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1,530 results on '"Joshi, P. K."'

151. On the mechanism of gas adsorption for pristine, defective and functionalized graphene

Author

You, Y., Deng, J., Tan, X., Gorjizadeh, N., Yoshimura, M., Smith, S. C., Sahajwalla, V., and Joshi, R. K.

Subjects
Condensed Matter - Materials Science
Abstract

Defect is no longer deemed an adverse aspect of graphene. Contrarily, it can pave ways of extending applicability of graphene. Here, we discuss the effects of three types of defects on graphene: carbon deficiency, adatom (single Fe) dopant and introduction of functional groups (carboxyl, pyran group) on NO2 gas adsorption via density functional theory method. We have observed that the unsaturated carbon in defected graphene is highly active to attract NO2 molecules. Our study suggests that introducing Fe on graphene can enhance the NO2 adsorption process. Adsorption energy calculations suggest the enhancement in NO2 adsorption is more profound for Fe-doped mono and tetra vacant graphene than Fe doped bi- and tri-vacant graphene. This study could potentially be useful in developing adsorption-based applications of graphene.

Published
2016
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152. HIV latency in isolated patient CD4+ T cells may be due to blocks in HIV transcriptional elongation, completion, and splicing

Author

Yukl, Steven A, Kaiser, Philipp, Kim, Peggy, Telwatte, Sushama, Joshi, Sunil K, Vu, Mai, Lampiris, Harry, and Wong, Joseph K

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Sexually Transmitted Infections, Genetics, HIV/AIDS, Clinical Research, Infectious Diseases, 5.1 Pharmaceuticals, Infection, Anti-Retroviral Agents, CD4-Positive T-Lymphocytes, HIV-1, Humans, Polymerase Chain Reaction, RNA Splicing, T-Lymphocytes, Biological Sciences, Medical and Health Sciences, Medical biotechnology, Biomedical engineering
Abstract

Latently infected CD4+ T cells are the main barrier to complete clearance of HIV infection, but it is unclear what mechanisms govern latent HIV infection in vivo. To address this question, we developed a new panel of reverse transcription droplet digital polymerase chain reaction (RT-ddPCR) assays specific for different HIV transcripts that define distinct blocks to transcription. We applied this panel of assays to CD4+ T cells freshly isolated from HIV-infected patients on suppressive antiretroviral therapy (ART) to quantify the degree to which different mechanisms inhibit HIV transcription. In addition, we measured the degree to which these transcriptional blocks could be reversed ex vivo by T cell activation (using anti-CD3/CD28 antibodies) or latency-reversing agents. We found that the main reversible block to HIV RNA transcription was not inhibition of transcriptional initiation but rather a series of blocks to proximal elongation, distal transcription/polyadenylation (completion), and multiple splicing. Cell dilution experiments suggested that these mechanisms operated in most of the HIV-infected CD4+ T cells examined. Latency-reversing agents exerted differential effects on the three blocks to HIV transcription, suggesting that these blocks may be governed by different mechanisms.

Published
2018

153. Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels

Author

Jiang, Xia, O’Reilly, Paul F, Aschard, Hugues, Hsu, Yi-Hsiang, Richards, J Brent, Dupuis, Josée, Ingelsson, Erik, Karasik, David, Pilz, Stefan, Berry, Diane, Kestenbaum, Bryan, Zheng, Jusheng, Luan, Jianan, Sofianopoulou, Eleni, Streeten, Elizabeth A, Albanes, Demetrius, Lutsey, Pamela L, Yao, Lu, Tang, Weihong, Econs, Michael J, Wallaschofski, Henri, Völzke, Henry, Zhou, Ang, Power, Chris, McCarthy, Mark I, Michos, Erin D, Boerwinkle, Eric, Weinstein, Stephanie J, Freedman, Neal D, Huang, Wen-Yi, Van Schoor, Natasja M, van der Velde, Nathalie, Groot, Lisette CPGM de, Enneman, Anke, Cupples, L Adrienne, Booth, Sarah L, Vasan, Ramachandran S, Liu, Ching-Ti, Zhou, Yanhua, Ripatti, Samuli, Ohlsson, Claes, Vandenput, Liesbeth, Lorentzon, Mattias, Eriksson, Johan G, Shea, M Kyla, Houston, Denise K, Kritchevsky, Stephen B, Liu, Yongmei, Lohman, Kurt K, Ferrucci, Luigi, Peacock, Munro, Gieger, Christian, Beekman, Marian, Slagboom, Eline, Deelen, Joris, Heemst, Diana van, Kleber, Marcus E, März, Winfried, de Boer, Ian H, Wood, Alexis C, Rotter, Jerome I, Rich, Stephen S, Robinson-Cohen, Cassianne, den Heijer, Martin, Jarvelin, Marjo-Riitta, Cavadino, Alana, Joshi, Peter K, Wilson, James F, Hayward, Caroline, Lind, Lars, Michaëlsson, Karl, Trompet, Stella, Zillikens, M Carola, Uitterlinden, Andre G, Rivadeneira, Fernando, Broer, Linda, Zgaga, Lina, Campbell, Harry, Theodoratou, Evropi, Farrington, Susan M, Timofeeva, Maria, Dunlop, Malcolm G, Valdes, Ana M, Tikkanen, Emmi, Lehtimäki, Terho, Lyytikäinen, Leo-Pekka, Kähönen, Mika, Raitakari, Olli T, Mikkilä, Vera, Ikram, M Arfan, Sattar, Naveed, Jukema, J Wouter, Wareham, Nicholas J, Langenberg, Claudia, Forouhi, Nita G, Gundersen, Thomas E, Khaw, Kay-Tee, Butterworth, Adam S, Danesh, John, and Spector, Timothy

Subjects
Epidemiology, Biological Sciences, Health Sciences, Genetics, Human Genome, Clinical Research, 1.1 Normal biological development and functioning, Inflammatory and immune system, Amidohydrolases, Autoimmune Diseases, Cohort Studies, Female, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Vesicular Transport Proteins, Vitamin D, White People
Abstract

Vitamin D is a steroid hormone precursor that is associated with a range of human traits and diseases. Previous GWAS of serum 25-hydroxyvitamin D concentrations have identified four genome-wide significant loci (GC, NADSYN1/DHCR7, CYP2R1, CYP24A1). In this study, we expand the previous SUNLIGHT Consortium GWAS discovery sample size from 16,125 to 79,366 (all European descent). This larger GWAS yields two additional loci harboring genome-wide significant variants (P = 4.7×10-9 at rs8018720 in SEC23A, and P = 1.9×10-14 at rs10745742 in AMDHD1). The overall estimate of heritability of 25-hydroxyvitamin D serum concentrations attributable to GWAS common SNPs is 7.5%, with statistically significant loci explaining 38% of this total. Further investigation identifies signal enrichment in immune and hematopoietic tissues, and clustering with autoimmune diseases in cell-type-specific analysis. Larger studies are required to identify additional common SNPs, and to explore the role of rare or structural variants and gene-gene interactions in the heritability of circulating 25-hydroxyvitamin D levels.

Published
2018

154. Large-scale GWAS identifies multiple loci for hand grip strength providing biological insights into muscular fitness.

Author

Willems, Sara M, Wright, Daniel J, Day, Felix R, Trajanoska, Katerina, Joshi, Peter K, Morris, John A, Matteini, Amy M, Garton, Fleur C, Grarup, Niels, Oskolkov, Nikolay, Thalamuthu, Anbupalam, Mangino, Massimo, Liu, Jun, Demirkan, Ayse, Lek, Monkol, Xu, Liwen, Wang, Guan, Oldmeadow, Christopher, Gaulton, Kyle J, Lotta, Luca A, Miyamoto-Mikami, Eri, Rivas, Manuel A, White, Tom, Loh, Po-Ru, Aadahl, Mette, Amin, Najaf, Attia, John R, Austin, Krista, Benyamin, Beben, Brage, Søren, Cheng, Yu-Ching, Cięszczyk, Paweł, Derave, Wim, Eriksson, Karl-Fredrik, Eynon, Nir, Linneberg, Allan, Lucia, Alejandro, Massidda, Myosotis, Mitchell, Braxton D, Miyachi, Motohiko, Murakami, Haruka, Padmanabhan, Sandosh, Pandey, Ashutosh, Papadimitriou, Ioannis, Rajpal, Deepak K, Sale, Craig, Schnurr, Theresia M, Sessa, Francesco, Shrine, Nick, Tobin, Martin D, Varley, Ian, Wain, Louise V, Wray, Naomi R, Lindgren, Cecilia M, MacArthur, Daniel G, Waterworth, Dawn M, McCarthy, Mark I, Pedersen, Oluf, Khaw, Kay-Tee, Kiel, Douglas P, GEFOS Any-Type of Fracture Consortium, Pitsiladis, Yannis, Fuku, Noriyuki, Franks, Paul W, North, Kathryn N, van Duijn, Cornelia M, Mather, Karen A, Hansen, Torben, Hansson, Ola, Spector, Tim, Murabito, Joanne M, Richards, J Brent, Rivadeneira, Fernando, Langenberg, Claudia, Perry, John RB, Wareham, Nick J, and Scott, Robert A

Subjects
GEFOS Any-Type of Fracture Consortium, Hand, Humans, Actins, Transforming Growth Factor alpha, Membrane Proteins, Neoplasm Proteins, Nuclear Proteins, Repressor Proteins, Hand Strength, Cohort Studies, Genetics, Population, Polymorphism, Single Nucleotide, Adult, Aged, Middle Aged, European Continental Ancestry Group, Female, Male, Genome-Wide Association Study, Genetic Loci, United Kingdom, Prevention, Genetics, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Musculoskeletal
Abstract

Hand grip strength is a widely used proxy of muscular fitness, a marker of frailty, and predictor of a range of morbidities and all-cause mortality. To investigate the genetic determinants of variation in grip strength, we perform a large-scale genetic discovery analysis in a combined sample of 195,180 individuals and identify 16 loci associated with grip strength (P

Published
2017

155. Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk.

Author

Day, Felix R, Thompson, Deborah J, Helgason, Hannes, Chasman, Daniel I, Finucane, Hilary, Sulem, Patrick, Ruth, Katherine S, Whalen, Sean, Sarkar, Abhishek K, Albrecht, Eva, Altmaier, Elisabeth, Amini, Marzyeh, Barbieri, Caterina M, Boutin, Thibaud, Campbell, Archie, Demerath, Ellen, Giri, Ayush, He, Chunyan, Hottenga, Jouke J, Karlsson, Robert, Kolcic, Ivana, Loh, Po-Ru, Lunetta, Kathryn L, Mangino, Massimo, Marco, Brumat, McMahon, George, Medland, Sarah E, Nolte, Ilja M, Noordam, Raymond, Nutile, Teresa, Paternoster, Lavinia, Perjakova, Natalia, Porcu, Eleonora, Rose, Lynda M, Schraut, Katharina E, Segrè, Ayellet V, Smith, Albert V, Stolk, Lisette, Teumer, Alexander, Andrulis, Irene L, Bandinelli, Stefania, Beckmann, Matthias W, Benitez, Javier, Bergmann, Sven, Bochud, Murielle, Boerwinkle, Eric, Bojesen, Stig E, Bolla, Manjeet K, Brand, Judith S, Brauch, Hiltrud, Brenner, Hermann, Broer, Linda, Brüning, Thomas, Buring, Julie E, Campbell, Harry, Catamo, Eulalia, Chanock, Stephen, Chenevix-Trench, Georgia, Corre, Tanguy, Couch, Fergus J, Cousminer, Diana L, Cox, Angela, Crisponi, Laura, Czene, Kamila, Davey Smith, George, de Geus, Eco JCN, de Mutsert, Renée, De Vivo, Immaculata, Dennis, Joe, Devilee, Peter, Dos-Santos-Silva, Isabel, Dunning, Alison M, Eriksson, Johan G, Fasching, Peter A, Fernández-Rhodes, Lindsay, Ferrucci, Luigi, Flesch-Janys, Dieter, Franke, Lude, Gabrielson, Marike, Gandin, Ilaria, Giles, Graham G, Grallert, Harald, Gudbjartsson, Daniel F, Guénel, Pascal, Hall, Per, Hallberg, Emily, Hamann, Ute, Harris, Tamara B, Hartman, Catharina A, Heiss, Gerardo, Hooning, Maartje J, Hopper, John L, Hu, Frank, Hunter, David J, Ikram, M Arfan, Im, Hae Kyung, Järvelin, Marjo-Riitta, Joshi, Peter K, Karasik, David, and Kellis, Manolis

Subjects
LifeLines Cohort Study, InterAct Consortium, kConFab/AOCS Investigators, Endometrial Cancer Association Consortium, Ovarian Cancer Association Consortium, PRACTICAL consortium, Humans, Neoplasms, Genetic Predisposition to Disease, Ubiquitin-Protein Ligases, Intercellular Signaling Peptides and Proteins, Calcium-Binding Proteins, Ribonucleoproteins, Membrane Proteins, Body Mass Index, Risk Factors, Age Factors, Genomic Imprinting, Puberty, Menarche, Polymorphism, Single Nucleotide, Quantitative Trait Loci, Databases, Genetic, Adolescent, Female, Male, Genome-Wide Association Study, Aging, Breast Cancer, Biotechnology, Cancer, Human Genome, Genetics, Prostate Cancer, Urologic Diseases, 2.1 Biological and endogenous factors, Aetiology, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10-8) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

Published
2017

156. Assays for precise quantification of total (including short) and elongated HIV-1 transcripts

Author

Kaiser, Philipp, Joshi, Sunil K, Kim, Peggy, Li, Peilin, Liu, Hongbing, Rice, Andrew P, Wong, Joseph K, and Yukl, Steven A

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, HIV/AIDS, Sexually Transmitted Infections, Infectious Diseases, Genetics, Infection, Gene Expression Regulation, Viral, HIV Infections, HIV Long Terminal Repeat, HIV-1, Humans, Male, Polyadenylation, RNA, Viral, Reverse Transcriptase Polymerase Chain Reaction, Reverse Transcription, Transcription, Genetic, Virus Latency, Latency, Transcription, Elongation, TAR, Short or abortive transcript, Microbiology, Virology, Medical microbiology
Abstract

Despite intensive study, it is unclear which mechanisms are responsible for latent HIV infection in vivo. One potential mechanism is inhibition of HIV transcriptional elongation, which results in short abortive transcripts containing the trans-activation response (TAR) region. Because the relative levels of total (including short) and processive transcripts provide measures of HIV transcriptional initiation and elongation, there is a compelling need for techniques that accurately measure both. Nonetheless, prior assays for total transcripts have been semi-quantitative and have seen limited application to patient samples. This manuscript reports the validation of quantitative reverse transcription (RT) droplet digital PCR assays for measurement of total (TAR) and processive (R-U5/gag) HIV transcripts. Traditional RT priming strategies can efficiently detect the TAR region on long HIV transcripts but detect 10-fold higher than elongated transcripts, implying a substantial block to transcriptional elongation in vivo. This approach may be applied to other difficult-to-prime RNA targets.

Published
2017

161. Approaching Tsirelson's bound in a photon pair experiment

Author

Poh, Hou Shun, Joshi, Siddarth K., Ceré, Alessandro, Cabello, Adán, and Kurtsiefer, Christian

Subjects
Quantum Physics
Abstract

Quantum theory introduces a cut between the observer and the observed system, but does not provide a definition of what is an observer. Based on an informational definition of observer, Grinbaum has recently predicted an upper bound on bipartite correlations in the Clauser-Horne-Shimony-Holt (CHSH) Bell scenario equal to 2.82537, which is slightly smaller than the Tsirelson bound of standard quantum theory, but is consistent with all the available experimental results. Not being able to exceed Grinbaum's limit would support that quantum theory is only an effective description of a more fundamental theory and would have a deep impact in physics and quantum information processing. Here we present a test of the CHSH Bell inequality on photon pairs in maximally entangled states of polarization in which a value 2.82759+-0.00051 is observed, violating Grinbaum's bound by 4.3 standard deviations and providing the smallest distance with respect to Tsirelson's bound ever reported, namely, 0.00084+-0.00051. This sets a new lower experimental bound for Tsirelson's bound, strengthening the value of principles that predict Tsirelson's bound as possible explanations of all natural limits of correlations, and has important consequences for cryptographic security, randomness certification, characterization of physical properties in device-independent scenarios, and certification of quantum computation., Comment: 4 pages, 2 figures, 1 number - updated error bars, references, and error discussion

Published
2015
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162. Variation in the SERPINA6/SERPINA1 locus alters morning plasma cortisol, hepatic corticosteroid binding globulin expression, gene expression in peripheral tissues, and risk of cardiovascular disease

Author

Crawford, Andrew A., Bankier, Sean, Altmaier, Elisabeth, Barnes, Catriona L. K., Clark, David W., Ermel, Raili, Friedrich, Nele, van der Harst, Pim, Joshi, Peter K., Karhunen, Ville, Lahti, Jari, Mahajan, Anubha, Mangino, Massimo, Nethander, Maria, Neumann, Alexander, Pietzner, Maik, Sukhavasi, Katyayani, Wang, Carol A., Bakker, Stephan J. L., Bjorkegren, Johan L. M., Campbell, Harry, Eriksson, Johan, Gieger, Christian, Hayward, Caroline, Jarvelin, Marjo-Riitta, McLachlan, Stela, Morris, Andrew P., Ohlsson, Claes, Pennell, Craig E., Price, Jackie, Rudan, Igor, Ruusalepp, Arno, Spector, Tim, Tiemeier, Henning, Völzke, Henry, Wilson, James F., Michoel, Tom, Timpson, Nicolas J., Smith, George Davey, and Walker, Brian R.

Published
2021
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166. A Randomized Controlled Trial of Lisinopril to Decrease Lymphoid Fibrosis in Antiretroviral-Treated, HIV-infected Individuals

Author

Cockerham, Leslie R, Yukl, Steven A, Harvill, Kara, Somsouk, Ma, Joshi, Sunil K, Sinclair, Elizabeth, Liegler, Teri, Hoh, Rebecca, Lyons, Sophie, Hunt, Peter W, Rupert, Adam, Sereti, Irini, Morcock, David R, Rhodes, Ajantha, Emson, Claire, Hellerstein, Marc K, Estes, Jacob D, Lewin, Sharon, Deeks, Steven G, and Hatano, Hiroyu

Subjects
Medical Microbiology, Biomedical and Clinical Sciences, Immunology, Clinical Research, HIV/AIDS, Infectious Diseases, Clinical Trials and Supportive Activities, Sexually Transmitted Infections, 6.1 Pharmaceuticals, Infection, Good Health and Well Being, Anti-Inflammatory Agents/*therapeutic use, CD4 Lymphocyte Count, Disease Reservoirs/*virology, HIV, Lymphoid fibrosis, T-cell activation, Clinical sciences, Medical microbiology
Abstract

BackgroundIn HIV infection, lymphoid tissue is disrupted by fibrosis. Angiotensin converting enzyme inhibitors have anti-fibrotic properties. We completed a pilot study to assess whether the addition of lisinopril to antiretroviral therapy (ART) reverses fibrosis of gut tissue, and whether this leads to reduction of HIV RNA and DNA levels.MethodsThirty HIV-infected individuals on ART were randomized to lisinopril at 20mg daily or matching placebo for 24 weeks. All participants underwent rectal biopsies prior to starting the study drug and at 22 weeks, and there were regular blood draws. The primary end point was the change in HIV RNA and DNA levels in rectal tissue. Secondary outcomes included the change in 1) HIV levels in blood; 2) Gag-specific T-cell responses; 3) levels of T-cell activation; and 4) collagen deposition.ResultsThe addition of lisinopril did not have a significant effect on the levels of HIV RNA or DNA in gut tissue or blood, Gag-specific responses, or levels of T-cell activation. Lisinopril also did not have a significant impact on lymphoid fibrosis in the rectum, as assessed by quantitative histology or heavy water labeling.ConclusionsTreatment with lisinopril for 24 weeks in HIV-infected adults did not have an effect on lymphoid fibrosis, immune activation, or gut tissue viral reservoirs. Further study is needed to see if other anti-fibrotic agents may be useful in reversing lymphoid fibrosis and reducing HIV levels.

Published
2017

169. KLB is associated with alcohol drinking, and its gene product β-Klotho is necessary for FGF21 regulation of alcohol preference

Author

Schumann, Gunter, Liu, Chunyu, O'Reilly, Paul, Gao, He, Song, Parkyong, Xu, Bing, Ruggeri, Barbara, Amin, Najaf, Jia, Tianye, Preis, Sarah, Segura Lepe, Marcelo, Akira, Shizuo, Barbieri, Caterina, Baumeister, Sebastian, Cauchi, Stephane, Clarke, Toni-Kim, Enroth, Stefan, Fischer, Krista, Hällfors, Jenni, Harris, Sarah E, Hieber, Saskia, Hofer, Edith, Hottenga, Jouke-Jan, Johansson, Åsa, Joshi, Peter K, Kaartinen, Niina, Laitinen, Jaana, Lemaitre, Rozenn, Loukola, Anu, Luan, Jian'an, Lyytikäinen, Leo-Pekka, Mangino, Massimo, Manichaikul, Ani, Mbarek, Hamdi, Milaneschi, Yuri, Moayyeri, Alireza, Mukamal, Kenneth, Nelson, Christopher, Nettleton, Jennifer, Partinen, Eemil, Rawal, Rajesh, Robino, Antonietta, Rose, Lynda, Sala, Cinzia, Satoh, Takashi, Schmidt, Reinhold, Schraut, Katharina, Scott, Robert, Smith, Albert Vernon, Starr, John M, Teumer, Alexander, Trompet, Stella, Uitterlinden, André G, Venturini, Cristina, Vergnaud, Anne-Claire, Verweij, Niek, Vitart, Veronique, Vuckovic, Dragana, Wedenoja, Juho, Yengo, Loic, Yu, Bing, Zhang, Weihua, Zhao, Jing Hua, Boomsma, Dorret I, Chambers, John, Chasman, Daniel I, Daniela, Toniolo, de Geus, Eco, Deary, Ian, Eriksson, Johan G, Esko, Tõnu, Eulenburg, Volker, Franco, Oscar H, Froguel, Philippe, Gieger, Christian, Grabe, Hans J, Gudnason, Vilmundur, Gyllensten, Ulf, Harris, Tamara B, Hartikainen, Anna-Liisa, Heath, Andrew C, Hocking, Lynne, Hofman, Albert, Huth, Cornelia, Jarvelin, Marjo-Riitta, Jukema, J Wouter, Kaprio, Jaakko, Kooner, Jaspal S, Kutalik, Zoltan, Lahti, Jari, Langenberg, Claudia, Lehtimäki, Terho, Liu, Yongmei, Madden, Pamela AF, Martin, Nicholas, Morrison, Alanna, Penninx, Brenda, Pirastu, Nicola, Psaty, Bruce, and Raitakari, Olli

Subjects
Biological Psychology, Pharmacology and Pharmaceutical Sciences, Biomedical and Clinical Sciences, Psychology, Alcoholism, Alcohol Use and Health, Genetics, Basic Behavioral and Social Science, Substance Misuse, Liver Disease, Behavioral and Social Science, Digestive Diseases, Neurosciences, Cardiovascular, Cancer, Oral and gastrointestinal, Stroke, Good Health and Well Being, Alcohol Drinking, Animals, Behavior, Animal, Brain, Emotions, Female, Fibroblast Growth Factors, Genome-Wide Association Study, Humans, Klotho Proteins, Liver, Male, Membrane Proteins, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Polymorphism, Single Nucleotide, alcohol consumption, human, beta-Klotho, FGF21, mouse model, β-Klotho
Abstract

Excessive alcohol consumption is a major public health problem worldwide. Although drinking habits are known to be inherited, few genes have been identified that are robustly linked to alcohol drinking. We conducted a genome-wide association metaanalysis and replication study among >105,000 individuals of European ancestry and identified β-Klotho (KLB) as a locus associated with alcohol consumption (rs11940694; P = 9.2 × 10-12). β-Klotho is an obligate coreceptor for the hormone FGF21, which is secreted from the liver and implicated in macronutrient preference in humans. We show that brain-specific β-Klotho KO mice have an increased alcohol preference and that FGF21 inhibits alcohol drinking by acting on the brain. These data suggest that a liver-brain endocrine axis may play an important role in the regulation of alcohol drinking behavior and provide a unique pharmacologic target for reducing alcohol consumption.

Published
2016

170. Genome-wide associations for birth weight and correlations with adult disease

Author

Horikoshi, Momoko, Beaumont, Robin N, Day, Felix R, Warrington, Nicole M, Kooijman, Marjolein N, Fernandez-Tajes, Juan, Feenstra, Bjarke, van Zuydam, Natalie R, Gaulton, Kyle J, Grarup, Niels, Bradfield, Jonathan P, Strachan, David P, Li-Gao, Ruifang, Ahluwalia, Tarunveer S, Kreiner, Eskil, Rueedi, Rico, Lyytikäinen, Leo-Pekka, Cousminer, Diana L, Wu, Ying, Thiering, Elisabeth, Wang, Carol A, Have, Christian T, Hottenga, Jouke-Jan, Vilor-Tejedor, Natalia, Joshi, Peter K, Boh, Eileen Tai Hui, Ntalla, Ioanna, Pitkänen, Niina, Mahajan, Anubha, van Leeuwen, Elisabeth M, Joro, Raimo, Lagou, Vasiliki, Nodzenski, Michael, Diver, Louise A, Zondervan, Krina T, Bustamante, Mariona, Marques-Vidal, Pedro, Mercader, Josep M, Bennett, Amanda J, Rahmioglu, Nilufer, Nyholt, Dale R, Ma, Ronald CW, Tam, Claudia HT, Tam, Wing Hung, Ganesh, Santhi K, van Rooij, Frank JA, Jones, Samuel E, Loh, Po-Ru, Ruth, Katherine S, Tuke, Marcus A, Tyrrell, Jessica, Wood, Andrew R, Yaghootkar, Hanieh, Scholtens, Denise M, Paternoster, Lavinia, Prokopenko, Inga, Kovacs, Peter, Atalay, Mustafa, Willems, Sara M, Panoutsopoulou, Kalliope, Wang, Xu, Carstensen, Lisbeth, Geller, Frank, Schraut, Katharina E, Murcia, Mario, van Beijsterveldt, Catharina EM, Willemsen, Gonneke, Appel, Emil VR, Fonvig, Cilius E, Trier, Caecilie, Tiesler, Carla MT, Standl, Marie, Kutalik, Zoltán, Bonàs-Guarch, Sílvia, Hougaard, David M, Sánchez, Friman, Torrents, David, Waage, Johannes, Hollegaard, Mads V, de Haan, Hugoline G, Rosendaal, Frits R, Medina-Gomez, Carolina, Ring, Susan M, Hemani, Gibran, McMahon, George, Robertson, Neil R, Groves, Christopher J, Langenberg, Claudia, Luan, Jian’an, Scott, Robert A, Zhao, Jing Hua, Mentch, Frank D, MacKenzie, Scott M, Reynolds, Rebecca M, Lowe, William L, Tönjes, Anke, Stumvoll, Michael, Lindi, Virpi, Lakka, Timo A, and van Duijn, Cornelia M

Subjects
Nutrition, Perinatal Period - Conditions Originating in Perinatal Period, Human Genome, Genetics, Clinical Research, Preterm, Low Birth Weight and Health of the Newborn, Obesity, Prevention, Pediatric, Infant Mortality, 2.1 Biological and endogenous factors, Aetiology, Adult, Aging, Anthropometry, Birth Weight, Blood Pressure, Chromatin Assembly and Disassembly, Cohort Studies, Coronary Artery Disease, Datasets as Topic, Diabetes Mellitus, Type 2, Female, Fetus, Genetic Loci, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genomic Imprinting, Genotype, Glucose, Glycogen, Humans, Insulin, Male, Phenotype, Signal Transduction, CHARGE Consortium Hematology Working Group, Early Growth Genetics (EGG) Consortium, General Science & Technology
Abstract

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P

Published
2016

171. Meta-analysis of 49 549 individuals imputed with the 1000 Genomes Project reveals an exonic damaging variant in ANGPTL4 determining fasting TG levels

Author

van Leeuwen, Elisabeth M, Sabo, Aniko, Bis, Joshua C, Huffman, Jennifer E, Manichaikul, Ani, Smith, Albert V, Feitosa, Mary F, Demissie, Serkalem, Joshi, Peter K, Duan, Qing, Marten, Jonathan, van Klinken, Jan B, Surakka, Ida, Nolte, Ilja M, Zhang, Weihua, Mbarek, Hamdi, Li-Gao, Ruifang, Trompet, Stella, Verweij, Niek, Evangelou, Evangelos, Lyytikäinen, Leo-Pekka, Tayo, Bamidele O, Deelen, Joris, van der Most, Peter J, van der Laan, Sander W, Arking, Dan E, Morrison, Alanna, Dehghan, Abbas, Franco, Oscar H, Hofman, Albert, Rivadeneira, Fernando, Sijbrands, Eric J, Uitterlinden, Andre G, Mychaleckyj, Josyf C, Campbell, Archie, Hocking, Lynne J, Padmanabhan, Sandosh, Brody, Jennifer A, Rice, Kenneth M, White, Charles C, Harris, Tamara, Isaacs, Aaron, Campbell, Harry, Lange, Leslie A, Rudan, Igor, Kolcic, Ivana, Navarro, Pau, Zemunik, Tatijana, Salomaa, Veikko, Study, The LifeLines Cohort, Kooner, Angad S, Kooner, Jaspal S, Lehne, Benjamin, Scott, William R, Tan, Sian-Tsung, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Willemsen, Gonneke, de Mutsert, Renée, Ford, Ian, Gansevoort, Ron T, Segura-Lepe, Marcelo P, Raitakari, Olli T, Viikari, Jorma S, Nikus, Kjell, Forrester, Terrence, McKenzie, Colin A, de Craen, Anton JM, de Ruijter, Hester M, Group, CHARGE Lipids Working, Pasterkamp, Gerard, Snieder, Harold, Oldehinkel, Albertine J, Slagboom, P Eline, Cooper, Richard S, Kähönen, Mika, Lehtimäki, Terho, Elliott, Paul, van der Harst, Pim, Jukema, J Wouter, Mook-Kanamori, Dennis O, Boomsma, Dorret I, Chambers, John C, Swertz, Morris, Ripatti, Samuli, van Dijk, Ko Willems, Vitart, Veronique, Polasek, Ozren, Hayward, Caroline, Wilson, James G, Wilson, James F, Gudnason, Vilmundur, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Boerwinkle, Eric, Rotter, Jerome I, Cupples, L Adrienne, and van Duijn, Cornelia M

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Angiopoietin-Like Protein 4, Angiopoietins, Exons, Fasting, Female, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, LifeLines Cohort Study, CHARGE Lipids Working Group, Complex traits, Epidemiology, Genome-wide, circulating lipid levels, Medical and Health Sciences, Genetics & Heredity, Clinical sciences
Abstract

BackgroundSo far, more than 170 loci have been associated with circulating lipid levels through genome-wide association studies (GWAS). These associations are largely driven by common variants, their function is often not known, and many are likely to be markers for the causal variants. In this study we aimed to identify more new rare and low-frequency functional variants associated with circulating lipid levels.MethodsWe used the 1000 Genomes Project as a reference panel for the imputations of GWAS data from ∼60 000 individuals in the discovery stage and ∼90 000 samples in the replication stage.ResultsOur study resulted in the identification of five new associations with circulating lipid levels at four loci. All four loci are within genes that can be linked biologically to lipid metabolism. One of the variants, rs116843064, is a damaging missense variant within the ANGPTL4 gene.ConclusionsThis study illustrates that GWAS with high-scale imputation may still help us unravel the biological mechanism behind circulating lipid levels.

Published
2016

172. Pyramiding of genes for grain protein content, grain quality, and rust resistance in eleven Indian bread wheat cultivars: a multi-institutional effort

Author

Gupta, Pushpendra K., Balyan, Harindra S., Chhuneja, Parveen, Jaiswal, Jai P., Tamhankar, Shubhada, Mishra, Vinod K., Bains, Navtej S., Chand, Ramesh, Joshi, Arun K., Kaur, Satinder, Kaur, Harinderjeet, Mavi, Gurvinder S., Oak, Manoj, Sharma, Achla, Srivastava, Puja, Sohu, Virinder S., Prasad, Pramod, Agarwal, Priyanka, Akhtar, Moin, Badoni, Saurabh, Chaudhary, Reeku, Gahlaut, Vijay, Gangwar, Rishi Pal, Gautam, Tinku, Jaiswal, Vandana, Kumar, Ravi Shekhar, Kumar, Sachin, Shamshad, M., Singh, Anupama, Taygi, Sandhya, Vasistha, Neeraj Kumar, and Vishwakarma, Manish Kumar

Published
2022
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173. A meta-analysis of 120 246 individuals identifies 18 new loci for fibrinogen concentration

Author

de Vries, Paul S, Chasman, Daniel I, Sabater-Lleal, Maria, Chen, Ming-Huei, Huffman, Jennifer E, Steri, Maristella, Tang, Weihong, Teumer, Alexander, Marioni, Riccardo E, Grossmann, Vera, Hottenga, Jouke J, Trompet, Stella, Müller-Nurasyid, Martina, Zhao, Jing Hua, Brody, Jennifer A, Kleber, Marcus E, Guo, Xiuqing, Wang, Jie Jin, Auer, Paul L, Attia, John R, Yanek, Lisa R, Ahluwalia, Tarunveer S, Lahti, Jari, Venturini, Cristina, Tanaka, Toshiko, Bielak, Lawrence F, Joshi, Peter K, Rocanin-Arjo, Ares, Kolcic, Ivana, Navarro, Pau, Rose, Lynda M, Oldmeadow, Christopher, Riess, Helene, Mazur, Johanna, Basu, Saonli, Goel, Anuj, Yang, Qiong, Ghanbari, Mohsen, Willemsen, Gonneke, Rumley, Ann, Fiorillo, Edoardo, de Craen, Anton JM, Grotevendt, Anne, Scott, Robert, Taylor, Kent D, Delgado, Graciela E, Yao, Jie, Kifley, Annette, Kooperberg, Charles, Qayyum, Rehan, Lopez, Lorna M, Berentzen, Tina L, Räikkönen, Katri, Mangino, Massimo, Bandinelli, Stefania, Peyser, Patricia A, Wild, Sarah, Trégouët, David-Alexandre, Wright, Alan F, Marten, Jonathan, Zemunik, Tatijana, Morrison, Alanna C, Sennblad, Bengt, Tofler, Geoffrey, de Maat, Moniek PM, de Geus, Eco JC, Lowe, Gordon D, Zoledziewska, Magdalena, Sattar, Naveed, Binder, Harald, Völker, Uwe, Waldenberger, Melanie, Khaw, Kay-Tee, Mcknight, Barbara, Huang, Jie, Jenny, Nancy S, Holliday, Elizabeth G, Qi, Lihong, Mcevoy, Mark G, Becker, Diane M, Starr, John M, Sarin, Antti-Pekka, Hysi, Pirro G, Hernandez, Dena G, Jhun, Min A, Campbell, Harry, Hamsten, Anders, Rivadeneira, Fernando, Mcardle, Wendy L, Slagboom, P Eline, Zeller, Tanja, Koenig, Wolfgang, Psaty, Bruce M, Haritunians, Talin, Liu, Jingmin, Palotie, Aarno, Uitterlinden, André G, Stott, David J, Hofman, Albert, and Franco, Oscar H

Subjects
Biological Sciences, Genetics, Human Genome, 2.1 Biological and endogenous factors, Adult, Aged, Aged, 80 and over, Female, Fibrinogen, Genetic Loci, Genome-Wide Association Study, Humans, INDEL Mutation, Male, Middle Aged, Polymorphism, Single Nucleotide, White People, Medical and Health Sciences, Genetics & Heredity
Abstract

Genome-wide association studies have previously identified 23 genetic loci associated with circulating fibrinogen concentration. These studies used HapMap imputation and did not examine the X-chromosome. 1000 Genomes imputation provides better coverage of uncommon variants, and includes indels. We conducted a genome-wide association analysis of 34 studies imputed to the 1000 Genomes Project reference panel and including ∼120 000 participants of European ancestry (95 806 participants with data on the X-chromosome). Approximately 10.7 million single-nucleotide polymorphisms and 1.2 million indels were examined. We identified 41 genome-wide significant fibrinogen loci; of which, 18 were newly identified. There were no genome-wide significant signals on the X-chromosome. The lead variants of five significant loci were indels. We further identified six additional independent signals, including three rare variants, at two previously characterized loci: FGB and IRF1. Together the 41 loci explain 3% of the variance in plasma fibrinogen concentration.

Published
2016

174. Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis

Author

Luk, Fu Sang, Kim, Roy Y, Li, Kang, Ching, Daniel, Wong, David K, Joshi, Sunil K, Imhof, Isabella, Honbo, Norman, Hoover, Holly, Zhu, Bo-Qing, Lovett, David H, Karliner, Joel S, and Raffai, Robert L

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Heart Disease - Coronary Heart Disease, Nutrition, Aging, Heart Disease, Prevention, Atherosclerosis, Cardiovascular, 2.1 Biological and endogenous factors, Aetiology, Animals, Apolipoproteins E, Coronary Artery Disease, Diet, High-Fat, Fingolimod Hydrochloride, Gene Expression Regulation, Immunosuppressive Agents, Mice, Mice, Transgenic, Myocardial Infarction, Scavenger Receptors, Class B, Survival Rate, FTY720, S1P, ApoE, coronary atherosclerosis, heart failure, cardioprotection, immunosuppression, Cardiorespiratory Medicine and Haematology, Pharmacology and Pharmaceutical Sciences, Cardiovascular System & Hematology, Cardiovascular medicine and haematology, Pharmacology and pharmaceutical sciences
Abstract

AIMS:We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI(–/–) mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study, we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI(–/–) mice that survive MI and subsequently develop chronic heart failure. METHODS/RESULTS:HypoE/SR-BI(–/–) mice were bred to Mx1-Cre transgenic mice, and offspring were fed a high-fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis, and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice 6 weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart. CONCLUSIONS:Our data demonstrate that immunosuppression with FTY720 prevents postinfarction myocardial remodeling and chronic heart failure.

Published
2016

175. Precise and ultrafast molecular sieving through graphene oxide membranes

Author

Joshi, R. K., Carbone, P., Wang, F. C., Kravets, V. G., Su, Y., Grigorieva, I. V., Wu, H. A., Geim, A. K., and Nair, R. R.

Subjects
Condensed Matter - Materials Science, Condensed Matter - Soft Condensed Matter, Physics - Fluid Dynamics
Abstract

There has been intense interest in filtration and separation properties of graphene-based materials that can have well-defined nanometer pores and exhibit low frictional water flow inside them. Here we investigate molecular permeation through graphene oxide laminates. They are vacuum-tight in the dry state but, if immersed in water, act as molecular sieves blocking all solutes with hydrated radii larger than 4.5A. Smaller ions permeate through the membranes with little impedance, many orders of magnitude faster than the diffusion mechanism can account for. We explain this behavior by a network of nanocapillaries that open up in the hydrated state and accept only species that fit in. The ultrafast separation of small salts is attributed to an 'ion sponge' effect that results in highly concentrated salt solutions inside graphene capillaries.

Published
2014
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178. Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals

Author

Folkersen, Lasse, Gustafsson, Stefan, Wang, Qin, Hansen, Daniel Hvidberg, Hedman, Åsa K., Schork, Andrew, Page, Karen, Zhernakova, Daria V., Wu, Yang, Peters, James, Eriksson, Niclas, Bergen, Sarah E., Boutin, Thibaud S., Bretherick, Andrew D., Enroth, Stefan, Kalnapenkis, Anette, Gådin, Jesper R., Suur, Bianca E., Chen, Yan, Matic, Ljubica, Gale, Jeremy D., Lee, Julie, Zhang, Weidong, Quazi, Amira, Ala-Korpela, Mika, Choi, Seung Hoan, Claringbould, Annique, Danesh, John, Davey Smith, George, de Masi, Federico, Elmståhl, Sölve, Engström, Gunnar, Fauman, Eric, Fernandez, Celine, Franke, Lude, Franks, Paul W., Giedraitis, Vilmantas, Haley, Chris, Hamsten, Anders, Ingason, Andres, Johansson, Åsa, Joshi, Peter K., Lind, Lars, Lindgren, Cecilia M., Lubitz, Steven, Palmer, Tom, Macdonald-Dunlop, Erin, Magnusson, Martin, Melander, Olle, Michaelsson, Karl, Morris, Andrew P., Mägi, Reedik, Nagle, Michael W., Nilsson, Peter M., Nilsson, Jan, Orho-Melander, Marju, Polasek, Ozren, Prins, Bram, Pålsson, Erik, Qi, Ting, Sjögren, Marketa, Sundström, Johan, Surendran, Praveen, Võsa, Urmo, Werge, Thomas, Wernersson, Rasmus, Westra, Harm-Jan, Yang, Jian, Zhernakova, Alexandra, Ärnlöv, Johan, Fu, Jingyuan, Smith, J. Gustav, Esko, Tõnu, Hayward, Caroline, Gyllensten, Ulf, Landen, Mikael, Siegbahn, Agneta, Wilson, James F., Wallentin, Lars, Butterworth, Adam S., Holmes, Michael V., Ingelsson, Erik, and Mälarstig, Anders

Published
2020
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182. Sustainable Development Goals: Role of Agriculture

Author

Paroda, R. S., Joshi, P. K., Chaturvedi, Sachin, Series Editor, Rahman, Mustafizur, Series Editor, Suleri, Abid, Series Editor, Weerakoon, Dushni, Series Editor, James, T. C., editor, Saha, Sabyasachi, editor, and Shaw, Prativa, editor

Published
2019
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185. Introduction

Author

Thapa, Ganesh, Kumar, Anjani, Joshi, P. K., Thapa, Ganesh, editor, Kumar, Anjani, editor, and Joshi, P.K., editor

Published
2019
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188. Directional dominance on stature and cognition in diverse human populations

Author

Joshi, Peter K, Esko, Tonu, Mattsson, Hannele, Eklund, Niina, Gandin, Ilaria, Nutile, Teresa, Jackson, Anne U, Schurmann, Claudia, Smith, Albert V, Zhang, Weihua, Okada, Yukinori, Stančáková, Alena, Faul, Jessica D, Zhao, Wei, Bartz, Traci M, Concas, Maria Pina, Franceschini, Nora, Enroth, Stefan, Vitart, Veronique, Trompet, Stella, Guo, Xiuqing, Chasman, Daniel I, O'Connel, Jeffrey R, Corre, Tanguy, Nongmaithem, Suraj S, Chen, Yuning, Mangino, Massimo, Ruggiero, Daniela, Traglia, Michela, Farmaki, Aliki-Eleni, Kacprowski, Tim, Bjonnes, Andrew, van der Spek, Ashley, Wu, Ying, Giri, Anil K, Yanek, Lisa R, Wang, Lihua, Hofer, Edith, Rietveld, Cornelius A, McLeod, Olga, Cornelis, Marilyn C, Pattaro, Cristian, Verweij, Niek, Baumbach, Clemens, Abdellaoui, Abdel, Warren, Helen R, Vuckovic, Dragana, Mei, Hao, Bouchard, Claude, Perry, John RB, Cappellani, Stefania, Mirza, Saira S, Benton, Miles C, Broeckel, Ulrich, Medland, Sarah E, Lind, Penelope A, Malerba, Giovanni, Drong, Alexander, Yengo, Loic, Bielak, Lawrence F, Zhi, Degui, van der Most, Peter J, Shriner, Daniel, Mägi, Reedik, Hemani, Gibran, Karaderi, Tugce, Wang, Zhaoming, Liu, Tian, Demuth, Ilja, Zhao, Jing Hua, Meng, Weihua, Lataniotis, Lazaros, van der Laan, Sander W, Bradfield, Jonathan P, Wood, Andrew R, Bonnefond, Amelie, Ahluwalia, Tarunveer S, Hall, Leanne M, Salvi, Erika, Yazar, Seyhan, Carstensen, Lisbeth, de Haan, Hugoline G, Abney, Mark, Afzal, Uzma, Allison, Matthew A, Amin, Najaf, Asselbergs, Folkert W, Bakker, Stephan JL, Barr, R Graham, Baumeister, Sebastian E, Benjamin, Daniel J, Bergmann, Sven, Boerwinkle, Eric, Bottinger, Erwin P, Campbell, Archie, Chakravarti, Aravinda, Chan, Yingleong, Chanock, Stephen J, Chen, Constance, and Chen, Y-D Ida

Subjects
Biological Sciences, Genetics, Human Genome, Clinical Research, 2.1 Biological and endogenous factors, Biological Evolution, Blood Pressure, Body Height, Cholesterol, LDL, Cognition, Cohort Studies, Educational Status, Female, Forced Expiratory Volume, Genome, Human, Homozygote, Humans, Lung Volume Measurements, Male, Phenotype, General Science & Technology
Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Published
2015

189. Genome of The Netherlands population-specific imputations identify an ABCA6 variant associated with cholesterol levels.

Author

van Leeuwen, Elisabeth M, Karssen, Lennart C, Deelen, Joris, Isaacs, Aaron, Medina-Gomez, Carolina, Mbarek, Hamdi, Kanterakis, Alexandros, Trompet, Stella, Postmus, Iris, Verweij, Niek, van Enckevort, David J, Huffman, Jennifer E, White, Charles C, Feitosa, Mary F, Bartz, Traci M, Manichaikul, Ani, Joshi, Peter K, Peloso, Gina M, Deelen, Patrick, van Dijk, Freerk, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Francioli, Laurent C, Menelaou, Androniki, Pulit, Sara L, Rivadeneira, Fernando, Hofman, Albert, Oostra, Ben A, Franco, Oscar H, Mateo Leach, Irene, Beekman, Marian, de Craen, Anton JM, Uh, Hae-Won, Trochet, Holly, Hocking, Lynne J, Porteous, David J, Sattar, Naveed, Packard, Chris J, Buckley, Brendan M, Brody, Jennifer A, Bis, Joshua C, Rotter, Jerome I, Mychaleckyj, Josyf C, Campbell, Harry, Duan, Qing, Lange, Leslie A, Wilson, James F, Hayward, Caroline, Polasek, Ozren, Vitart, Veronique, Rudan, Igor, Wright, Alan F, Rich, Stephen S, Psaty, Bruce M, Borecki, Ingrid B, Kearney, Patricia M, Stott, David J, Adrienne Cupples, L, Genome of The Netherlands Consortium, Jukema, J Wouter, van der Harst, Pim, Sijbrands, Eric J, Hottenga, Jouke-Jan, Uitterlinden, Andre G, Swertz, Morris A, van Ommen, Gert-Jan B, de Bakker, Paul IW, Eline Slagboom, P, Boomsma, Dorret I, Wijmenga, Cisca, and van Duijn, Cornelia M

Subjects
Genome of The Netherlands Consortium, Humans, Cholesterol, ATP-Binding Cassette Transporters, Gene Frequency, Mutation, Missense, Netherlands, Genetic Association Studies, Mutation, Missense
Abstract

Variants associated with blood lipid levels may be population-specific. To identify low-frequency variants associated with this phenotype, population-specific reference panels may be used. Here we impute nine large Dutch biobanks (~35,000 samples) with the population-specific reference panel created by the Genome of The Netherlands Project and perform association testing with blood lipid levels. We report the discovery of five novel associations at four loci (P value

Published
2015

191. Small Quadrupole Deformation for the Dipole Bands in 112In

Author

Trivedi, T., Palit, R., Sethi, J., Saha, S., Kumar, S., Naik, Z., Parkar, V. V., Naidu, B. S., Deo, A. Y., Raghav, A., Joshi, P. K., Jain, H. C., Sihotra, S., Mehta, D., Jain, A. K., Choudhury, D., Negi, D., Roy, S., Chattopadhyay, S., Singh, A. K., Singh, P., Biswas, D. C., Bhowmik, R. K., Muralithar, S., Singh, R. P., Kumar, R., and Rani, K.

Subjects
Nuclear Experiment, Nuclear Theory
Abstract

High spin states in $^{112}$In were investigated using $^{100}$Mo($^{16}$O, p3n) reaction at 80 MeV. The excited level have been observed up to 5.6 MeV excitation energy and spin $\sim$ 20$\hbar$ with the level scheme showing three dipole bands. The polarization and lifetime measurements were carried out for the dipole bands. Tilted axis cranking model calculations were performed for different quasi-particle configurations of this doubly odd nucleus. Comparison of the calculations of the model with the B(M1) transition strengths of the positive and negative parity bands firmly established their configurations., Comment: 10 pages, 11 figures, 2 tables

Published
2012
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192. Whole-genome analysis of plasma fibrinogen reveals population-differentiated genetic regulators with putative liver roles

Author

Huffman, Jennifer E., Nicholas, Jayna, Hahn, Julie, Heath, Adam S., Raffield, Laura M., Yanek, Lisa R., Brody, Jennifer A., Thibord, Florian, Almasy, Laura, Bartz, Traci M., Bielak, Lawrence F., Bowler, Russell P., Carrasquilla, Germán D., Chasman, Daniel I., Chen, Ming-Huei, Emmert, David B., Ghanbari, Mohsen, Haessler, Jeffrey, Hottenga, Jouke-Jan, Kleber, Marcus E., Le, Ngoc-Quynh, Lee, Jiwon, Lewis, Joshua P., Li-Gao, Ruifang, Luan, Jian'an, Malmberg, Anni, Mangino, Massimo, Marioni, Riccardo E., Martinez-Perez, Angel, Pankratz, Nathan, Polasek, Ozren, Richmond, Anne, Rodriguez, Benjamin A. T., Rotter, Jerome I., Steri, Maristella, Suchon, Pierre, Trompet, Stella, Weiss, Stefan, Zare, Marjan, Auer, Paul, Cho, Michael H., Christofidou, Paraskevi, Davies, Gail, de Geus, Eco, Deleuze, Jean-François, Delgado, Graciela E., Ekunwe, Lynette, Faraday, Nauder, Gögele, Martin, Greinacher, Andreas, Gao, He, Howard, Tom, Joshi, Peter K., Kilpeläinen, Tuomas O., Lahti, Jari, Linneberg, Allan, Naitza, Silvia, Noordam, Raymond, Paüls-Vergés, Ferran, Rich, Stephen S., Rosendaal, Frits R., Rudan, Igor, Ryan, Kathleen A., Souto, Juan Carlos, van Rooij, Frank J. A., Wang, Heming, Zhao, Wei, Becker, Lewis C., Beswick, Andrew, Brown, Michael R., Cade, Brian E., Campbell, Harry, Cho, Kelly, Crapo, James D., Curran, Joanne E., de Maat, Moniek P. M., Doyle, Margaret, Elliott, Paul, Floyd, James S., Fuchsberger, Christian, Grarup, Niels, Guo, Xiuqing, Harris, Sarah E., Hou, Lifang, Kolcic, Ivana, Kooperberg, Charles, Menni, Cristina, Nauck, Matthias, O'Connell, Jeffrey R., Orrù, Valeria, Psaty, Bruce M., Räikkönen, Katri, Smith, Jennifer A., Soria, Jose Manuel, Stott, David J., van Hylckama Vlieg, Astrid, Watkins, Hugh, Willemsen, Gonneke, Wilson, Peter W. F., Ben-Shlomo, Yoav, Blangero, John, Boomsma, Dorret, Cox, Simon R., Dehghan, Abbas, Eriksson, Johan G., Fiorillo, Edoardo, Fornage, Myriam, Hansen, Torben, Hayward, Caroline, Ikram, M. Arfan, Jukema, J. Wouter, Kardia, Sharon L. R., Lange, Leslie A., März, Winfried, Mathias, Rasika A., Mitchell, Braxton D., Mook-Kanamori, Dennis O., Morange, Pierre-Emmanuel, Pedersen, Oluf, Pramstaller, Peter P., Redline, Susan, Reiner, Alexander, Ridker, Paul M., Silverman, Edwin K., Spector, Tim D., Völker, Uwe, Wareham, Nicholas J., Wilson, James F., Yao, Jie, Trégouët, David-Alexandre, Johnson, Andrew D., Wolberg, Alisa S., de Vries, Paul S., Sabater-Lleal, Maria, Morrison, Alanna C., and Smith, Nicholas L.

Abstract

•Largest and most diverse genetic study of plasma fibrinogen identifies 54 regions (18 novel), housing 69 distinct variants (20 novel).•Links to (1) liver enzyme, blood cell, and lipid genetic signals, (2) liver regulatory elements, and (3) thrombotic and inflammatory disease.

Published
2024
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194. Iron-Catalyzed Chemoselective Transfer Hydrogenation of α,β-Unsaturated Ketones Using H2O as a Surrogate of Hydrogen

Author

Manisha, Manisha, Kumari, Sangeeta, Sharma, Deepak, Negi, Lalit, and Joshi, Raj K.

Abstract

Sustainable and highly economical iron-catalyzed chemoselective reduction of C═C of α,β-unsaturated ketones has been established under mild reaction protocols. Water is used as a green and abundant surrogate of hydrogen and is scarcely used in organic synthetic transformations as a source of hydrogen. The developed protocol offers a broad spectrum for chemoselective transfer hydrogenation of α,β-unsaturated ketones. Moreover, the method was found to be highly effective for aryl and ferrocenyl α,β-unsaturated ketones consisting of one or two double bonds and with multiple functionalities. Moreover, the present method avoids prolonged reaction time, provides a wide range of substrates with excellent yield, and circumvents the tedious chromatographic workup.

Published
2024
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195. An Object-Oriented Metamodel for Bunge-Wand-Weber Ontology

Author

Kiwelekar, Arvind W. and Joshi, Rushikesh K.

Subjects
Computer Science - Software Engineering, D.2.11
Abstract

A UML based metamodel for Bunge-Wand-Weber (BWW) ontology is presented. BWW ontology is a generic framework for analysis and conceptualization of real world objects. It includes categories that can be applied to analyze and classify objects found in an information system. In the context of BWW ontology, the metamodel is a representation of the ontological categories and relationships among them. An objective behind developing an object-oriented metamodel has been to model BWW ontology in terms of widely used notions in software development. The main contributions of this paper are a classification for ontological categories, a description template, and representations through UML and typed based models., Comment: 8 Pages, 7 Tables, 8 Figures

Published
2010

196. Band crossing in Shears band of $^{108}$Cd

Author

Roy, Santosh, Datta, Pradip, Pal, S., Chattopadhyay, S., Bhattacharya, S., Goswami, A., Jain, H. C., Joshi, P. K., Bhowmik, R. K., Kumar, R., Muralithar, S., Singh, R. P., Madhavan, N., and Rao, P. V. Madhusudhana

Subjects
Nuclear Experiment
Abstract

The level lifetimes have been measured for a Shears band of $^{108}$Cd which exhibits bandcrossing. The observed level energies and B(M1) rates have been successfully described by a semi-classical geometric model based on shear mechanism. In this geometric model, the bandcrossing in Shears band has been described as the reopening of the angle between the blades of a shear., Comment: 14 pages including 3 figures and two tables

Published
2010
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197. Fine mapping the CETP region reveals a common intronic insertion associated to HDL-C

Author

van Leeuwen, Elisabeth M, Huffman, Jennifer E, Bis, Joshua C, Isaacs, Aaron, Mulder, Monique, Sabo, Aniko, Smith, Albert V, Demissie, Serkalem, Manichaikul, Ani, Brody, Jennifer A, Feitosa, Mary F, Duan, Qing, Schraut, Katharina E, Navarro, Pau, van Vliet-Ostaptchouk, Jana V, Zhu, Gu, Mbarek, Hamdi, Trompet, Stella, Verweij, Niek, Lyytikäinen, Leo-Pekka, Deelen, Joris, Nolte, Ilja M, van der Laan, Sander W, Davies, Gail, Vermeij-Verdoold, Andrea JM, van Oosterhout, Andy ALJ, Vergeer-Drop, Jeannette M, Arking, Dan E, Trochet, Holly, Medina-Gomez, Carolina, Rivadeneira, Fernando, Uitterlinden, Andre G, Dehghan, Abbas, Franco, Oscar H, Sijbrands, Eric J, Hofman, Albert, White, Charles C, Mychaleckyj, Josyf C, Peloso, Gina M, Swertz, Morris A, Willemsen, Gonneke, de Geus, Eco J, Milaneschi, Yuri, Penninx, Brenda WJH, Ford, Ian, Buckley, Brendan M, de Craen, Anton JM, Starr, John M, Deary, Ian J, Pasterkamp, Gerard, Oldehinkel, Albertine J, Snieder, Harold, Slagboom, P Eline, Nikus, Kjell, Kähönen, Mika, Lehtimäki, Terho, Viikari, Jorma S, Raitakari, Olli T, van der Harst, Pim, Jukema, J Wouter, Hottenga, Jouke-Jan, Boomsma, Dorret I, Whitfield, John B, Montgomery, Grant, Martin, Nicholas G, Polasek, Ozren, Vitart, Veronique, Hayward, Caroline, Kolcic, Ivana, Wright, Alan F, Rudan, Igor, Joshi, Peter K, Wilson, James F, Lange, Leslie A, Wilson, James G, Gudnason, Vilmundur, Harris, Tamar B, Morrison, Alanna C, Borecki, Ingrid B, Rich, Stephen S, Padmanabhan, Sandosh, Psaty, Bruce M, Rotter, Jerome I, Smith, Blair H, Boerwinkle, Eric, Cupples, L Adrienne, and van Duijn, Cornelia

Subjects
Biological Sciences, Genetics, 2.1 Biological and endogenous factors, Generation Scotland, LifeLines Cohort Study, CHARGE Lipids Working Group, Biochemistry and Cell Biology, Medical Biotechnology, Clinical Sciences, Biochemistry and cell biology
Abstract

BackgroundIndividuals with exceptional longevity and their offspring have significantly larger high-density lipoprotein concentrations (HDL-C) particle sizes due to the increased homozygosity for the I405V variant in the cholesteryl ester transfer protein (CETP) gene. In this study, we investigate the association of CETP and HDL-C further to identify novel, independent CETP variants associated with HDL-C in humans.MethodsWe performed a meta-analysis of HDL-C within the CETP region using 59,432 individuals imputed with 1000 Genomes data. We performed replication in an independent sample of 47,866 individuals and validation was done by Sanger sequencing.ResultsThe meta-analysis of HDL-C within the CETP region identified five independent variants, including an exonic variant and a common intronic insertion. We replicated these 5 variants significantly in an independent sample of 47,866 individuals. Sanger sequencing of the insertion within a single family confirmed segregation of this variant. The strongest reported association between HDL-C and CETP variants, was rs3764261; however, after conditioning on the five novel variants we identified the support for rs3764261 was highly reduced (βunadjusted=3.179 mg/dl (P value=5.25×10-509), βadjusted=0.859 mg/dl (P value=9.51×10-25)), and this finding suggests that these five novel variants may partly explain the association of CETP with HDL-C. Indeed, three of the five novel variants (rs34065661, rs5817082, rs7499892) are independent of rs3764261.ConclusionsThe causal variants in CETP that account for the association with HDL-C remain unknown. We used studies imputed to the 1000 Genomes reference panel for fine mapping of the CETP region. We identified and validated five variants within this region that may partly account for the association of the known variant (rs3764261), as well as other sources of genetic contribution to HDL-C.

Published
2015

198. Study of nuclei in the vicinity of the 'Island of Inversion' through fusion-evaporation reaction

Author

Chakrabarti, R., Krishichayan, S. Mukhopadhyay, Chakraborty, A., Ghosh, A., Ray, S., Ghugre, S. S., Sinha, A. K., Chaturvedi, L., Deo, A. Y., Mazumdar, I., Joshi, P. K., Palit, R., Naik, Z., Kumar, S., Madhavan, N., Singh, R. P., Muralithar, S., Yogi, B. K., and Garg, U.

Subjects
Nuclear Experiment
Abstract

We report the first observation of high-spin states in nuclei in the vicinity of the "island of inversion", populated via the 18O+18O fusion reaction at an incident beam energy of 34 MeV. The fusion reaction mechanism circumvents the limitations of non-equilibrated reactions used to populate these nuclei. Detailed spin-parity measurements in these difficult to populate nuclei have been possible from the observed coincidence anisotropy and the linear polarization measurements. The spectroscopy of 33,34P and 33S is presented in detail along with the results of calculations within the shell model framework.

Published
2009
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199. Upregulation of transforming growth factor-β signaling in a rat model of rotator cuff tears

Author

Liu, Xuhui, Joshi, Sunil K, Ravishankar, Bharat, Laron, Dominique, Kim, Hubert T, and Feeley, Brian T

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Physical Injury - Accidents and Adverse Effects, Musculoskeletal, Animals, Disease Models, Animal, Female, Fibrosis, Peripheral Nerve Injuries, RNA, Messenger, Rats, Rats, Sprague-Dawley, Rotator Cuff, Rotator Cuff Injuries, Tendon Injuries, Transforming Growth Factor beta, Up-Regulation, Massive rotator cuff tear, transforming growth factor-beta, fibrosis, transforming growth factor-β, Clinical Sciences, Orthopedics, Clinical sciences
Abstract

BackgroundMuscle atrophy, fatty infiltration, and fibrosis of the muscle have been described as important factors governing outcome after rotator cuff injury and repair. Muscle fibrosis is also thought to have a role in determining muscle compliance at the time of surgery. The transforming growth factor-β (TGF-β) pathways are highly conserved pathways that exert a potent level of control over muscle gene expression and are critical regulators of fibrosis in multiple organ systems. It has been shown that TGF-β can regulate important pathways of muscle atrophy, including the Akt/mammalian target of rapamycin pathway. The purpose of this study was to evaluate the expression of TGF-β and its downstream effectors of fibrosis after a massive rotator cuff tear (RCT) in a previously established rat model.MethodsTo simulate a massive RCT, infraspinatus and supraspinatus tenotomy and suprascapular nerve transection were performed on Sprague-Dawley rats with use of a validated model. Two and 6 weeks after surgery, supraspinatus muscles were harvested to study alterations in TGF-β signaling by Western blotting, quantitative polymerase chain reaction, and histologic analysis.ResultsThere was a significant increase in fibrosis in the rotator cuff muscle after RCT in our animal model. There was a concomitant increase in TGF-β gene and protein expression at both 2 and 6 weeks after RCT. Evaluation of the TGF-β signaling pathway revealed an increase in SMAD2 activation but not in SMAD3. There was an increase in profibrotic markers collagen I, collagen III, and α-smooth muscle actin.ConclusionsTGF-β signaling is significantly upregulated in rat supraspinatus muscles after RCTs.

Published
2014

200. Matrix metalloproteinase-2 plays a critical role in overload induced skeletal muscle hypertrophy.

Author

Zhang, Qia, Joshi, Sunil K, Lovett, David H, Zhang, Bryon, Bodine, Sue, Kim, Hubert T, and Liu, Xuhui

Subjects
basement membrane, extracellular matrix, matrix metalloproteinase-2, skeletal muscle hypertrophy, synergistic ablation, Musculoskeletal, Physiology, Human Movement and Sports Sciences, Medical Physiology
Abstract

Backgroundextracellular matrix (ECM) components are instrumental in maintaining homeostasis and muscle fiber functional integrity. Skeletal muscle hypertrophy is associated with ECM remodeling. Specifically, recent studies have reported the involvement of matrix metalloproteinases (MMPs) in muscle ECM remodeling. However, the functional role of MMPs in muscle hypertrophy remains largely unknown.Methodsin this study, we examined the role of MMP-2 in skeletal muscle hypertrophy using a previously validated method where the plantaris muscle of mice were subjected to mechanical overload due to the surgical removal of synergist muscles (gastrocnemius and soleus).Resultsfollowing two weeks of overload, we observed a significant increase in MMP-2 activity and up-regulation of ECM components and remodeling enzymes in the plantaris muscles of wild-type mice. However, MMP-2 knockout mice developed significantly less hypertrophy and ECM remodeling in response to overload compared to their wild-type littermates. Investigation of protein synthesis rate and Akt/mTOR signaling revealed no difference between wild-type and MMP-2 knockout mice, suggesting that a difference in hypertrophy was independent of protein synthesis.Conclusiontaken together, our results suggest that MMP-2 is a key mediator of ECM remodeling in the setting of skeletal muscle hypertrophy.

Published
2014

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