Text
- View/download PDF
9. Inherited human sex reversal due to impaired nucleocytoplasmic trafficking of SRY defines a male transcriptional threshold
- Author
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Chen, Yen-Shan, Racca, Joseph D., Phillips, Nelson B., and Weiss, Michael A.
- Published
- 2013
10. Microsatellite-encoded domain in rodent Sry functions as a genetic capacitor to enable the rapid evolution of biological novelty
- Author
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Chen, Yen-Shan, Racca, Joseph D., Sequeira, Paul W., Phillips, Nelson B., and Weiss, Michael A.
- Published
- 2013
11. α-Helical element at the hormone-binding surface of the insulin receptor functions as a signaling element to activate its tyrosine kinase
- Author
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Whittaker, Jonathan, Whittaker, Linda J., Roberts,, Charles T., Phillips, Nelson B., Ismail-Beigi, Faramarz, Lawrence, Michael C., and Weiss, Michael A.
- Published
- 2012
12. Genome-wide association and genetic functional studies identify autism susceptibility candidate 2 gene (AUTS2) in the regulation of alcohol consumption
- Author
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Schumann, Gunter, Coin, Lachlan J., Lourdusamy, Anbarasu, Charoen, Pimphen, Berger, Karen H., Stacey, David, Desrivières, Sylvane, Aliev, Fazil A., Khan, Anokhi A., Amin, Najaf, Aulchenko, Yurii S., Bakalkin, Georgy, Bakker, Stephan J., Balkau, Beverley, Beulens, Joline W., Bilbao, Ainhoa, de Boer, Rudolf A., Beury, Delphine, Bots, Michiel L., Breetvelt, Elemi J., Cauchi, Stéphane, Cavalcanti-Proença, Christine, Chambers, John C., Clarke, Toni-Kim, Dahmen, Norbert, de Geus, Eco J., Dick, Danielle, Ducci, Francesca, Easton, Alanna, Edenberg, Howard J., Esk, Tõnu, Fernández-Medarde, Alberto, Foroud, Tatiana, Freimer, Nelson B., Girault, Jean-Antoine, Grobbee, Diederick E., Guarrera, Simonetta, Gudbjartsson, Daniel F., Hartikainen, Anna-Liisa, Heath, Andrew C., Hesselbrock, Victor, Hofman, Albert, Hottenga, Jouke-Jan, Isohanni, Matti K., Kaprio, Jaakko, Khaw, Kay-Tee, Kuehnel, Brigitte, Laitinen, Jaana, Lobbens, Stéphane, Luan, Jian'an, Mangino, Massimo, Maroteaux, Matthieu, Matullo, Giuseppe, McCarthy, Mark I., Mueller, Christian, Navis, Gerjan, Numans, Mattijs E., Núñez, Alejandro, Nyholt, Dale R., Onland-Moret, Charlotte N., Oostra, Ben A., O'Reilly, Paul F., Palkovits, Miklos, Penninx, Brenda W., Polidoro, Silvia, Pouta, Anneli, Prokopenko, Inga, Ricceri, Fulvio, Santos, Eugenio, Smit, Johannes H., Soranzo, Nicole, Song, Kijoung, Sovio, Ulla, Stumvoll, Michael, Surakk, Ida, Thorgeirsson, Thorgeir E., Thorsteinsdottir, Unnur, Troakes, Claire, Tyrfingsson, Thorarinn, Tönjes, Anke, Uiterwaal, Cuno S., Uitterlinden, Andre G., van der Harst, Pim, van der Schouw, Yvonne T., Staehlin, Oliver, Vogelzangs, Nicole, Vollenweider, Peter, Waeber, Gerard, Wareham, Nicholas J., Waterworth, Dawn M., Whitfield, John B., Wichmann, Erich H., Willemsen, Gonneke, Witteman, Jacqueline C., Yuan, Xin, Zhai, Guangju, Zhao, Jing H., Zhang, Weihua, Martin, Nicholas G., Metspalu, Andres, Doering, Angela, Scott, James, Spector, Tim D., Loos, Ruth J., Boomsma, Dorret I., Mooser, Vincent, Peltonen, Leena, Stefansson, Kari, van Duijn, Cornelia M., Vineis, Paolo, Sommer, Wolfgang H., Kooner, Jaspal S., Spanagel, Rainer, Heberlein, Ulrike A., Jarvelin, Marjo-Riitta, Elliott, Paul, and Singer, Burton H.
- Published
- 2011
13. A Quantitative Trait Locus for Variation in Dopamine Metabolism Mapped in a Primate Model Using Reference Sequences from Related Species
- Author
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Freimer, Nelson B., Service, Susan K., Ophoff, Roel A., Jasinska, Anna J., McKee, Kevin, Villeneuve, Amelie, Belisle, Alexandre, Bailey, Julia N., Breidenthal, Sherry E., Jorgensen, Matthew J., Mann, J. John, Cantor, Rita M., Dewar, Ken, and Fairbanks, Lynn A.
- Published
- 2007
- Full Text
- View/download PDF
14. Insertion of a synthetic switch into insulin provides metabolite-dependent regulation of hormone-receptor activation.
- Author
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Yen-Shan Chen, Gleaton, Jeremy, Yanwu Yang, Dhayalan, Balamurugan, Phillips, Nelson B., Yule Liu, Broadwater, Laurie, Jarosinski, Mark A., Chatterjee, Deepak, Lawrence, Michael C., Hattier, Thomas, Michael, M. Dodson, and Weiss, Michael A.
- Subjects
INSULIN derivatives ,INSULIN ,CINNAMON ,HORMONE receptors ,METABOLIC regulation ,CURCUMIN ,GENETIC regulation ,FIREPROOFING agents - Abstract
Insulin-signaling requires conformational change: whereas the free hormone and its receptor each adopt autoinhibited conformations, their binding leads to structural reorganization. To test the functional coupling between insulin's "hinge opening" and receptor activation, we inserted an artificial ligand-dependent switch into the insulin molecule. Ligand-binding disrupts an internal tether designed to stabilize the hormone's native closed and inactive conformation, thereby enabling productive receptor engagement. This scheme exploited a diol sensor (meta-fluoro-phenylboronic acid at Gly
A1 ) and internal diol (3,4-dihydroxybenzoate at LysB28 ). The sensor recognizes monosaccharides (fructose > glucose). Studies of insulin-signaling in human hepatoma-derived cells (HepG2) demonstrated fructose-dependent receptor autophosphorylation leading to appropriate downstream signaling events, including a specific kinase cascade and metabolic gene regulation (gluconeogenesis and lipogenesis). Addition of glucose (an isomeric ligand with negligible sensor affinity) did not activate the hormone. Similarly, metabolite-regulated signaling was not observed in control studies of 1) an unmodified insulin analog or 2) an analog containing a diol sensor without internal tethering. Although secondary structure (as probed by circular dichroism) was unaffected by ligand-binding, heteronuclear NMR studies revealed subtle local and nonlocal monosaccharide-dependent changes in structure. Insertion of a synthetic switch into insulin has thus demonstrated coupling between hinge-opening and allosteric holoreceptor signaling. In addition to this foundational finding, our results provide proof of principle for design of a mechanism-based metabolite-responsive insulin. In particular, replacement of the present fructose sensor by an analogous glucose sensor may enable translational development of a "smart" insulin analog to mitigate hypoglycemic risk in diabetes therapy. [ABSTRACT FROM AUTHOR]- Published
- 2021
- Full Text
- View/download PDF
15. Negamycin induces translational stalling and miscoding by binding to the small subunit head domain of the Escherichia coli ribosome
- Author
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Nelson B. Olivier, D. Bryan Prince, Jian Huang, Ed T. Buurman, Andrew D. Ferguson, Matthew D. Miller, Jonas Noeske, Gregory S. Basarab, Ning Gao, Roger B. Altman, Manuel F. Juette, Erin Code, Scott C. Blanchard, Jamie H. D. Cate, and Stephania Livchak
- Subjects
Models, Molecular ,Protein subunit ,Minocycline ,GTPase ,Biology ,Bioinformatics ,Crystallography, X-Ray ,Ribosome ,Binding, Competitive ,Tigecycline ,RNA, Transfer ,Drug Resistance, Multiple, Bacterial ,RNA, Ribosomal, 16S ,Escherichia coli ,Point Mutation ,Binding site ,Base Pairing ,Multidisciplinary ,Binding Sites ,Tetracycline Resistance ,Amino Acids, Diamino ,Translation (biology) ,Cell biology ,Anti-Bacterial Agents ,A-site ,RNA, Bacterial ,Förster resonance energy transfer ,Tetracyclines ,Protein Biosynthesis ,Transfer RNA ,Physical Sciences ,Nucleic Acid Conformation ,Ribosomes - Abstract
Negamycin is a natural product with broad-spectrum antibacterial activity and efficacy in animal models of infection. Although its precise mechanism of action has yet to be delineated, negamycin inhibits cellular protein synthesis and causes cell death. Here, we show that single point mutations within 16S rRNA that confer resistance to negamycin are in close proximity of the tetracycline binding site within helix 34 of the small subunit head domain. As expected from its direct interaction with this region of the ribosome, negamycin was shown to displace tetracycline. However, in contrast to tetracycline-class antibiotics, which serve to prevent cognate tRNA from entering the translating ribosome, single-molecule fluorescence resonance energy transfer investigations revealed that negamycin specifically stabilizes near-cognate ternary complexes within the A site during the normally transient initial selection process to promote miscoding. The crystal structure of the 70S ribosome in complex with negamycin, determined at 3.1 A resolution, sheds light on this finding by showing that negamycin occupies a site that partially overlaps that of tetracycline-class antibiotics. Collectively, these data suggest that the small subunit head domain contributes to the decoding mechanism and that small-molecule binding to this domain may either prevent or promote tRNA entry by altering the initial selection mechanism after codon recognition and before GTPase activation.
- Published
- 2014
16. Dichotomy and perceptual distortions in absolute pitch ability
- Author
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Jason Zemansky, Alan Bostrom, E. Alexandra Athos, Nelson B. Freimer, Jane Gitschier, Barbara Levinson, and Amy L Kistler
- Subjects
Adult ,Male ,Adolescent ,media_common.quotation_subject ,Pitch Discrimination ,Tone (musical instrument) ,Perception ,Surveys and Questionnaires ,medicine ,Auditory system ,Humans ,Perceptual Distortion ,Child ,media_common ,Multidisciplinary ,Hearing Tests ,Age Factors ,Absolute pitch ,Reference tone ,medicine.anatomical_structure ,Acoustic Stimulation ,Trait ,Commentary ,Female ,Psychology ,Algorithms ,Music ,Cognitive psychology - Abstract
Absolute pitch (AP) is the rare ability to identify the pitch of a tone without the aid of a reference tone. Understanding both the nature and genesis of AP can provide insights into neuroplasticity in the auditory system. We explored factors that may influence the accuracy of pitch perception in AP subjects both during the development of the trait and in later age. We used a Web-based survey and a pitch-labeling test to collect perceptual data from 2,213 individuals, 981 (44%) of whom proved to have extraordinary pitch-naming ability. The bimodal distribution in pitch-naming ability signifies AP as a distinct perceptual trait, with possible implications for its genetic basis. The wealth of these data has allowed us to uncover unsuspected note-naming irregularities suggestive of a “perceptual magnet” centered at the note “A.” In addition, we document a gradual decline in pitch-naming accuracy with age, characterized by a perceptual shift in the “sharp” direction. These findings speak both to the process of acquisition of AP and to its stability.
- Published
- 2007
17. Country-level gender inequality is associated with structural differences in the brains of women and men.
- Author
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Zugman A, Alliende LM, Medel V, Bethlehem RAI, Seidlitz J, Ringlein G, Arango C, Arnatkevičiūtė A, Asmal L, Bellgrove M, Benegal V, Bernardo M, Billeke P, Bosch-Bayard J, Bressan R, Busatto GF, Castro MN, Chaim-Avancini T, Compte A, Costanzi M, Czepielewski L, Dazzan P, de la Fuente-Sandoval C, Di Forti M, Díaz-Caneja CM, María Díaz-Zuluaga A, Du Plessis S, Duran FLS, Fittipaldi S, Fornito A, Freimer NB, Gadelha A, Gama CS, Garani R, Garcia-Rizo C, Gonzalez Campo C, Gonzalez-Valderrama A, Guinjoan S, Holla B, Ibañez A, Ivanovic D, Jackowski A, Leon-Ortiz P, Lochner C, López-Jaramillo C, Luckhoff H, Massuda R, McGuire P, Miyata J, Mizrahi R, Murray R, Ozerdem A, Pan PM, Parellada M, Phahladira L, Ramirez-Mahaluf JP, Reckziegel R, Reis Marques T, Reyes-Madrigal F, Roos A, Rosa P, Salum G, Scheffler F, Schumann G, Serpa M, Stein DJ, Tepper A, Tiego J, Ueno T, Undurraga J, Undurraga EA, Valdes-Sosa P, Valli I, Villarreal M, Winton-Brown TT, Yalin N, Zamorano F, Zanetti MV, Winkler AM, Pine DS, Evans-Lacko S, and Crossley NA
- Subjects
- Male, Adult, Humans, Female, Sex Factors, Gender Equity, Brain diagnostic imaging
- Abstract
Gender inequality across the world has been associated with a higher risk to mental health problems and lower academic achievement in women compared to men. We also know that the brain is shaped by nurturing and adverse socio-environmental experiences. Therefore, unequal exposure to harsher conditions for women compared to men in gender-unequal countries might be reflected in differences in their brain structure, and this could be the neural mechanism partly explaining women's worse outcomes in gender-unequal countries. We examined this through a random-effects meta-analysis on cortical thickness and surface area differences between adult healthy men and women, including a meta-regression in which country-level gender inequality acted as an explanatory variable for the observed differences. A total of 139 samples from 29 different countries, totaling 7,876 MRI scans, were included. Thickness of the right hemisphere, and particularly the right caudal anterior cingulate, right medial orbitofrontal, and left lateral occipital cortex, presented no differences or even thicker regional cortices in women compared to men in gender-equal countries, reversing to thinner cortices in countries with greater gender inequality. These results point to the potentially hazardous effect of gender inequality on women's brains and provide initial evidence for neuroscience-informed policies for gender equality.
- Published
- 2023
- Full Text
- View/download PDF
18. Structural basis for KIT receptor tyrosine kinase inhibition by antibodies targeting the D4 membrane-proximal region.
- Author
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Reshetnyak AV, Nelson B, Shi X, Boggon TJ, Pavlenco A, Mandel-Bausch EM, Tome F, Suzuki Y, Sidhu SS, Lax I, and Schlessinger J
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Baculoviridae, Cell Surface Display Techniques, Crystallization, Enzyme-Linked Immunosorbent Assay, Immunoblotting, Immunoprecipitation, Mutation genetics, Neoplasms immunology, Proto-Oncogene Proteins c-kit antagonists & inhibitors, Proto-Oncogene Proteins c-kit genetics, Sf9 Cells, Spodoptera, Antibodies, Monoclonal chemistry, Models, Molecular, Multiprotein Complexes chemistry, Neoplasms drug therapy, Protein Conformation, Proto-Oncogene Proteins c-kit chemistry
- Abstract
Somatic oncogenic mutations in the receptor tyrosine kinase KIT function as major drivers of gastrointestinal stromal tumors and a subset of acute myeloid leukemia, melanoma, and other cancers. Although treatment of these cancers with tyrosine kinase inhibitors shows dramatic responses and durable disease control, drug resistance followed by clinical progression of disease eventually occurs in virtually all patients. In this report, we describe inhibitory KIT antibodies that bind to the membrane-proximal Ig-like D4 of KIT with significant overlap with an epitope in D4 that mediates homotypic interactions essential for KIT activation. Crystal structures of the anti-KIT antibody in complex with KIT D4 and D5 allowed design of affinity-matured libraries that were used to isolate variants with increased affinity and efficacy. Isolated antibodies showed KIT inhibition together with suppression of cell proliferation driven by ligand-stimulated WT or constitutively activated oncogenic KIT mutant. These antibodies represent a unique therapeutic approach and a step toward the development of "naked" or toxin-conjugated KIT antibodies for the treatment of KIT-driven cancers.
- Published
- 2013
- Full Text
- View/download PDF
19. Rates and patterns of great ape retrotransposition.
- Author
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Hormozdiari F, Konkel MK, Prado-Martinez J, Chiatante G, Herraez IH, Walker JA, Nelson B, Alkan C, Sudmant PH, Huddleston J, Catacchio CR, Ko A, Malig M, Baker C, Marques-Bonet T, Ventura M, Batzer MA, and Eichler EE
- Subjects
- Alu Elements genetics, Animals, Cluster Analysis, DNA Primers genetics, Genomics, Hominidae classification, Humans, Likelihood Functions, Long Interspersed Nucleotide Elements genetics, Polymerase Chain Reaction, Polymorphism, Single Nucleotide, Principal Component Analysis, Species Specificity, Genetic Variation, Genome genetics, Hominidae genetics, Phylogeny
- Abstract
We analyzed 83 fully sequenced great ape genomes for mobile element insertions, predicting a total of 49,452 fixed and polymorphic Alu and long interspersed element 1 (L1) insertions not present in the human reference assembly and assigning each retrotransposition event to a different time point during great ape evolution. We used these homoplasy-free markers to construct a mobile element insertions-based phylogeny of humans and great apes and demonstrate their differential power to discern ape subspecies and populations. Within this context, we find a good correlation between L1 diversity and single-nucleotide polymorphism heterozygosity (r(2) = 0.65) in contrast to Alu repeats, which show little correlation (r(2) = 0.07). We estimate that the "rate" of Alu retrotransposition has differed by a factor of 15-fold in these lineages. Humans, chimpanzees, and bonobos show the highest rates of Alu accumulation--the latter two since divergence 1.5 Mya. The L1 insertion rate, in contrast, has remained relatively constant, with rates differing by less than a factor of three. We conclude that Alu retrotransposition has been the most variable form of genetic variation during recent human-great ape evolution, with increases and decreases occurring over very short periods of evolutionary time.
- Published
- 2013
- Full Text
- View/download PDF
20. A polymorphism within a conserved beta(1)-adrenergic receptor motif alters cardiac function and beta-blocker response in human heart failure.
- Author
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Liggett SB, Mialet-Perez J, Thaneemit-Chen S, Weber SA, Greene SM, Hodne D, Nelson B, Morrison J, Domanski MJ, Wagoner LE, Abraham WT, Anderson JL, Carlquist JF, Krause-Steinrauf HJ, Lazzeroni LC, Port JD, Lavori PW, and Bristow MR
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Animals, Cricetinae, Female, Genotype, Heart Ventricles pathology, Humans, Male, Molecular Sequence Data, Pharmacogenetics methods, Propanolamines pharmacology, Sequence Homology, Amino Acid, Adrenergic beta-Antagonists pharmacology, Heart Failure drug therapy, Heart Failure pathology, Polymorphism, Genetic, Receptors, Adrenergic, beta-1 genetics
- Abstract
Heterogeneity of heart failure (HF) phenotypes indicates contributions from underlying common polymorphisms. We considered polymorphisms in the beta(1)-adrenergic receptor (beta(1)AR), a beta-blocker target, as candidate pharmacogenomic loci. Transfected cells, genotyped human nonfailing and failing ventricles, and a clinical trial were used to ascertain phenotype and mechanism. In nonfailing and failing isolated ventricles, beta(1)-Arg-389 had respective 2.8 +/- 0.3- and 4.3 +/- 2.1-fold greater agonist-promoted contractility vs. beta(1)-Gly-389, defining enhanced physiologic coupling under relevant conditions of endogenous expression and HF. The beta-blocker bucindolol was an inverse agonist in failing Arg, but not Gly, ventricles, without partial agonist activity at either receptor; carvedilol was a genotype-independent neutral antagonist. In transfected cells, bucindolol antagonized agonist-stimulated cAMP, with a greater absolute decrease observed for Arg-389 (435 +/- 80 vs. 115 +/- 23 fmol per well). Potential pathophysiologic correlates were assessed in a placebo-controlled trial of bucindolol in 1,040 HF patients. No outcome was associated with genotype in the placebo group, indicating little impact on the natural course of HF. However, the Arg-389 homozygotes treated with bucindolol had an age-, sex-, and race-adjusted 38% reduction in mortality (P = 0.03) and 34% reduction in mortality or hospitalization (P = 0.004) vs. placebo. In contrast, Gly-389 carriers had no clinical response to bucindolol compared with placebo. Those with Arg-389 and high baseline norepinephrine levels trended toward improved survival, but no advantage with this allele and exaggerated sympatholysis was identified. We conclude that beta(1)AR-389 variation alters signaling in multiple models and affects the beta-blocker therapeutic response in HF and, thus, might be used to individualize treatment of the syndrome.
- Published
- 2006
- Full Text
- View/download PDF
21. Cytosol-endoplasmic reticulum interplay by Sec61alpha translocon in polyglutamine-mediated neurotoxicity in Drosophila.
- Author
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Kanuka H, Kuranaga E, Hiratou T, Igaki T, Nelson B, Okano H, and Miura M
- Subjects
- Animals, Cell Line, Cysteine Endopeptidases, Drosophila, Multienzyme Complexes antagonists & inhibitors, Nervous System cytology, Proteasome Endopeptidase Complex, Ubiquitin metabolism, Carrier Proteins genetics, Cytosol metabolism, Endoplasmic Reticulum metabolism, Nervous System drug effects, Peptides toxicity
- Abstract
Intracellular deposition of aggregated and ubiquitinated proteins is a prominent cytopathological feature of most neurodegenerative disorders frequently correlated with neural cell death. To elucidate mechanisms in neural cell death and degeneration, we characterized the Drosophila ortholog of Sec61alpha (DSec61alpha), a component of the translocon that is involved in both protein import and endoplasmic reticulum-associated degradation. Loss-of-function experiments for DSec61alpha revealed that the translocon contributes to expanded polyglutamine-mediated neuronal toxicity, likely resulting from proteasome inhibition and leading to accumulation of ubiquitinated proteins. Taken together, proteasome inhibition by expanded polyglutamine tracts may lead to the accumulation of toxic undegraded proteins normally transported by the Sec61alpha translocon.
- Published
- 2003
- Full Text
- View/download PDF
22. Requirement for an initial signal from the membrane-proximal region of the interleukin 2 receptor gamma(c) chain for Janus kinase activation leading to T cell proliferation.
- Author
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Nelson BH, McIntosh BC, Rosencrans LL, and Greenberg PD
- Subjects
- Amino Acid Sequence, Cell Division, Dimerization, Enzyme Activation, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Homeodomain Proteins metabolism, Janus Kinase 1, Janus Kinase 3, Molecular Sequence Data, Mutagenesis, Site-Directed, Phosphorylation, Precipitin Tests, Protein-Tyrosine Kinases chemistry, Receptors, Cytokine metabolism, Receptors, Interleukin-2 genetics, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Signal Transduction, T-Lymphocytes enzymology, Tyrosine metabolism, Protein-Tyrosine Kinases metabolism, Receptors, Interleukin-2 metabolism, T-Lymphocytes cytology
- Abstract
The interleukin 2 receptor (IL-2R) generates proliferative signals in T lymphocytes by ligand-induced heterodimerization of two chains, IL-2Rbeta and gamma(c), which associate with the tyrosine kinases Jak1 and Jak3, respectively. Genetic and molecular studies have demonstrated that Jak3 is essential for mitogenic signaling by the gamma(c) chain; because it is also the only molecule known to associate with gamma(c), we speculated that Jak3 might be sufficient for signaling by this chain. Therefore, fusion proteins were constructed in which all or part of the cytoplasmic domain of gamma(c) was replaced by Jak3. Signaling was evaluated in the IL-2-dependent T cell line CTLL-2 using chimeric IL-2Rbeta and gamma(c) chains that bind and are activated by the cytokine granulocyte-macrophage colony-stimulating factor. Chimeric gamma(c) chains containing only Jak3 in the cytoplasmic domain failed to mediate proliferation of CTLL-2 cells, but addition of a conserved membrane-proximal (PROX) domain of gamma(c) in tandem with Jak3 fully reconstituted gamma(c) function. The requirement for the PROX domain reflected an essential role in the activation of Jak3 in vivo. Despite lacking defined catalytic motifs, PROX induced an early Jak-independent signal, including tyrosine phosphorylation of IL-2Rbeta and the tyrosine phosphatase SHP-2. The results define the minimal signaling components of gamma(c) and suggest a new mechanism by which the IL-2R initiates signaling in response to ligand.
- Published
- 1997
- Full Text
- View/download PDF
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