[Identification of novel variable number tandem repeat (VNTR) loci in Mycobacterium avium and development of an effective means of VNTR typing].

Science.gov (United States)

Kurokawa, Kazuhiro; Uchiya, Kei-Ichi; Yagi, Tetsuya; Takahashi, Hiroyasu; Niimi, Masaki; Ichikawa, Kazuya; Inagaki, Takayuki; Moriyama, Makoto; Nikai, Toshiaki; Hayashi, Yuta; Nakagawa, Taku; Ogawa, Kenji

2012-07-01

To make more effective use of variable number tandem repeat (VNTR) typing, we identified novel VNTR loci in Mycobacterium avium and used them for modified M. avium tandem repeat-VNTR (MATR-VNTR) typing. Analysis of a DNA sample extracted from a clinical isolate (strain HN135) with the FLX system genome sequencer (Roche Diagnostic System) led to discovery of several novel VNTR loci. The allelic diversity of the novel VNTR loci was evaluated for 71 clinical isolates and compared with the diversity of the MATR-VNTR loci. To improve efficacy of MATR-VNTR typing, we tested typing using 2 sets of loci selected from the newly identified loci and the MATR loci, i.e., one set containing 7 and another 16 loci. Hunter Gaston's discriminatory index (HGDI) was calculated for these sets. Six VNTR loci were newly identified, of which 5 showed a high diversity. The HGDI was 0.980 for the improved new typing using a set of 7 loci, and 0.995 for another set of 16 loci, while it was 0.992 for the conventional MATR-VNTR typing. VNTR typing with the set of the 7 loci enabled a rapid analysis, and another set of 16 loci enabled a precise analysis, as compared with conventional MATR-VNTR typing. A method that uses only VNTR loci with relatively high allelic diversity is considered to be a useful tool for VNTR typing of MAC isolates.

Nuclear positioning rather than contraction controls ordered rearrangements of immunoglobulin loci

NARCIS (Netherlands)

M.B. Rother (Magdalena); R.-J.T.S. Palstra (Robert-Jan); S. Jhunjhunwala (Suchit); K.A.M. Van Kester (Kevin A. M.); W.F.J. van IJcken (Wilfred); R.W. Hendriks (Rudi); J.J.M. van Dongen (Jacques); C. Murre (Cornelis); M.C. van Zelm (Menno)

2016-01-01

textabstractProgenitor-B cells recombine their immunoglobulin (Ig) loci to create unique antigen receptors. Despite a common recombination machinery, the Ig heavy and Ig light chain loci rearrange in a stepwise manner. We studied pre-pro-B cells and Rag-/- progenitor-B cells to determine whether Ig

Genetic fine-mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

Science.gov (United States)

Mahajan, Anubha; Locke, Adam; Rayner, N William; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Goncalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Borringer, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex SF; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian’an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Perry, John RB; Platou, Carl GP; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth JF; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin NA; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O’Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

2015-01-01

We performed fine-mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in/near KCNQ1. “Credible sets” of variants most likely to drive each distinct signal mapped predominantly to non-coding sequence, implying that T2D association is mediated through gene regulation. Credible set variants were enriched for overlap with FOXA2 chromatin immunoprecipitation binding sites in human islet and liver cells, including at MTNR1B, where fine-mapping implicated rs10830963 as driving T2D association. We confirmed that this T2D-risk allele increases FOXA2-bound enhancer activity in islet- and liver-derived cells. We observed allele-specific differences in NEUROD1 binding in islet-derived cells, consistent with evidence that the T2D-risk allele increases islet MTNR1B expression. Our study demonstrates how integration of genetic and genomic information can define molecular mechanisms through which variants underlying association signals exert their effects on disease. PMID:26551672

The role of height-associated loci identified in genome wide association studies in the determination of pediatric stature

Directory of Open Access Journals (Sweden)

Frackelton Edward C

2010-06-01

Full Text Available Abstract Background Human height is considered highly heritable and correlated with certain disorders, such as type 2 diabetes and cancer. Despite environmental influences, genetic factors are known to play an important role in stature determination. A number of genetic determinants of adult height have already been established through genome wide association studies. Methods To examine 51 single nucleotide polymorphisms (SNPs corresponding to the 46 previously reported genomic loci for height in 8,184 European American children with height measurements. We leveraged genotyping data from our ongoing GWA study of height variation in children in order to query the 51 SNPs in this pediatric cohort. Results Sixteen of these SNPs yielded at least nominally significant association to height, representing fifteen different loci including EFEMP1-PNPT1, GPR126, C6orf173, SPAG17, Histone class 1, HLA class III and GDF5-UQCC. Other loci revealed no evidence for association, including HMGA1 and HMGA2. For the 16 associated variants, the genotype score explained 1.64% of the total variation for height z-score. Conclusion Among 46 loci that have been reported to associate with adult height to date, at least 15 also contribute to the determination of height in childhood.

Mapping of five candidate sex-determining loci in rainbow trout (Oncorhynchus mykiss

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Drew Robert E

2009-01-01

Full Text Available Abstract Background Rainbow trout have an XX/XY genetic mechanism of sex determination where males are the heterogametic sex. The homology of the sex-determining gene (SDG in medaka to Dmrt1 suggested that SDGs evolve from downstream genes by gene duplication. Orthologous sequences of the major genes of the mammalian sex determination pathway have been reported in the rainbow trout but the map position for the majority of these genes has not been assigned. Results Five loci of four candidate genes (Amh, Dax1, Dmrt1 and Sox6 were tested for linkage to the Y chromosome of rainbow trout. We exclude the role of all these loci as candidates for the primary SDG in this species. Sox6i and Sox6ii, duplicated copies of Sox6, mapped to homeologous linkage groups 10 and 18 respectively. Genotyping fishes of the OSU × Arlee mapping family for Sox6i and Sox6ii alleles indicated that Sox6i locus might be deleted in the Arlee lineage. Conclusion Additional candidate genes should be tested for their linkage to the Y chromosome. Mapping data of duplicated Sox6 loci supports previously suggested homeology between linkage groups 10 and 18. Enrichment of the rainbow trout genomic map with known gene markers allows map comparisons with other salmonids. Mapping of candidate sex-determining loci is important for analyses of potential autosomal modifiers of sex-determination in rainbow trout.

SOX2 and p63 colocalize at genetic loci in squamous cell carcinomas.

Science.gov (United States)

Watanabe, Hideo; Ma, Qiuping; Peng, Shouyong; Adelmant, Guillaume; Swain, Danielle; Song, Wenyu; Fox, Cameron; Francis, Joshua M; Pedamallu, Chandra Sekhar; DeLuca, David S; Brooks, Angela N; Wang, Su; Que, Jianwen; Rustgi, Anil K; Wong, Kwok-kin; Ligon, Keith L; Liu, X Shirley; Marto, Jarrod A; Meyerson, Matthew; Bass, Adam J

2014-04-01

The transcription factor SOX2 is an essential regulator of pluripotent stem cells and promotes development and maintenance of squamous epithelia. We previously reported that SOX2 is an oncogene and subject to highly recurrent genomic amplification in squamous cell carcinomas (SCCs). Here, we have further characterized the function of SOX2 in SCC. Using ChIP-seq analysis, we compared SOX2-regulated gene profiles in multiple SCC cell lines to ES cell profiles and determined that SOX2 binds to distinct genomic loci in SCCs. In SCCs, SOX2 preferentially interacts with the transcription factor p63, as opposed to the transcription factor OCT4, which is the preferred SOX2 binding partner in ES cells. SOX2 and p63 exhibited overlapping genomic occupancy at a large number of loci in SCCs; however, coordinate binding of SOX2 and p63 was absent in ES cells. We further demonstrated that SOX2 and p63 jointly regulate gene expression, including the oncogene ETV4, which was essential for SOX2-amplified SCC cell survival. Together, these findings demonstrate that the action of SOX2 in SCC differs substantially from its role in pluripotency. The identification of the SCC-associated interaction between SOX2 and p63 will enable deeper characterization the downstream targets of this interaction in SCC and normal squamous epithelial physiology.

The Case for High Resolution Extended 6-Loci HLA Typing for Identifying Related Donors in the Indian Subcontinent.

Science.gov (United States)

Agarwal, Rajat Kumar; Kumari, Ankita; Sedai, Amit; Parmar, Lalith; Dhanya, Rakesh; Faulkner, Lawrence

2017-09-01

Three-loci low-resolution (LR) or intermediate-resolution HLA typing is generally considered adequate in the related blood and marrow transplantation (BMT) context. However, a single high-resolution (HR) mismatch may have a similar adverse impact on BMT outcome as an LR one. We sought to determine the frequency of mismatches that may go undetected when standard typing (LR or 3-loci HR) is used compared with 6-loci HR typing for related donor compatibility testing, and to assess its impact on relevant BMT outcomes. We analyzed data from a total of 2554 6-loci (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) HR sequence-based typing (full typing [FT]) from 754 patients, 1011 siblings, and 789 parents done at DKMS Germany (www.DKMS.de) between January 1, 2014, and June 21, 2016. We also studied 38 cases in which the family had undergone 3-loci HLA typing (standard typing [ST]). Patients were from India (70%), Pakistan (22%), and Sri Lanka (8%). The IMGT/HLA database (www.ebi.ac.uk/ipd/imgt/hla) was used to tease out nonpermissive DPB1 mismatches. HLA disparity-related outcomes, such as rejection and graft-versus-host disease (GVHD) were assessed in a retrospective matched-pair cohort of 50 patients (25 with ST and 25 with FT) who underwent BMT for severe thalassemia from compatible related donors. We found fully matched (either 12/12 HR matches or with a single permissive DPB1 mismatch) related donors for 285 patients (38%). Of these donors, 89% were siblings and 11% were parents. The likelihood of matching on an individual locus on LR but not on HR was found to be 5%. A total of 9 donors (3%; 7 siblings and 2 parents) who would have been considered a full match by HR typing on A, B, and DRB1 alone were not a match by extended 6-loci HR typing. Five of these 9 donors had a mismatch on C or DQB1, and 4 had a nonpermissive DPB1 mismatch. In this group, 5 donors (56%) belonged to a consanguineous family, in 2 donors (22%) there was no reported consanguinity, and in 2 donors (22

Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers

DEFF Research Database (Denmark)

Onengut-Gumuscu, Suna; Chen, Wei-Min; Burren, Oliver

2015-01-01

Genetic studies of type 1 diabetes (T1D) have identified 50 susceptibility regions, finding major pathways contributing to risk, with some loci shared across immune disorders. To make genetic comparisons across autoimmune disorders as informative as possible, a dense genotyping array...... and significantly least similar to ulcerative colitis, and provided support for three additional new T1D risk loci. Using a Bayesian approach, we defined credible sets for the T1D-associated SNPs. The associated SNPs localized to enhancer sequences active in thymus, T and B cells, and CD34(+) stem cells. Enhancer-promoter......, the Immunochip, was developed, from which we identified four new T1D-associated regions (P comparative analysis with 15 immune diseases showed that T1D is more similar genetically to other autoantibody-positive diseases, significantly most similar to juvenile idiopathic arthritis...

TRAIL causes deletions at the HPRT and TK1 loci of clonogenically competent cells

Energy Technology Data Exchange (ETDEWEB)

Miles, Mark A.; Shekhar, Tanmay M. [Department of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria (Australia); La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia); Hall, Nathan E. [La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia); Life Sciences Computation Centre, Victorian Life Sciences Computation Initiative, Melbourne, Victoria (Australia); Hawkins, Christine J., E-mail: c.hawkins@latrobe.edu.au [Department of Biochemistry and Genetics, La Trobe University, Bundoora, Victoria (Australia); La Trobe Institute for Molecular Science, La Trobe University, Bundoora, Victoria (Australia)

2016-05-15

Highlights: • Treatment with TRAIL or EMS provokes mutations in clonogenically viable TK6 cells. • TRAIL is 2–5-fold less mutagenic than an equivalently lethal concentration of EMS. • EMS mainly causes transition mutations at the HPRT and TK1 loci of TK6 cells. • Most loss-of-function HPRT or TK1 mutations caused by TRAIL treatment are deletions. - Abstract: When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of

TRAIL causes deletions at the HPRT and TK1 loci of clonogenically competent cells

International Nuclear Information System (INIS)

Miles, Mark A.; Shekhar, Tanmay M.; Hall, Nathan E.; Hawkins, Christine J.

2016-01-01

Highlights: • Treatment with TRAIL or EMS provokes mutations in clonogenically viable TK6 cells. • TRAIL is 2–5-fold less mutagenic than an equivalently lethal concentration of EMS. • EMS mainly causes transition mutations at the HPRT and TK1 loci of TK6 cells. • Most loss-of-function HPRT or TK1 mutations caused by TRAIL treatment are deletions. - Abstract: When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of

Three new loci for determining x chromosome inactivation patterns

DEFF Research Database (Denmark)

Bertelsen, Birgitte; Tümer, Zeynep; Ravn, Kirstine

2011-01-01

. The reliability of the loci was validated by showing a high correlation between the results obtained by employing the new loci and the AR locus using DNA from 15 females who were informative for all four loci. Altogether, we show that these loci can be applied easily in molecular diagnostic laboratories, either...

Replication study for the association of 9 East Asian GWAS-derived loci with susceptibility to type 2 diabetes in a Japanese population.

Directory of Open Access Journals (Sweden)

Kensuke Sakai

Full Text Available AIMS: East Asian genome-wide association studies (GWAS for type 2 diabetes identified 8 loci with genome-wide significance, and 2 loci with a borderline association. However, the associations of these loci except MAEA locus with type 2 diabetes have not been evaluated in independent East Asian cohorts. We performed a replication study to investigate the association of these susceptibility loci with type 2 diabetes in an independent Japanese population. METHODS: We genotyped 7,379 Japanese participants (5,315 type 2 diabetes and 2,064 controls for each of the 9 single nucleotide polymorphisms (SNPs, rs7041847 in GLIS3, rs6017317 in FITM2-R3HDML-HNF4A, rs6467136 near GCCI-PAX4, rs831571 near PSMD6, rs9470794 in ZFAND3, rs3786897 in PEPD, rs1535500 in KCNK16, rs16955379 in CMIP, and rs17797882 near WWOX. Because the sample size in this study was not sufficient to replicate single SNP associations, we constructed a genetic risk score (GRS by summing a number of risk alleles of the 9 SNPs, and examined the association of the GRS with type 2 diabetes using logistic regression analysis. RESULTS: With the exception of rs1535500 in KCNK16, all SNPs had the same direction of effect (odds ratio [OR]>1.0 as in the original reports. The GRS constructed from the 9 SNPs was significantly associated with type 2 diabetes in the Japanese population (p = 4.0 × 10(-4, OR = 1.05, 95% confidence interval: 1.02-1.09. In quantitative trait analyses, rs16955379 in CMIP was nominally associated with a decreased homeostasis model assessment of β-cell function and with increased fasting plasma glucose, but neither the individual SNPs nor the GRS showed a significant association with the glycemic traits. CONCLUSIONS: These results indicate that 9 loci that were identified in the East Asian GWAS meta-analysis have a significant effect on the susceptibility to type 2 diabetes in the Japanese population.

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

NARCIS (Netherlands)

K. Gaulton (Kyle); T. Ferreira (Teresa); Y. Lee (Yeji); A. Raimondo (Anne); R. Mägi (Reedik); M.E. Reschen (Michael E.); A. Mahajan (Anubha); A. Locke (Adam); N.W. Rayner (Nigel William); N.R. Robertson (Neil); R.A. Scott (Robert); I. Prokopenko (Inga); L.J. Scott (Laura); T. Green (Todd); T. Sparsø (Thomas); D. Thuillier (Dorothee); L. Yengo (Loic); H. Grallert (Harald); S. Wahl (Simone); M. Frånberg (Mattias); R.J. Strawbridge (Rona); H. Kestler (Hans); H. Chheda (Himanshu); L. Eisele (Lewin); S. Gustafsson (Stefan); V. Steinthorsdottir (Valgerdur); G. Thorleifsson (Gudmar); L. Qi (Lu); L.C. Karssen (Lennart); E.M. van Leeuwen (Elisa); S.M. Willems (Sara); M. Li (Man); H. Chen (Han); C. Fuchsberger (Christian); P. Kwan (Phoenix); C. Ma (Clement); M. Linderman (Michael); Y. Lu (Yingchang); S.K. Thomsen (Soren K.); J.K. Rundle (Jana K.); N.L. Beer (Nicola L.); M. van de Bunt (Martijn); A. Chalisey (Anil); H.M. Kang (Hyun Min); B.F. Voight (Benjamin); G.R. Abecasis (Gonçalo); P. Almgren (Peter); D. Baldassarre (Damiano); B. Balkau (Beverley); R. Benediktsson (Rafn); M. Blüher (Matthias); H. Boeing (Heiner); L.L. Bonnycastle (Lori); E.P. Bottinger (Erwin P.); N.P. Burtt (Noël); J. Carey (Jason); G. Charpentier (Guillaume); P.S. Chines (Peter); M. Cornelis (Marilyn); D.J. Couper (David J.); A. Crenshaw (Andrew); R.M. van Dam (Rob); A.S.F. Doney (Alex); M. Dorkhan (Mozhgan); T. Edkins (Ted); J.G. Eriksson (Johan G.); T. Esko (Tõnu); E. Eury (Elodie); J. Fadista (João); J. Flannick (Jason); P. Fontanillas (Pierre); C.S. Fox (Caroline); P.W. Franks (Paul W.); K. Gertow (Karl); C. Gieger (Christian); B. Gigante (Bruna); R.F. Gottesman (Rebecca); G.B. Grant (George); N. Grarup (Niels); C.J. Groves (Christopher J.); M. Hassinen (Maija); C.T. Have (Christian T.); C. Herder (Christian); O.L. Holmen (Oddgeir); A.B. Hreidarsson (Astradur); S.E. Humphries (Steve E.); D.J. Hunter (David J.); A.U. Jackson (Anne); A. Jonsson (Anna); M.E. Jørgensen (Marit E.); T. Jørgensen (Torben); W.H.L. Kao (Wen); N.D. Kerrison (Nicola D.); L. Kinnunen (Leena); N. Klopp (Norman); A. Kong (Augustine); P. Kovacs (Peter); P. Kraft (Peter); J. Kravic (Jasmina); C. Langford (Cordelia); K. Leander (Karin); L. Liang (Liming); P. Lichtner (Peter); C.M. Lindgren (Cecilia M.); B. Lindholm (Bengt); A. Linneberg (Allan); C.-T. Liu (Ching-Ti); S. Lobbens (Stéphane); J. Luan (Jian'fan); V. Lyssenko (Valeriya); S. Männistö (Satu); O. McLeod (Olga); J. Meyer (Jobst); E. Mihailov (Evelin); G. Mirza (Ghazala); T.W. Mühleisen (Thomas); M. Müller-Nurasyid (Martina); C. Navarro (Carmen); M.M. Nöthen (Markus); N.N. Oskolkov (Nikolay N.); K.R. Owen (Katharine); D. Palli (Domenico); S. Pechlivanis (Sonali); L. Peltonen (Leena Johanna); J.R.B. Perry (John); C.P. Platou (Carl); M. Roden (Michael); D. Ruderfer (Douglas); D. Rybin (Denis); Y.T. Van Der Schouw (Yvonne T.); B. Sennblad (Bengt); G. Sigurosson (Gunnar); A. Stancáková (Alena); D. Steinbach; P. Storm (Petter); K. Strauch (Konstantin); H.M. Stringham (Heather); Q. Sun; B. Thorand (Barbara); E. Tikkanen (Emmi); A. Tönjes (Anke); J. Trakalo (Joseph); E. Tremoli (Elena); T. Tuomi (Tiinamaija); R. Wennauer (Roman); S. Wiltshire (Steven); A.R. Wood (Andrew); E. Zeggini (Eleftheria); I. Dunham (Ian); E. Birney (Ewan); L. Pasquali (Lorenzo); J. Ferrer (Jorge); R.J.F. Loos (Ruth); J. Dupuis (Josée); J.C. Florez (Jose); E.A. Boerwinkle (Eric); J.S. Pankow (James); C.M. van Duijn (Cornelia); E.J.G. Sijbrands (Eric); J.B. Meigs (James B.); F.B. Hu (Frank B.); U. Thorsteinsdottir (Unnur); J-A. Zwart (John-Anker); T.A. Lakka (Timo); R. Rauramaa (Rainer); M. Stumvoll (Michael); N.L. Pedersen (Nancy L.); L. Lind (Lars); S. Keinanen-Kiukaanniemi (Sirkka); E. Korpi-Hyövälti (Eeva); T. Saaristo (Timo); J. Saltevo (Juha); J. Kuusisto (Johanna); M. Laakso (Markku); A. Metspalu (Andres); R. Erbel (Raimund); K.-H. Jöckel (Karl-Heinz); S. Moebus (Susanne); S. Ripatti (Samuli); V. Salomaa (Veikko); E. Ingelsson (Erik); B.O. Boehm (Bernhard); R.N. Bergman (Richard N.); F.S. Collins (Francis S.); K.L. Mohlke (Karen L.); H. Koistinen (Heikki); J. Tuomilehto (Jaakko); K. Hveem (Kristian); I. Njølstad (Inger); P. Deloukas (Panagiotis); P.J. Donnelly (Peter J.); T.M. Frayling (Timothy); A.T. Hattersley (Andrew); U. de Faire (Ulf); A. Hamsten (Anders); T. Illig (Thomas); A. Peters (Annette); S. Cauchi (Stephane); R. Sladek (Rob); P. Froguel (Philippe); T. Hansen (Torben); O. Pedersen (Oluf); A.D. Morris (Andrew); C.N.A. Palmer (Collin N. A.); S. Kathiresan (Sekar); O. Melander (Olle); P.M. Nilsson (Peter M.); L. Groop (Leif); I.E. Barroso (Inês); C. Langenberg (Claudia); N.J. Wareham (Nicholas J.); C.A. O'Callaghan (Christopher A.); A.L. Gloyn (Anna); D. Altshuler (David); M. Boehnke (Michael); T.M. Teslovich (Tanya M.); M.I. McCarthy (Mark); A.P. Morris (Andrew)

2015-01-01

textabstractWe performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each

Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci

NARCIS (Netherlands)

Gaulton, Kyle J; Ferreira, Teresa; Lee, Yeji; Raimondo, Anne; Mägi, Reedik; Reschen, Michael E; Mahajan, Anubha; Locke, Adam; William Rayner, N; Robertson, Neil; Scott, Robert A; Prokopenko, Inga; Scott, Laura J; Green, Todd; Sparso, Thomas; Thuillier, Dorothee; Yengo, Loic; Grallert, Harald; Wahl, Simone; Frånberg, Mattias; Strawbridge, Rona J; Kestler, Hans; Chheda, Himanshu; Eisele, Lewin; Gustafsson, Stefan; Steinthorsdottir, Valgerdur; Thorleifsson, Gudmar; Qi, Lu; Karssen, Lennart C; van Leeuwen, Elisabeth M; Willems, Sara M; Li, Man; Chen, Han; Fuchsberger, Christian; Kwan, Phoenix; Ma, Clement; Linderman, Michael; Lu, Yingchang; Thomsen, Soren K; Rundle, Jana K; Beer, Nicola L; van de Bunt, Martijn; Chalisey, Anil; Kang, Hyun Min; Voight, Benjamin F; Abecasis, Gonçalo R; Almgren, Peter; Baldassarre, Damiano; Balkau, Beverley; Benediktsson, Rafn; Blüher, Matthias; Boeing, Heiner; Bonnycastle, Lori L; Bottinger, Erwin P; Burtt, Noël P; Carey, Jason; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn C; Couper, David J; Crenshaw, Andrew T; van Dam, Rob M; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Eriksson, Johan G; Esko, Tonu; Eury, Elodie; Fadista, João; Flannick, Jason; Fontanillas, Pierre; Fox, Caroline; Franks, Paul W; Gertow, Karl; Gieger, Christian; Gigante, Bruna; Gottesman, Omri; Grant, George B; Grarup, Niels; Groves, Christopher J; Hassinen, Maija; Have, Christian T; Herder, Christian; Holmen, Oddgeir L; Hreidarsson, Astradur B; Humphries, Steve E; Hunter, David J; Jackson, Anne U; Jonsson, Anna; Jørgensen, Marit E; Jørgensen, Torben; Kao, Wen-Hong L; Kerrison, Nicola D; Kinnunen, Leena; Klopp, Norman; Kong, Augustine; Kovacs, Peter; Kraft, Peter; Kravic, Jasmina; Langford, Cordelia; Leander, Karin; Liang, Liming; Lichtner, Peter; Lindgren, Cecilia M; Lindholm, Eero; Linneberg, Allan; Liu, Ching-Ti; Lobbens, Stéphane; Luan, Jian'an; Lyssenko, Valeriya; Männistö, Satu; McLeod, Olga; Meyer, Julia; Mihailov, Evelin; Mirza, Ghazala; Mühleisen, Thomas W; Müller-Nurasyid, Martina; Navarro, Carmen; Nöthen, Markus M; Oskolkov, Nikolay N; Owen, Katharine R; Palli, Domenico; Pechlivanis, Sonali; Peltonen, Leena; Perry, John R B; Platou, Carl G P; Roden, Michael; Ruderfer, Douglas; Rybin, Denis; van der Schouw, Yvonne T; Sennblad, Bengt; Sigurðsson, Gunnar; Stančáková, Alena; Steinbach, Gerald; Storm, Petter; Strauch, Konstantin; Stringham, Heather M; Sun, Qi; Thorand, Barbara; Tikkanen, Emmi; Tonjes, Anke; Trakalo, Joseph; Tremoli, Elena; Tuomi, Tiinamaija; Wennauer, Roman; Wiltshire, Steven; Wood, Andrew R; Zeggini, Eleftheria; Dunham, Ian; Birney, Ewan; Pasquali, Lorenzo; Ferrer, Jorge; Loos, Ruth J F; Dupuis, Josée; Florez, Jose C; Boerwinkle, Eric; Pankow, James S; van Duijn, Cornelia; Sijbrands, Eric; Meigs, James B; Hu, Frank B; Thorsteinsdottir, Unnur; Stefansson, Kari; Lakka, Timo A; Rauramaa, Rainer; Stumvoll, Michael; Pedersen, Nancy L; Lind, Lars; Keinanen-Kiukaanniemi, Sirkka M; Korpi-Hyövälti, Eeva; Saaristo, Timo E; Saltevo, Juha; Kuusisto, Johanna; Laakso, Markku; Metspalu, Andres; Erbel, Raimund; Jöcke, Karl-Heinz; Moebus, Susanne; Ripatti, Samuli; Salomaa, Veikko; Ingelsson, Erik; Boehm, Bernhard O; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Koistinen, Heikki; Tuomilehto, Jaakko; Hveem, Kristian; Njølstad, Inger; Deloukas, Panagiotis; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; de Faire, Ulf; Hamsten, Anders; Illig, Thomas; Peters, Annette; Cauchi, Stephane; Sladek, Rob; Froguel, Philippe; Hansen, Torben; Pedersen, Oluf; Morris, Andrew D; Palmer, Collin N A; Kathiresan, Sekar; Melander, Olle; Nilsson, Peter M; Groop, Leif C; Barroso, Inês; Langenberg, Claudia; Wareham, Nicholas J; O'Callaghan, Christopher A; Gloyn, Anna L; Altshuler, David; Boehnke, Michael; Teslovich, Tanya M; McCarthy, Mark I; Morris, Andrew P

2015-01-01

We performed fine mapping of 39 established type 2 diabetes (T2D) loci in 27,206 cases and 57,574 controls of European ancestry. We identified 49 distinct association signals at these loci, including five mapping in or near KCNQ1. 'Credible sets' of the variants most likely to drive each distinct

Genome-Wide Meta-Analyses of Breast, Ovarian, and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by at Least Two Cancer Types

DEFF Research Database (Denmark)

Kar, Siddhartha P; Beesley, Jonathan; Amin Al Olama, Ali

2016-01-01

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112...... (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell......-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P cancer meta-analysis. SIGNIFICANCE...

Genome-wide Meta-analyses of Breast, Ovarian and Prostate Cancer Association Studies Identify Multiple New Susceptibility Loci Shared by At Least Two Cancer Types

Science.gov (United States)

Kar, Siddhartha P.; Beesley, Jonathan; Al Olama, Ali Amin; Michailidou, Kyriaki; Tyrer, Jonathan; Kote-Jarai, ZSofia; Lawrenson, Kate; Lindstrom, Sara; Ramus, Susan J.; Thompson, Deborah J.; Kibel, Adam S.; Dansonka-Mieszkowska, Agnieszka; Michael, Agnieszka; Dieffenbach, Aida K.; Gentry-Maharaj, Aleksandra; Whittemore, Alice S.; Wolk, Alicja; Monteiro, Alvaro; Peixoto, Ana; Kierzek, Andrzej; Cox, Angela; Rudolph, Anja; Gonzalez-Neira, Anna; Wu, Anna H.; Lindblom, Annika; Swerdlow, Anthony; Ziogas, Argyrios; Ekici, Arif B.; Burwinkel, Barbara; Karlan, Beth Y.; Nordestgaard, Børge G.; Blomqvist, Carl; Phelan, Catherine; McLean, Catriona; Pearce, Celeste Leigh; Vachon, Celine; Cybulski, Cezary; Slavov, Chavdar; Stegmaier, Christa; Maier, Christiane; Ambrosone, Christine B.; Høgdall, Claus K.; Teerlink, Craig C.; Kang, Daehee; Tessier, Daniel C.; Schaid, Daniel J.; Stram, Daniel O.; Cramer, Daniel W.; Neal, David E.; Eccles, Diana; Flesch-Janys, Dieter; Velez Edwards, Digna R.; Wokozorczyk, Dominika; Levine, Douglas A.; Yannoukakos, Drakoulis; Sawyer, Elinor J.; Bandera, Elisa V.; Poole, Elizabeth M.; Goode, Ellen L.; Khusnutdinova, Elza; Høgdall, Estrid; Song, Fengju; Bruinsma, Fiona; Heitz, Florian; Modugno, Francesmary; Hamdy, Freddie C.; Wiklund, Fredrik; Giles, Graham G.; Olsson, Håkan; Wildiers, Hans; Ulmer, Hans-Ulrich; Pandha, Hardev; Risch, Harvey A.; Darabi, Hatef; Salvesen, Helga B.; Nevanlinna, Heli; Gronberg, Henrik; Brenner, Hermann; Brauch, Hiltrud; Anton-Culver, Hoda; Song, Honglin; Lim, Hui-Yi; McNeish, Iain; Campbell, Ian; Vergote, Ignace; Gronwald, Jacek; Lubiński, Jan; Stanford, Janet L.; Benítez, Javier; Doherty, Jennifer A.; Permuth, Jennifer B.; Chang-Claude, Jenny; Donovan, Jenny L.; Dennis, Joe; Schildkraut, Joellen M.; Schleutker, Johanna; Hopper, John L.; Kupryjanczyk, Jolanta; Park, Jong Y.; Figueroa, Jonine; Clements, Judith A.; Knight, Julia A.; Peto, Julian; Cunningham, Julie M.; Pow-Sang, Julio; Batra, Jyotsna; Czene, Kamila; Lu, Karen H.; Herkommer, Kathleen; Khaw, Kay-Tee; Matsuo, Keitaro; Muir, Kenneth; Offitt, Kenneth; Chen, Kexin; Moysich, Kirsten B.; Aittomäki, Kristiina; Odunsi, Kunle; Kiemeney, Lambertus A.; Massuger, Leon F.A.G.; Fitzgerald, Liesel M.; Cook, Linda S.; Cannon-Albright, Lisa; Hooning, Maartje J.; Pike, Malcolm C.; Bolla, Manjeet K.; Luedeke, Manuel; Teixeira, Manuel R.; Goodman, Marc T.; Schmidt, Marjanka K.; Riggan, Marjorie; Aly, Markus; Rossing, Mary Anne; Beckmann, Matthias W.; Moisse, Matthieu; Sanderson, Maureen; Southey, Melissa C.; Jones, Michael; Lush, Michael; Hildebrandt, Michelle A. T.; Hou, Ming-Feng; Schoemaker, Minouk J.; Garcia-Closas, Montserrat; Bogdanova, Natalia; Rahman, Nazneen; Le, Nhu D.; Orr, Nick; Wentzensen, Nicolas; Pashayan, Nora; Peterlongo, Paolo; Guénel, Pascal; Brennan, Paul; Paulo, Paula; Webb, Penelope M.; Broberg, Per; Fasching, Peter A.; Devilee, Peter; Wang, Qin; Cai, Qiuyin; Li, Qiyuan; Kaneva, Radka; Butzow, Ralf; Kopperud, Reidun Kristin; Schmutzler, Rita K.; Stephenson, Robert A.; MacInnis, Robert J.; Hoover, Robert N.; Winqvist, Robert; Ness, Roberta; Milne, Roger L.; Travis, Ruth C.; Benlloch, Sara; Olson, Sara H.; McDonnell, Shannon K.; Tworoger, Shelley S.; Maia, Sofia; Berndt, Sonja; Lee, Soo Chin; Teo, Soo-Hwang; Thibodeau, Stephen N.; Bojesen, Stig E.; Gapstur, Susan M.; Kjær, Susanne Krüger; Pejovic, Tanja; Tammela, Teuvo L.J.; Dörk, Thilo; Brüning, Thomas; Wahlfors, Tiina; Key, Tim J.; Edwards, Todd L.; Menon, Usha; Hamann, Ute; Mitev, Vanio; Kosma, Veli-Matti; Setiawan, Veronica Wendy; Kristensen, Vessela; Arndt, Volker; Vogel, Walther; Zheng, Wei; Sieh, Weiva; Blot, William J.; Kluzniak, Wojciech; Shu, Xiao-Ou; Gao, Yu-Tang; Schumacher, Fredrick; Freedman, Matthew L.; Berchuck, Andrew; Dunning, Alison M.; Simard, Jacques; Haiman, Christopher A.; Spurdle, Amanda; Sellers, Thomas A.; Hunter, David J.; Henderson, Brian E.; Kraft, Peter; Chanock, Stephen J.; Couch, Fergus J.; Hall, Per; Gayther, Simon A.; Easton, Douglas F.; Chenevix-Trench, Georgia; Eeles, Rosalind; Pharoah, Paul D.P.; Lambrechts, Diether

2016-01-01

Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P cancer meta-analysis. PMID:27432226

Physiologic characterization of type 2 diabetes-related loci

DEFF Research Database (Denmark)

Grarup, Niels; Sparsø, Thomas; Hansen, Torben

2010-01-01

For the past two decades, genetics has been widely explored as a tool for unraveling the pathogenesis of diabetes. Many risk alleles for type 2 diabetes and hyperglycemia have been detected in recent years through massive genome-wide association studies and evidence exists that most...... diabetes-related traits is a likely scenario and identification of new pathways involved in type 2 diabetes predisposition will offer opportunities for the development of novel therapeutic and preventative approaches....... indications of more specific pathologic mechanisms for diabetes-related risk variants. Such studies have shed light on the function of some loci but also underlined the complex nature of disease mechanism. In the future, sequencing-based discovery of low-frequency variants with higher impact on intermediate...

Genes affecting β-cell function in type 1 diabetes

DEFF Research Database (Denmark)

Fløyel, Tina; Kaur, Simranjeet; Pociot, Flemming

2015-01-01

Type 1 diabetes (T1D) is a multifactorial disease resulting from an immune-mediated destruction of the insulin-producing pancreatic β cells. Several environmental and genetic risk factors predispose to the disease. Genome-wide association studies (GWAS) have identified around 50 genetic regions...... that affect the risk of developing T1D, but the disease-causing variants and genes are still largely unknown. In this review, we discuss the current status of T1D susceptibility loci and candidate genes with focus on the β cell. At least 40 % of the genes in the T1D susceptibility loci are expressed in human...... islets and β cells, where they according to recent studies modulate the β-cell response to the immune system. As most of the risk variants map to noncoding regions of the genome, i.e., promoters, enhancers, intergenic regions, and noncoding genes, their possible involvement in T1D pathogenesis as gene...

Evolutionary dynamics of mating-type loci of Mycosphaerella spp. occurring on banana

NARCIS (Netherlands)

Arzanlou, M.; Crous, P.W.; Zwiers, L.H.

2010-01-01

The devastating Sigatoka disease complex of banana is primarily caused by three closely related heterothallic fungi belonging to the genus Mycosphaerella: M. fijiensis, M. musicola, and M. eumusae. Previous phylogenetic work showing common ancestry led us to analyze the mating-type loci of these

Cell-type-specific responses of RT4 neural cell lines to dibutyryl-cAMP: branch determination versus maturation

International Nuclear Information System (INIS)

Droms, K.; Sueoka, N.

1987-01-01

This report describes the induction of cell-type-specific maturation, by dibutyryl-cAMP and testololactone, of neuronal and glial properties in a family of cell lines derived from a rat peripheral neurotumor, RT4. This maturation allows further understanding of the process of determination because of the close lineage relationship between the cell types of the RT4 family. The RT4 family is characterized by the spontaneous conversion of one of the cell types, RT4-AC (stem-cell type), to any of three derivative cell types, RT4-B, RT4-D, or RT4-E, with a frequency of about 10(-5). The RT4-AC cells express some properties characteristic of both neuronal and glial cells. Of these neural properties expressed by RT4-AC cells, only the neuronal properties are expressed by the RT4-B and RT4-E cells, and only the glial properties are expressed by the RT4-D cells. This in vitro cell-type conversion of RT4-AC to three derivative cell types is a branch point for the coordinate regulation of several properties and seems to resemble determination in vivo. In our standard culture conditions, several other neuronal and glial properties are not expressed by these cell types. However, addition of dibutyryl-cAMP induces expression of additional properties, in a cell-type-specific manner: formation of long cellular processes in the RT4-B8 and RT4-E5 cell lines and expression of high-affinity uptake of gamma-aminobutyric acid, by a glial-cell-specific mechanism, in the RT4-D6-2 cell line. These new properties are maximally expressed 2-3 days after addition of dibutyryl-cAMP

The most common spoligotype of Mycobacterium bovis isolated in the world and the recommended loci for VNTR typing; A systematic review.

Science.gov (United States)

Ghavidel, Mahdis; Mansury, Davood; Nourian, Kimiya; Ghazvini, Kiarash

2018-03-22

Mycobacterium bovis is a neglected zoonotic organism that epidemiological studies are of crucial importance in identifying its source, control it and prevent it from spreading. The aim of this study was to investigate the most common spoligotypes of Mycobacterium bovis circulating around the world and introduce the most and least strong determine powers of loci for VNTR. We have used different databases such as ISC, science direct, Embase (Elsevier), Web of Science, Scopus and Medline via PubMed. Searches were performed by key words including: Mycobacterium bovis, MIRU -VNTR, spoligotyping and discrimination power. Finally, thirty-one articles were selected after filtering out some titles, abstracts and full texts. Spoligotype SB0120 was the most common circulating type on several continents while SB0121 existed in Europe, Africa and America. SB0140 was also detected in Asia, Europe and America. QUB3232 and QUB11b were more appropriate loci among the loci with high discriminatory power. MIRU 10 and MIRU4 were among the loci with poor discriminatory power. Taking the published data into consideration, SB0120 and SB0121 are predominant spoligotypes of M. bovis circulating among animals around the world. Determining the most common spoligotype of M. bovis is the key to find source of infection, control and prevent the disease. Copyright © 2018 Elsevier Ltd. All rights reserved.

A genome-wide screen in human embryonic stem cells reveals novel sites of allele-specific histone modification associated with known disease loci

LENUS (Irish Health Repository)

Prendergast, James G D

2012-05-19

AbstractBackgroundChromatin structure at a given site can differ between chromosome copies in a cell, and such imbalances in chromatin structure have been shown to be important in understanding the molecular mechanisms controlling several disease loci. Human genetic variation, DNA methylation, and disease have been intensely studied, uncovering many sites of allele-specific DNA methylation (ASM). However, little is known about the genome-wide occurrence of sites of allele-specific histone modification (ASHM) and their relationship to human disease. The aim of this study was to investigate the extent and characteristics of sites of ASHM in human embryonic stem cells (hESCs).ResultsUsing a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.ConclusionThese results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.

Type 1 Diabetes Candidate Genes Linked to Pancreatic Islet Cell Inflammation and Beta-Cell Apoptosis

DEFF Research Database (Denmark)

Størling, Joachim; Pociot, Flemming

2017-01-01

(GWAS) have identified more than 50 genetic regions that affect the risk of developing T1D. Most of these susceptibility loci, however, harbor several genes, and the causal variant(s) and gene(s) for most of the loci remain to be established. A significant part of the genes located in the T1D...... susceptibility loci are expressed in human islets and β cells and mounting evidence suggests that some of these genes modulate the β-cell response to the immune system and viral infection and regulate apoptotic β-cell death. Here, we discuss the current status of T1D susceptibility loci and candidate genes...

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

DEFF Research Database (Denmark)

Imamura, Minako; Takahashi, Atsushi; Yamauchi, Toshimasa

2016-01-01

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery...... and subsequent validation analyses (23,399 T2D cases and 31,722 controls) identify 7 new loci with genome-wide significance (P2, rs7107784 near MIR4686 and rs67839313 near INAFM2....... Of these, the association of 4 loci with T2D is replicated in multi-ethnic populations other than Japanese (up to 65,936 T2Ds and 158,030 controls, P

Genome-Derived Cytosolic DNA Mediates Type I Interferon-Dependent Rejection of B Cell Lymphoma Cells

Directory of Open Access Journals (Sweden)

Yu J. Shen

2015-04-01

Full Text Available The DNA damage response (DDR induces the expression of type I interferons (IFNs, but the underlying mechanisms are poorly understood. Here, we show the presence of cytosolic DNA in different mouse and human tumor cells. Treatment of cells with genotoxic agents increased the levels of cytosolic DNA in a DDR-dependent manner. Cloning of cytosolic DNA molecules from mouse lymphoma cells suggests that cytosolic DNA is derived from unique genomic loci and has the potential to form non-B DNA structures, including R-loops. Overexpression of Rnaseh1, which resolves R-loops, reduced the levels of cytosolic DNA, type I Ifn transcripts, and type I IFN-dependent rejection of lymphoma cells. Live-cell imaging showed a dynamic contact of cytosolic DNA with mitochondria, an important organelle for innate immune recognition of cytosolic nucleotides. In summary, we found that cytosolic DNA is present in many tumor cells and contributes to the immunogenicity of tumor cells.

A PQL (protein quantity loci) analysis of mature pea seed proteins identifies loci determining seed protein composition.

Science.gov (United States)

Bourgeois, Michael; Jacquin, Françoise; Cassecuelle, Florence; Savois, Vincent; Belghazi, Maya; Aubert, Grégoire; Quillien, Laurence; Huart, Myriam; Marget, Pascal; Burstin, Judith

2011-05-01

Legume seeds are a major source of dietary proteins for humans and animals. Deciphering the genetic control of their accumulation is thus of primary significance towards their improvement. At first, we analysed the genetic variability of the pea seed proteome of three genotypes over 3 years of cultivation. This revealed that seed protein composition variability was under predominant genetic control, with as much as 60% of the spots varying quantitatively among the three genotypes. Then, by combining proteomic and quantitative trait loci (QTL) mapping approaches, we uncovered the genetic architecture of seed proteome variability. Protein quantity loci (PQL) were searched for 525 spots detected on 2-D gels obtained for 157 recombinant inbred lines. Most protein quantity loci mapped in clusters, suggesting that the accumulation of the major storage protein families was under the control of a limited number of loci. While convicilin accumulation was mainly under the control of cis-regulatory regions, vicilins and legumins were controlled by both cis- and trans-regulatory regions. Some loci controlled both seed protein composition and protein content and a locus on LGIIa appears to be a major regulator of protein composition and of protein in vitro digestibility. Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Variable Extent of Lineage-Specificity and Developmental Stage-Specificity of Cohesin and CCCTC-Binding Factor Binding Within the Immunoglobulin and T Cell Receptor Loci

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Salvatore Loguercio

2018-03-01

Full Text Available CCCTC-binding factor (CTCF is largely responsible for the 3D architecture of the genome, in concert with the action of cohesin, through the creation of long-range chromatin loops. Cohesin is hypothesized to be the main driver of these long-range chromatin interactions by the process of loop extrusion. Here, we performed ChIP-seq for CTCF and cohesin in two stages each of T and B cell differentiation and examined the binding pattern in all six antigen receptor (AgR loci in these lymphocyte progenitors and in mature T and B cells, ES cells, and fibroblasts. The four large AgR loci have many bound CTCF sites, most of which are only occupied in lymphocytes, while only the CTCF sites at the end of each locus near the enhancers or J genes tend to be bound in non-lymphoid cells also. However, despite the generalized lymphocyte restriction of CTCF binding in AgR loci, the Igκ locus is the only locus that also shows significant lineage-specificity (T vs. B cells and developmental stage-specificity (pre-B vs. pro-B in CTCF binding. We show that cohesin binding shows greater lineage- and stage-specificity than CTCF at most AgR loci, providing more specificity to the loops. We also show that the culture of pro-B cells in IL7, a common practice to expand the number of cells before ChIP-seq, results in a CTCF-binding pattern resembling pre-B cells, as well as other epigenetic and transcriptional characteristics of pre-B cells. Analysis of the orientation of the CTCF sites show that all sites within the large V portions of the Igh and TCRβ loci have the same orientation. This suggests either a lack of requirement for convergent CTCF sites creating loops, or indicates an absence of any loops between CTCF sites within the V region portion of those loci but only loops to the convergent sites at the D-J-enhancer end of each locus. The V region portions of the Igκ and TCRα/δ loci, by contrast, have CTCF sites in both orientations, providing many options for

Determination of combined sibship indices "gray zone" using 15 STR loci for central Bosnian human population.

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Musanovic, Jasmin; Filipovska-Musanovic, Marijana; Kovacevic, Lejla; Buljugic, Dzenisa; Dzehverovic, Mirela; Avdic, Jasna; Marjanovic, Damir

2012-05-01

In our previous population studies of Bosnia and Herzegovina human population, we have used autosomal STR, Y-STR, and X-STR loci, as well as Y-chromosome NRY biallelic markers. All obtained results were included in Bosnian referent database. In order of future development of applied population molecular genetics researches of Bosnia and Herzegovina human population, we have examined the effectiveness of 15 STR loci system in determination of sibship by using 15 STR loci and calculating different cut-off points of combined sibship indices (CSI) and distribution of sharing alleles. From the perspective of its application, it is very difficult and complicated to establish strict CSI cut-off values for determination of the doubtless sibship. High statistically significant difference between the means of CSI values and in distribution of alleles sharing in siblings and non-siblings was noticed (P < 0.0001). After constructing the "gray zone", only one false positive result was found in three CSI cut-off levels with the highest percent of determined sibship/non-sibship at the CSI = 0.067, confirming its practical benefit. Concerning the distribution of sharing alleles, it is recommended as an informative estimator for its usage within Bosnia and Herzegovina human population.

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

NARCIS (Netherlands)

Dupuis, J.; Langenberg, C.; Prokopenko, I.; Saxena, R.; Soranzo, N.; Jackson, A.U.; Wheeler, E.; Glazer, N.L.; Bouatia-Naji, N.; Gloyn, A.L.; Lindgren, C.M.; Mägi, R.; Morris, A.P.; Randall, J.; Johnson, T.; Hottenga, J.J.; de Geus, E.J.C.; Kaprio, J.; Kyvik, K.O.; Pedersen, N.L.; Perola, M.; Posthuma, D.; Rivadeneira, F.; Uitterlinden, A.G.; Willems van Dijk, K.; van Hoek, M.; Vogelzangs, N.; Willemsen, G.; Witteman, J.C.M.; Zillikens, M.C.; Penninx, B.W.J.H.; Boomsma, D.I.; van Duijn, C.M.; Aulchenko, Y.S.; Waterworth, D.; Vollenweider, P.; Peltonen, L.; Mooser, V.; Abecasis, G.R.; Wareham, N.J.; Sladek, R.; Froguel, P.; Watanabe, R.M.; Meigs, J.B.; Groop, L.C.; Boehnke, M.; McCarthy, M.I.; Florez, J.C.; Barroso, I.

2010-01-01

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up

Use of the VNTR typing technique to determine the origin of Mycobacterium tuberculosis strains isolated from Filipino patients in Korea.

Science.gov (United States)

Lee, Jihye; Tupasi, Thelma E; Park, Young Kil

2014-05-01

With increasing international interchange of personnel, international monitoring is necessary to decrease tuberculosis incidence in the world. This study aims to develop a new tool to determine origin of Mycobacterium tuberculosis strains isolated from Filipino patients living in Korea. Thirty-two variable number tandem repeat (VNTR) loci were used for discrimination of 50 Filipino M. tuberculosis strains isolated in the Philippines, 317 Korean strains isolated in Korea, and 8 Filipino strains isolated in Korea. We found that the VNTR loci 0580, 0960, 2531, 2687, 2996, 0802, 2461, 2163a, 4052, 0424, 1955, 2074, 2347, 2401, 3171, 3690, 2372, 3232, and 4156 had different mode among copy numbers or exclusively distinct copy number in VNTR typing between Filipino and Korean M. tuberculosis strains. When these differences of the VNTR loci were applied to 8 Filipino M. tuberculosis strains isolated in Korea, 6 of them revealed Filipino type while 2 of them had Korean type. Using the differences of mode or repeated number of VNTR loci were very useful in distinguishing the Filipino strain from Korean strain.

Genome-wide association study identifies multiple susceptibility loci for diffuse large B cell lymphoma

NARCIS (Netherlands)

Cerhan, James R.; Berndt, Sonja I.; Vijai, Joseph; Ghesquières, Hervé; McKay, James; Wang, Sophia S.; Wang, Zhaoming; Yeager, Meredith; Conde, Lucia; De Bakker, Paul I W; Nieters, Alexandra; Cox, David; Burdett, Laurie; Monnereau, Alain; Flowers, Christopher R.; De Roos, Anneclaire J.; Brooks-Wilson, Angela R.; Lan, Qing; Severi, Gianluca; Melbye, Mads; Gu, Jian; Jackson, Rebecca D.; Kane, Eleanor; Teras, Lauren R.; Purdue, Mark P.; Vajdic, Claire M.; Spinelli, John J.; Giles, Graham G.; Albanes, Demetrius; Kelly, Rachel S.; Zucca, Mariagrazia; Bertrand, Kimberly A.; Zeleniuch-Jacquotte, Anne; Lawrence, Charles; Hutchinson, Amy; Zhi, Degui; Habermann, Thomas M.; Link, Brian K.; Novak, Anne J.; Dogan, Ahmet; Asmann, Yan W.; Liebow, Mark; Thompson, Carrie A.; Ansell, Stephen M.; Witzig, Thomas E.; Weiner, George J.; Veron, Amelie S.; Zelenika, Diana; Tilly, Hervé; Haioun, Corinne; Molina, Thierry Jo; Hjalgrim, Henrik; Glimelius, Bengt; Adami, Hans Olov; Bracci, Paige M.; Riby, Jacques; Smith, Martyn T.; Holly, Elizabeth A.; Cozen, Wendy; Hartge, Patricia; Morton, Lindsay M.; Severson, Richard K.; Tinker, Lesley F.; North, Kari E.; Becker, Nikolaus; Benavente, Yolanda; Boffetta, Paolo; Brennan, Paul; Foretova, Lenka; Maynadie, Marc; Staines, Anthony; Lightfoot, Tracy; Crouch, Simon; Smith, Alex; Roman, Eve; Diver, W. Ryan; Offit, Kenneth; Zelenetz, Andrew; Klein, Robert J.; Villano, Danylo J.; Zheng, Tongzhang; Zhang, Yawei; Holford, Theodore R.; Kricker, Anne; Turner, Jenny; Southey, Melissa C.; Clavel, Jacqueline; Virtamo, Jarmo; Weinstein, Stephanie; Riboli, Elio; Vineis, Paolo; Kaaks, Rudolph; Trichopoulos, Dimitrios; Vermeulen, Roel C H; Boeing, Heiner; Tjonneland, Anne; Angelucci, Emanuele; Di Lollo, Simonetta; Rais, Marco; Birmann, Brenda M.; Laden, Francine; Giovannucci, Edward; Kraft, Peter; Huang, Jinyan; Ma, Baoshan; Ye, Yuanqing; Chiu, Brian C H; Sampson, Joshua; Liang, Liming; Park, Ju Hyun; Chung, Charles C.; Weisenburger, Dennis D.; Chatterjee, Nilanjan; Fraumeni, Joseph F.; Slager, Susan L.; Wu, Xifeng; De Sanjose, Silvia; Smedby, Karin E.; Salles, Gilles; Skibola, Christine F.; Rothman, Nathaniel; Chanock, Stephen J.

2014-01-01

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of

The Florida manatee (Trichechus manatus latirostris) T cell receptor loci exhibit V subgroup synteny and chain-specific evolution

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Breaux, Breanna; Hunter, Margaret; Cruz-Schneider, Maria Paula; Sena, Leonardo; Bonde, Robert K.; Criscitiello, Michael F.

2018-01-01

The Florida manatee (Trichechus manatus latirostris) has limited diversity in the immunoglobulin heavy chain. We therefore investigated the antigen receptor loci of the other arm of the adaptive immune system: the T cell receptor. Manatees are the first species from Afrotheria, a basal eutherian superorder, to have an in-depth characterization of all T cell receptor loci. By annotating the genome and expressed transcripts, we found that each chain has distinct features that correlates to their individual functions. The genomic organization also plays a role in modulating sequence conservation between species. There were extensive V subgroup synteny blocks in the TRA and TRB loci between T. m. latirostrisand human. Increased genomic locus complexity correlated to increased locus synteny. We also identified evidence for a VHD pseudogene for the first time in a eutherian mammal. These findings emphasize the value of including species within this basal eutherian radiation in comparative studies.

CRISPRstrand: predicting repeat orientations to determine the crRNA-encoding strand at CRISPR loci

DEFF Research Database (Denmark)

Alkhnbashi, Omer S.; Costa, Fabrizio; Shah, Shiraz Ali

2014-01-01

Motivation: The discovery of CRISPR-Cas systems almost 20 years ago rapidly changed our perception of the bacterial and archaeal immune systems. CRISPR loci consist of several repetitive DNA sequences called repeats, inter-spaced by stretches of variable length sequences called spacers. This CRISPR...... array is transcribed and processed into multiple mature RNA species (crRNAs). A single crRNA is integrated into an interference complex, together with CRISPR-associated (Cas) proteins, to bind and degrade invading nucleic acids. Although existing bioinformatics tools can recognize CRISPR loci...... by their characteristic repeat-spacer architecture, they generally output CRISPR arrays of ambiguous orientation and thus do not determine the strand from which crRNAs are processed. Knowledge of the correct orientation is crucial for many tasks, including the classification of CRISPR conservation, the detection...

The development of functional mapping by three sex-related loci on the third whorl of different sex types of Carica papaya L.

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Chen-Yu Lee

Full Text Available Carica papaya L. is an important economic crop worldwide and is used as a model plant for sex-determination research. To study the different flower sex types, we screened sex-related genes using alternative splicing sequences (AS-seqs from a transcriptome database of the three flower sex types, i.e., males, females, and hermaphrodites, established at 28 days before flowering using 15 bacterial artificial chromosomes (BACs of C. papaya L. After screening, the cDNA regions of the three sex-related loci, including short vegetative phase-like (CpSVPL, the chromatin assembly factor 1 subunit A-like (CpCAF1AL, and the somatic embryogenesis receptor kinase (CpSERK, which contained eight sex-related single-nucleotide polymorphisms (SNPs from the different sex types of C. papaya L., were genotyped using high-resolution melting (HRM. The three loci were examined regarding the profiles of the third whorl, as described below. CpSVPL, which had one SNP associated with the three sex genotypes, was highly expressed in the male and female sterile flowers (abnormal hermaphrodite flowers that lacked the fourth whorl structure. CpCAF1AL, which had three SNPs associated with the male genotype, was highly expressed in male and normal hermaphrodite flowers, and had no AS-seqs, whereas it exhibited low expression and an AS-seqs in intron 11 in abnormal hermaphrodite flowers. Conversely, carpellate flowers (abnormal hermaphrodite flowers showed low expression of CpSVPL and AS-seqs in introns 5, 6, and 7 of CpSERK, which contained four SNPs associated with the female genotype. Specifically, the CpSERK and CpCAF1AL loci exhibited no AS-seq expression in the third whorl of the male and normal hermaphrodite flowers, respectively, and variance in the AS-seq expression of all other types of flowers. Functional mapping of the third whorl of normal hermaphrodites indicated no AS-seq expression in CpSERK, low CpSVPL expression, and, for CpCAF1AL, high expression and no AS

Invariant TAD Boundaries Constrain Cell-Type-Specific Looping Interactions between Promoters and Distal Elements around the CFTR Locus.

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Smith, Emily M; Lajoie, Bryan R; Jain, Gaurav; Dekker, Job

2016-01-07

Three-dimensional genome structure plays an important role in gene regulation. Globally, chromosomes are organized into active and inactive compartments while, at the gene level, looping interactions connect promoters to regulatory elements. Topologically associating domains (TADs), typically several hundred kilobases in size, form an intermediate level of organization. Major questions include how TADs are formed and how they are related to looping interactions between genes and regulatory elements. Here we performed a focused 5C analysis of a 2.8 Mb chromosome 7 region surrounding CFTR in a panel of cell types. We find that the same TAD boundaries are present in all cell types, indicating that TADs represent a universal chromosome architecture. Furthermore, we find that these TAD boundaries are present irrespective of the expression and looping of genes located between them. In contrast, looping interactions between promoters and regulatory elements are cell-type specific and occur mostly within TADs. This is exemplified by the CFTR promoter that in different cell types interacts with distinct sets of distal cell-type-specific regulatory elements that are all located within the same TAD. Finally, we find that long-range associations between loci located in different TADs are also detected, but these display much lower interaction frequencies than looping interactions within TADs. Interestingly, interactions between TADs are also highly cell-type-specific and often involve loci clustered around TAD boundaries. These data point to key roles of invariant TAD boundaries in constraining as well as mediating cell-type-specific long-range interactions and gene regulation. Copyright © 2016 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Genome-wide association studies in the Japanese population identify seven novel loci for type 2 diabetes

DEFF Research Database (Denmark)

Imamura, Minako; Takahashi, Atsushi; Yamauchi, Toshimasa

2016-01-01

Genome-wide association studies (GWAS) have identified more than 80 susceptibility loci for type 2 diabetes (T2D), but most of its heritability still remains to be elucidated. In this study, we conducted a meta-analysis of GWAS for T2D in the Japanese population. Combined data from discovery and ...

Insight into Genotype-Phenotype Associations through eQTL Mapping in Multiple Cell Types in Health and Immune-Mediated Disease.

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James E Peters

2016-03-01

Full Text Available Genome-wide association studies (GWAS have transformed our understanding of the genetics of complex traits such as autoimmune diseases, but how risk variants contribute to pathogenesis remains largely unknown. Identifying genetic variants that affect gene expression (expression quantitative trait loci, or eQTLs is crucial to addressing this. eQTLs vary between tissues and following in vitro cellular activation, but have not been examined in the context of human inflammatory diseases. We performed eQTL mapping in five primary immune cell types from patients with active inflammatory bowel disease (n = 91, anti-neutrophil cytoplasmic antibody-associated vasculitis (n = 46 and healthy controls (n = 43, revealing eQTLs present only in the context of active inflammatory disease. Moreover, we show that following treatment a proportion of these eQTLs disappear. Through joint analysis of expression data from multiple cell types, we reveal that previous estimates of eQTL immune cell-type specificity are likely to have been exaggerated. Finally, by analysing gene expression data from multiple cell types, we find eQTLs not previously identified by database mining at 34 inflammatory bowel disease-associated loci. In summary, this parallel eQTL analysis in multiple leucocyte subsets from patients with active disease provides new insights into the genetic basis of immune-mediated diseases.

LOL2 and LOL5 loci control latex production by laticifer cells in Euphorbia lathyris.

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Castelblanque, Lourdes; Balaguer, Begoña; Marti, Cristina; Orozco, Marianela; Vera, Pablo

2018-06-07

Laticifers are specialized plant cells capable of indefinite elongation that ramify extensively and are responsible for latex biosynthesis and accumulation. However, the mechanisms underlying laticifer cell differentiation, growth and production of latex remain largely unknown. In a search for mutants showing enhanced accumulation of latex we identified two LOT OF LATEX (LOL) loci in Euphorbia lathyris. lol2 and lol5 mutants show enhanced production of latex contained within laticifer cells. The recessive lol2 mutant carries increased biosynthesis of the plant hormone jasmonoyl-isoleucine (JA-Ile) and therefore establishes a genetic link between jasmonic acid (JA) signaling and latex production in laticifers. Instead, heightened production of latex in lol5 plants obeys to enhanced proliferation of laticifer cells. Phylogenetic analysis of laticifer-expressed genes in E. lathyris and in two other latex-bearing species, Euphorbia corallioides and Euphorbia palustris, allowed the identification of canonical JA responsive elements present in the gene promoter regions of laticifer marker genes. Moreover, we identified that the hormone JA functions not as a morphogen for laticifer differentiation but as a trigger for the fill out of laticifers with latex and the associated triterpenoids. The identification of LOL loci represents a further step towards the understanding of mechanisms controlling latex production in laticifer cells. No claim to original US Government works New Phytologist © 2018 New Phytologist Trust.

Live visualization of genomic loci with BiFC-TALE.

Science.gov (United States)

Hu, Huan; Zhang, Hongmin; Wang, Sheng; Ding, Miao; An, Hui; Hou, Yingping; Yang, Xiaojing; Wei, Wensheng; Sun, Yujie; Tang, Chao

2017-01-11

Tracking the dynamics of genomic loci is important for understanding the mechanisms of fundamental intracellular processes. However, fluorescent labeling and imaging of such loci in live cells have been challenging. One of the major reasons is the low signal-to-background ratio (SBR) of images mainly caused by the background fluorescence from diffuse full-length fluorescent proteins (FPs) in the living nucleus, hampering the application of live cell genomic labeling methods. Here, combining bimolecular fluorescence complementation (BiFC) and transcription activator-like effector (TALE) technologies, we developed a novel method for labeling genomic loci (BiFC-TALE), which largely reduces the background fluorescence level. Using BiFC-TALE, we demonstrated a significantly improved SBR by imaging telomeres and centromeres in living cells in comparison with the methods using full-length FP.

Genetic data for 15 STR loci in a Kadazan-Dusun population from East Malaysia.

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Kee, B P; Lian, L H; Lee, P C; Lai, T X; Chua, K H

2011-04-26

Allele frequencies of 15 short tandem repeat (STR) loci, namely D5S818, D7S820, D13S317, D16S539, TH01, TPOX, Penta D, Penta E, D3S1358, D8S1179, D18S51, D21S11, CSF1PO, vWA, and FGA, were determined for 154 individuals from the Kadazan-Dusun tribe, an indigenous population of East Malaysia. All loci were amplified by polymerase chain reaction, using the Powerplex 16 system. Alleles were typed using a gene analyzer and the Genemapper ID software. Various statistical parameters were calculated and the combined power of discrimination for the 15 loci in the population was calculated as 0.999999999999999. These loci are thus, informative and can be used effectively in forensic and genetic studies of this indigenous population.

Mapping of four distinct BCR-related loci to chromosome region 22q11: order of BCR loci relative to chronic myelogenous leukemia and acute lymphoblastic leukemia breakpoints

International Nuclear Information System (INIS)

Croce, C.M.; Huebner, K.; Isobe, M.; Fainstain, E.; Lifshitz, B.; Shtivelman, E.; Canaani, E.

1987-01-01

A probe derived from the 3' region of the BCR gene (breakpoint cluster region gene) detects four distinct loci in the human genome. One of the loci corresponds to the complete BCR gene, whereas the other contain a 3' segment of the gene. After HindIII cleavage of human DNA, these four loci are detected as 23-, 19-, 13-, and 9-kikobase-pair fragments, designated BCR4, BCR3, BCR2, and BCR1, respectively, with BCR1 deriving from the original complete BCR gene. All four BCR loci segregate 100% concordantly with human chromosome 22 in a rodent-human somatic cell hybrid panel and are located at chromosome region 22q11.2 by chromosomal in situ hybridization. The BCR2 and BCR4 loci are amplified in leukemia cell line K562 cells, indicating that they fall within the amplification unit that includes immunoglobulin λ light chain locus (IGL) and ABL locus on the K562 Philadelphia chromosome (Ph 1 ). Similarly, in mouse-human hybrids retaining a Ph 1 chromosome derived from an acute lymphoblastic leukemia-in the absence of the 9q + and 22, only BCR2 and BCR4 loci are retained. Thus, the order of loci on chromosome 22 is centromere → BCR2, BCR4, and IGL → BCR1 → BCR3 → SIS, possibly eliminating BCR2 and BCR4 loci as candidate targets for juxtaposition to the ABL gene in the acute lymphoblastic leukemia Ph 1 chromosome

Identification of 19 new risk loci and potential regulatory mechanisms influencing susceptibility to testicular germ cell tumor.

Science.gov (United States)

Litchfield, Kevin; Levy, Max; Orlando, Giulia; Loveday, Chey; Law, Philip J; Migliorini, Gabriele; Holroyd, Amy; Broderick, Peter; Karlsson, Robert; Haugen, Trine B; Kristiansen, Wenche; Nsengimana, Jérémie; Fenwick, Kerry; Assiotis, Ioannis; Kote-Jarai, ZSofia; Dunning, Alison M; Muir, Kenneth; Peto, Julian; Eeles, Rosalind; Easton, Douglas F; Dudakia, Darshna; Orr, Nick; Pashayan, Nora; Bishop, D Timothy; Reid, Alison; Huddart, Robert A; Shipley, Janet; Grotmol, Tom; Wiklund, Fredrik; Houlston, Richard S; Turnbull, Clare

2017-07-01

Genome-wide association studies (GWAS) have transformed understanding of susceptibility to testicular germ cell tumors (TGCTs), but much of the heritability remains unexplained. Here we report a new GWAS, a meta-analysis with previous GWAS and a replication series, totaling 7,319 TGCT cases and 23,082 controls. We identify 19 new TGCT risk loci, roughly doubling the number of known TGCT risk loci to 44. By performing in situ Hi-C in TGCT cells, we provide evidence for a network of physical interactions among all 44 TGCT risk SNPs and candidate causal genes. Our findings implicate widespread disruption of developmental transcriptional regulators as a basis of TGCT susceptibility, consistent with failed primordial germ cell differentiation as an initiating step in oncogenesis. Defective microtubule assembly and dysregulation of KIT-MAPK signaling also feature as recurrently disrupted pathways. Our findings support a polygenic model of risk and provide insight into the biological basis of TGCT.

CRISPR/Cas9-mediated knock-in of an optimized TetO repeat for live cell imaging of endogenous loci.

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Tasan, Ipek; Sustackova, Gabriela; Zhang, Liguo; Kim, Jiah; Sivaguru, Mayandi; HamediRad, Mohammad; Wang, Yuchuan; Genova, Justin; Ma, Jian; Belmont, Andrew S; Zhao, Huimin

2018-06-15

Nuclear organization has an important role in determining genome function; however, it is not clear how spatiotemporal organization of the genome relates to functionality. To elucidate this relationship, a method for tracking any locus of interest is desirable. Recently clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) or transcription activator-like effectors were adapted for imaging endogenous loci; however, they are mostly limited to visualization of repetitive regions. Here, we report an efficient and scalable method named SHACKTeR (Short Homology and CRISPR/Cas9-mediated Knock-in of a TetO Repeat) for live cell imaging of specific chromosomal regions without the need for a pre-existing repetitive sequence. SHACKTeR requires only two modifications to the genome: CRISPR/Cas9-mediated knock-in of an optimized TetO repeat and its visualization by TetR-EGFP expression. Our simplified knock-in protocol, utilizing short homology arms integrated by polymerase chain reaction, was successful at labeling 10 different loci in HCT116 cells. We also showed the feasibility of knock-in into lamina-associated, heterochromatin regions, demonstrating that these regions prefer non-homologous end joining for knock-in. Using SHACKTeR, we were able to observe DNA replication at a specific locus by long-term live cell imaging. We anticipate the general applicability and scalability of our method will enhance causative analyses between gene function and compartmentalization in a high-throughput manner.

Overlap of disease susceptibility loci for rheumatoid arthritis and juvenile idiopathic arthritis

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Hinks, Anne; Eyre, Steve; Ke, Xiayi; Barton, Anne; Martin, Paul; Flynn, Edward; Packham, Jon; Worthington, Jane; Thomson, Wendy

2010-01-01

Background Genome-wide association studies (GWAS) have been extremely successful in the search for susceptibility risk factors for complex genetic autoimmune diseases. As more studies are published, evidence is emerging of considerable overlap of loci between these diseases. In juvenile idiopathic arthritis (JIA), another complex genetic autoimmune disease, the strategy of using information from autoimmune disease GWAS or candidate gene studies to help in the search for novel JIA susceptibility loci has been successful, with confirmed association with two genes, PTPN22 and IL2RA. Rheumatoid arthritis (RA) is an autoimmune disease that shares similar clinical and pathological features with JIA and, therefore, recently identified confirmed RA susceptibility loci are also excellent JIA candidate loci. Objective To determine the overlap of disease susceptibility loci for RA and JIA. Methods Fifteen single nucleotide polymorphisms (SNPs) at nine RA-associated loci were genotyped in Caucasian patients with JIA (n=1054) and controls (n=3531) and tested for association with JIA. Allele and genotype frequencies were compared between cases and controls using the genetic analysis software, PLINK. Results Two JIA susceptibility loci were identified, one of which was a novel JIA association (STAT4) and the second confirmed previously published associations of the TRAF1/C5 locus with JIA. Weak evidence of association of JIA with three additional loci (Chr6q23, KIF5A and PRKCQ) was also obtained, which warrants further investigation. Conclusion All these loci are good candidates in view of the known pathogenesis of JIA, as genes within these regions (TRAF1, STAT4, TNFAIP3, PRKCQ) are known to be involved in T-cell receptor signalling or activation pathways. PMID:19674979

Evaluation and selection of tandem repeat loci for a Brucella MLVA typing assay

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Denoeud France

2006-02-01

Full Text Available Abstract Background The classification of Brucella into species and biovars relies on phenotypic characteristics and sometimes raises difficulties in the interpretation of the results due to an absence of standardization of the typing reagents. In addition, the resolution of this biotyping is moderate and requires the manipulation of the living agent. More efficient DNA-based methods are needed, and this work explores the suitability of multiple locus variable number tandem repeats analysis (MLVA for both typing and species identification. Results Eighty tandem repeat loci predicted to be polymorphic by genome sequence analysis of three available Brucella genome sequences were tested for polymorphism by genotyping 21 Brucella strains (18 reference strains representing the six 'classical' species and all biovars as well as 3 marine mammal strains currently recognized as members of two new species. The MLVA data efficiently cluster the strains as expected according to their species and biovar. For practical use, a subset of 15 loci preserving this clustering was selected and applied to the typing of 236 isolates. Using this MLVA-15 assay, the clusters generated correspond to the classical biotyping scheme of Brucella spp. The 15 markers have been divided into two groups, one comprising 8 user-friendly minisatellite markers with a good species identification capability (panel 1 and another complementary group of 7 microsatellite markers with higher discriminatory power (panel 2. Conclusion The MLVA-15 assay can be applied to large collections of Brucella strains with automated or manual procedures, and can be proposed as a complement, or even a substitute, of classical biotyping methods. This is facilitated by the fact that MLVA is based on non-infectious material (DNA whereas the biotyping procedure itself requires the manipulation of the living agent. The data produced can be queried on a dedicated MLVA web service site.

A family with autosomal dominant mutilating neuropathy not linked to either Charcot-Marie-Tooth disease type 2B (CMT2B) or hereditary sensory neuropathy type I (HSN I) loci.

Science.gov (United States)

Bellone, Emilia; Rodolico, Carmelo; Toscano, Antonio; Di Maria, Emilio; Cassandrini, Denise; Pizzuti, Antonio; Pigullo, Simona; Mazzeo, Anna; Macaione, Vincenzo; Girlanda, Paolo; Vita, Giuseppe; Ajmar, Franco; Mandich, Paola

2002-03-01

Sensory loss and ulcero-mutilating features have been observed in hereditary sensory neuropathy type I and in hereditary motor and sensory neuropathy type IIB, also referred as Charcot-Marie-Tooth disease type 2B. To date two loci associated with ulcero-mutilating neuropathy have been described: CMT2B at 3q13-q22 and HSN I at 9q22.1-q22.3. We performed linkage analysis with chromosomal markers representing the hereditary sensory neuropathy type I and Charcot-Marie-Tooth disease type 2B loci on an Italian family with a severe distal sensory loss leading to an ulcero-mutilating peripheral neuropathy. Negative likelihood-of-odds scores excluded any evidence of linkage to both chromosome 3q13 and chromosome 9q22 markers, confirming the genetic heterogeneity of this clinical entity and the presence of a third locus responsible for ulcero-mutilating neuropathies.

Maternal T-Cell Engraftment Interferes With Human Leukocyte Antigen Typing in Severe Combined Immunodeficiency.

Science.gov (United States)

Liu, Chang; Duffy, Brian; Bednarski, Jeffrey J; Calhoun, Cecelia; Lay, Lindsay; Rundblad, Barrett; Payton, Jacqueline E; Mohanakumar, Thalachallour

2016-02-01

To report the laboratory investigation of a case of severe combined immunodeficiency (SCID) with maternal T-cell engraftment, focusing on the interference of human leukocyte antigen (HLA) typing by blood chimerism. HLA typing was performed with three different methods, including sequence-specific primer (SSP), sequence-specific oligonucleotide, and Sanger sequencing on peripheral blood leukocytes and buccal cells, from a 3-month-old boy and peripheral blood leukocytes from his parents. Short tandem repeat (STR) testing was performed in parallel. HLA typing of the patient's peripheral blood leukocytes using the SSP method demonstrated three different alleles for each of the HLA-B and HLA-C loci, with both maternal alleles present at each locus. Typing results from the patient's buccal cells showed a normal pattern of inheritance for paternal and maternal haplotypes. STR enrichment testing of the patient's CD3+ T lymphocytes and CD15+ myeloid cells confirmed maternal T-cell engraftment, while the myeloid cell profile matched the patient's buccal cells. Maternal T-cell engraftment may interfere with HLA typing in patients with SCID. Selection of the appropriate typing methods and specimens is critical for accurate HLA typing and immunologic assessment before allogeneic hematopoietic stem cell transplantation. © American Society for Clinical Pathology, 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

DEFF Research Database (Denmark)

Zhao, Wei; Rasheed, Asif; Tikkanen, Emmi

2017-01-01

To evaluate the shared genetic etiology of type 2 diabetes (T2D) and coronary heart disease (CHD), we conducted a genome-wide, multi-ancestry study of genetic variation for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for ...

Variance-component analysis of obesity in Type 2 Diabetes confirms loci on chromosomes 1q and 11q

NARCIS (Netherlands)

Haeften, T.W. van; Pearson, P.L.; Tilburg, J.H.O. van; Strengman, E.; Sandkuijl, L.A.; Wijmenga, C.

2003-01-01

To study genetic loci influencing obesity in nuclear families with type 2 diabetes, we performed a genome-wide screen with 325 microsatellite markers that had an average spacing of 11 cM and a mean heterozygosity of ~75% covering all 22 autosomes. Genotype data were obtained from 562

Two new loci and gene sets related to sex determination and cancer progression are associated with susceptibility to testicular germ cell tumor.

Science.gov (United States)

Kristiansen, Wenche; Karlsson, Robert; Rounge, Trine B; Whitington, Thomas; Andreassen, Bettina K; Magnusson, Patrik K; Fosså, Sophie D; Adami, Hans-Olov; Turnbull, Clare; Haugen, Trine B; Grotmol, Tom; Wiklund, Fredrik

2015-07-15

Genome-wide association (GWA) studies have reported 19 distinct susceptibility loci for testicular germ cell tumor (TGCT). A GWA study for TGCT was performed by genotyping 610 240 single-nucleotide polymorphisms (SNPs) in 1326 cases and 6687 controls from Sweden and Norway. No novel genome-wide significant associations were observed in this discovery stage. We put forward 27 SNPs from 15 novel regions and 12 SNPs previously reported, for replication in 710 case-parent triads and 289 cases and 290 controls. Predefined biological pathways and processes, in addition to a custom-built sex-determination gene set, were subject to enrichment analyses using Meta-Analysis Gene Set Enrichment of Variant Associations (M) and Improved Gene Set Enrichment Analysis for Genome-wide Association Study (I). In the combined meta-analysis, we observed genome-wide significant association for rs7501939 on chromosome 17q12 (OR = 0.78, 95% CI = 0.72-0.84, P = 1.1 × 10(-9)) and rs2195987 on chromosome 19p12 (OR = 0.76, 95% CI: 0.69-0.84, P = 3.2 × 10(-8)). The marker rs7501939 on chromosome 17q12 is located in an intron of the HNF1B gene, encoding a member of the homeodomain-containing superfamily of transcription factors. The sex-determination gene set (false discovery rate, FDRM cancer and apoptosis, was associated with TGCT (FDR utero are implicated in the development of TGCT. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Systematic evaluation of genes and genetic variants associated with type 1 diabetes susceptibility

DEFF Research Database (Denmark)

Ram, Ramesh; Mehta, Munish; Nguyen, Tri Quang

2016-01-01

levels of genes in four different cell types: EBV-transformed B cell lines (resting and 6 h PMA stimulated) and purified CD4+ and CD8+ T cells. We mapped cis-acting expression quantitative trait loci and found 24 non-HLA loci that affected the expression of 31 transcripts significantly in at least one...

Identification of genetic loci in Lactobacillus plantarum that modulate the immune response of dendritic cells using comparative genome hybridization.

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Marjolein Meijerink

Full Text Available BACKGROUND: Probiotics can be used to stimulate or regulate epithelial and immune cells of the intestinal mucosa and generate beneficial mucosal immunomodulatory effects. Beneficial effects of specific strains of probiotics have been established in the treatment and prevention of various intestinal disorders, including allergic diseases and diarrhea. However, the precise molecular mechanisms and the strain-dependent factors involved are poorly understood. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we aimed to identify gene loci in the model probiotic organism Lactobacillus plantarum WCFS1 that modulate the immune response of host dendritic cells. The amounts of IL-10 and IL-12 secreted by dendritic cells (DCs after stimulation with 42 individual L. plantarum strains were measured and correlated with the strain-specific genomic composition using comparative genome hybridisation and the Random Forest algorithm. This in silico "gene-trait matching" approach led to the identification of eight candidate genes in the L. plantarum genome that might modulate the DC cytokine response to L. plantarum. Six of these genes were involved in bacteriocin production or secretion, one encoded a bile salt hydrolase and one encoded a transcription regulator of which the exact function is unknown. Subsequently, gene deletions mutants were constructed in L. plantarum WCFS1 and compared to the wild-type strain in DC stimulation assays. All three bacteriocin mutants as well as the transcription regulator (lp_2991 had the predicted effect on cytokine production confirming their immunomodulatory effect on the DC response to L. plantarum. Transcriptome analysis and qPCR data showed that transcript level of gtcA3, which is predicted to be involved in glycosylation of cell wall teichoic acids, was substantially increased in the lp_2991 deletion mutant (44 and 29 fold respectively. CONCLUSION: Comparative genome hybridization led to the identification of gene loci in L

Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians

DEFF Research Database (Denmark)

Cho, Yoon Shin; Chen, Chien-Hsiun; Hu, Cheng

2012-01-01

We conducted a three-stage genetic study to identify susceptibility loci for type 2 diabetes (T2D) in east Asian populations. We followed our stage 1 meta-analysis of eight T2D genome-wide association studies (6,952 cases with T2D and 11,865 controls) with a stage 2 in silico replication analysis...... (5,843 cases and 4,574 controls) and a stage 3 de novo replication analysis (12,284 cases and 13,172 controls). The combined analysis identified eight new T2D loci reaching genome-wide significance, which mapped in or near GLIS3, PEPD, FITM2-R3HDML-HNF4A, KCNK16, MAEA, GCC1-PAX4, PSMD6 and ZFAND3...

eRNAs promote transcription by establishing chromatin accessibility at defined genomic loci

DEFF Research Database (Denmark)

Mousavi, Kambiz; Zare, Hossein; Dell'orso, Stefania

2013-01-01

)RNA acted to activate the downstream myogenic genes. The deployment of transcriptional machinery to appropriate loci is contingent on chromatin accessibility, a rate-limiting step preceding Pol II assembly. By nuclease sensitivity assay, we found that eRNAs regulate genomic access of the transcriptional...... complex to defined regulatory regions. In conclusion, our data suggest that eRNAs contribute to establishing a cell-type-specific transcriptional circuitry by directing chromatin-remodeling events....

Human red cell 2,3-diphosphoglycerate mutase and monophosphoglycerate mutase: genetic evidence for two separate loci.

Science.gov (United States)

Chen, S H; Anderson, J E; Giblett, E R

1977-01-01

Rare genetic variants of human red cell 2,3-diphosphoglycerate mutase (DPGM) and monophosphoglycerate mutase (MPGM) were compared by starch gel electrophoresis. The isozyme patterns showed that genetic variation of the enzymes were independent from each other, thus DPGM and MPGM must be controlled by two separate loci. Images Fig. 1 PMID:195467

Discovery of cell-type specific DNA motif grammar in cis-regulatory elements using random Forest.

Science.gov (United States)

Wang, Xin; Lin, Peijie; Ho, Joshua W K

2018-01-19

It has been observed that many transcription factors (TFs) can bind to different genomic loci depending on the cell type in which a TF is expressed in, even though the individual TF usually binds to the same core motif in different cell types. How a TF can bind to the genome in such a highly cell-type specific manner, is a critical research question. One hypothesis is that a TF requires co-binding of different TFs in different cell types. If this is the case, it may be possible to observe different combinations of TF motifs - a motif grammar - located at the TF binding sites in different cell types. In this study, we develop a bioinformatics method to systematically identify DNA motifs in TF binding sites across multiple cell types based on published ChIP-seq data, and address two questions: (1) can we build a machine learning classifier to predict cell-type specificity based on motif combinations alone, and (2) can we extract meaningful cell-type specific motif grammars from this classifier model. We present a Random Forest (RF) based approach to build a multi-class classifier to predict the cell-type specificity of a TF binding site given its motif content. We applied this RF classifier to two published ChIP-seq datasets of TF (TCF7L2 and MAX) across multiple cell types. Using cross-validation, we show that motif combinations alone are indeed predictive of cell types. Furthermore, we present a rule mining approach to extract the most discriminatory rules in the RF classifier, thus allowing us to discover the underlying cell-type specific motif grammar. Our bioinformatics analysis supports the hypothesis that combinatorial TF motif patterns are cell-type specific.

High-density genotyping of immune loci in Koreans and Europeans identifies eight new rheumatoid arthritis risk loci.

Science.gov (United States)

Kim, Kwangwoo; Bang, So-Young; Lee, Hye-Soon; Cho, Soo-Kyung; Choi, Chan-Bum; Sung, Yoon-Kyoung; Kim, Tae-Hwan; Jun, Jae-Bum; Yoo, Dae Hyun; Kang, Young Mo; Kim, Seong-Kyu; Suh, Chang-Hee; Shim, Seung-Cheol; Lee, Shin-Seok; Lee, Jisoo; Chung, Won Tae; Choe, Jung-Yoon; Shin, Hyoung Doo; Lee, Jong-Young; Han, Bok-Ghee; Nath, Swapan K; Eyre, Steve; Bowes, John; Pappas, Dimitrios A; Kremer, Joel M; Gonzalez-Gay, Miguel A; Rodriguez-Rodriguez, Luis; Ärlestig, Lisbeth; Okada, Yukinori; Diogo, Dorothée; Liao, Katherine P; Karlson, Elizabeth W; Raychaudhuri, Soumya; Rantapää-Dahlqvist, Solbritt; Martin, Javier; Klareskog, Lars; Padyukov, Leonid; Gregersen, Peter K; Worthington, Jane; Greenberg, Jeffrey D; Plenge, Robert M; Bae, Sang-Cheol

2015-03-01

A highly polygenic aetiology and high degree of allele-sharing between ancestries have been well elucidated in genetic studies of rheumatoid arthritis. Recently, the high-density genotyping array Immunochip for immune disease loci identified 14 new rheumatoid arthritis risk loci among individuals of European ancestry. Here, we aimed to identify new rheumatoid arthritis risk loci using Korean-specific Immunochip data. We analysed Korean rheumatoid arthritis case-control samples using the Immunochip and genome-wide association studies (GWAS) array to search for new risk alleles of rheumatoid arthritis with anticitrullinated peptide antibodies. To increase power, we performed a meta-analysis of Korean data with previously published European Immunochip and GWAS data for a total sample size of 9299 Korean and 45,790 European case-control samples. We identified eight new rheumatoid arthritis susceptibility loci (TNFSF4, LBH, EOMES, ETS1-FLI1, COG6, RAD51B, UBASH3A and SYNGR1) that passed a genome-wide significance threshold (p<5×10(-8)), with evidence for three independent risk alleles at 1q25/TNFSF4. The risk alleles from the seven new loci except for the TNFSF4 locus (monomorphic in Koreans), together with risk alleles from previously established RA risk loci, exhibited a high correlation of effect sizes between ancestries. Further, we refined the number of single nucleotide polymorphisms (SNPs) that represent potentially causal variants through a trans-ethnic comparison of densely genotyped SNPs. This study demonstrates the advantage of dense-mapping and trans-ancestral analysis for identification of potentially causal SNPs. In addition, our findings support the importance of T cells in the pathogenesis and the fact of frequent overlap of risk loci among diverse autoimmune diseases. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Meta-analysis of five genome-wide association studies identifies multiple new loci associated with testicular germ cell tumor

DEFF Research Database (Denmark)

Wang, Zhaoming; McGlynn, Katherine A.; Rajpert-De Meyts, Ewa

2017-01-01

The international Testicular Cancer Consortium (TECAC) combined five published genome-wide association studies of testicular germ cell tumor (TGCT; 3,558 cases and 13,970 controls) to identify new susceptibility loci. We conducted a fixed-effects meta-analysis, including, to our knowledge, the fi...

Analysis of three variable number terminal repeat loci is sufficient to characterize the deoxyribonucleic acid fingerprints of a panel of human tumor cell lines.

Science.gov (United States)

Anding, Allyson L; Reiss, Tanika; Germain, Glen S

2003-01-01

Using primers for the MCT118, YNZ22, and COL2A1 loci in polymerase chain reaction analysis we could distinguish among the approximately 20 cell lines routinely maintained in our laboratory. We also demonstrated that the cell line NB-1691 (a neuroblastoma) and its xenograft had an identical number of repeats at two loci. Rh30 (a rhabdomyosarcoma) made resistant to rapamycin was identical to its parent line and to a subline that had reverted to sensitivity after it was cultured without rapamycin in the medium.

Chromosomal localization of microsatellite loci in Drosophila mediopunctata

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Renato Cavasini

2015-03-01

Full Text Available Drosophila mediopunctata has been used as a model organism for genetics and evolutionary studies in the last three decades. A linkage map with 48 microsatellite loci recently published for this species showed five syntenic groups, which had their homology determined to Drosophila melanogaster chromosomes. Then, by inference, each of the groups was associated with one of the five major chromosomes of D. mediopunctata. Our objective was to carry out a genetic (chromosomal analysis to increase the number of available loci with known chromosomal location. We made a simultaneous analysis of visible mutant phenotypes and microsatellite genotypes in a backcross of a standard strain and a mutant strain, which had each major autosome marked. Hence, we could establish the chromosomal location of seventeen loci; including one from each of the five major linkage groups previously published, and twelve new loci. Our results were congruent with the previous location and they open new possibilities to future work integrating microsatellites, chromosomal inversions, and genetic determinants of physiological and morphological variation.

Association study of 25 type 2 diabetes related Loci with measures of obesity in Indian sib pairs.

Science.gov (United States)

Gupta, Vipin; Vinay, Donipadi Guru; Sovio, Ulla; Rafiq, Sajjad; Kranthi Kumar, Madamchetty Venkata; Janipalli, Charles Spurgeon; Evans, David; Mani, Kulathu Radha; Sandeep, Madana Narasimha; Taylor, Amy; Kinra, Sanjay; Sullivan, Ruth; Bowen, Liza; Timpson, Nicholas; Smith, George Davey; Dudbridge, Frank; Prabhakaran, Dorairaj; Ben-Shlomo, Yoav; Reddy, Kolli Srinath; Ebrahim, Shah; Chandak, Giriraj Ratan

2013-01-01

Obesity is an established risk factor for type 2 diabetes (T2D) and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI), we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs) recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206) and HHEX (rs5015480) with higher body mass index (BMI) (β=0.13, p=0.001) and (β=0.09, p=0.002), respectively and weight (β=0.13, p=0.001) and (β=0.09, p=0.001), respectively. CXCR4 variant was also strongly associated with body fat (β=0.10, p=0.0004). In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR=1.6, p=0.003) and (OR=1.4, p=0.002), respectively, in 1333 sib-pairs (2666 individuals). We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ39370 and THADA) and waist hip ratio (WHR), BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations) showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.

Association study of 25 type 2 diabetes related Loci with measures of obesity in Indian sib pairs.

Directory of Open Access Journals (Sweden)

Vipin Gupta

Full Text Available Obesity is an established risk factor for type 2 diabetes (T2D and they are metabolically related through the mechanism of insulin resistance. In order to explore how common genetic variants associated with T2D correlate with body mass index (BMI, we examined the influence of 25 T2D associated loci on obesity risk. We used 5056 individuals (2528 sib-pairs recruited in Indian Migration Study and conducted within sib-pair analysis for six obesity phenotypes. We found associations of variants in CXCR4 (rs932206 and HHEX (rs5015480 with higher body mass index (BMI (β=0.13, p=0.001 and (β=0.09, p=0.002, respectively and weight (β=0.13, p=0.001 and (β=0.09, p=0.001, respectively. CXCR4 variant was also strongly associated with body fat (β=0.10, p=0.0004. In addition, we demonstrated associations of CXCR4 and HHEX with overweight/obesity (OR=1.6, p=0.003 and (OR=1.4, p=0.002, respectively, in 1333 sib-pairs (2666 individuals. We observed marginal evidence of associations between variants at six loci (TCF7L2, NGN3, FOXA2, LOC646279, FLJ39370 and THADA and waist hip ratio (WHR, BMI and/or overweight which needs to be validated in larger set of samples. All the above findings were independent of daily energy consumption and physical activity level. The risk score estimates based on eight significant loci (including nominal associations showed associations with WHR and body fat which were independent of BMI. In summary, we establish the role of T2D associated loci in influencing the measures of obesity in Indian population, suggesting common underlying pathophysiology across populations.

Identification of new susceptibility loci for type 2 diabetes and shared etiological pathways with coronary heart disease

Science.gov (United States)

Zhao, Wei; Rasheed, Asif; Tikkanen, Emmi; Lee, Jung-Jin; Butterworth, Adam S; Howson, Joanna MM; Assimes, Themistocles L; Chowdhury, Rajiv; Orho-Melander, Marju; Damrauer, Scott; Small, Aeron; Asma, Senay; Imamura, Minako; Yamauch, Toshimasa; Chambers, John C; Chen, Peng; Sapkota, Bishwa R; Shah, Nabi; Jabeen, Sehrish; Surendran, Praveen; Lu, Yingchang; Zhang, Weihua; Imran, Atif; Abbas, Shahid; Majeed, Faisal; Trindade, Kevin; Qamar, Nadeem; Mallick, Nadeem Hayyat; Yaqoob, Zia; Saghir, Tahir; Rizvi, Syed Nadeem Hasan; Memon, Anis; Rasheed, Syed Zahed; Memon, Fazal-ur-Rehman; Mehmood, Khalid; Ahmed, Naveeduddin; Qureshi, Irshad Hussain; Tanveer-us-Salam; Iqbal, Wasim; Malik, Uzma; Mehra, Narinder; Kuo, Jane Z; Sheu, Wayne H-H; Guo, Xiuqing; Hsiung, Chao A; Juang, Jyh-Ming J; Taylor, Kent D; Hung, Yi-Jen; Lee, Wen-Jane; Quertermous, Thomas; Lee, I-Te; Hsu, Chih-Cheng; Bottinger, Erwin P.; Ralhan, Sarju; Teo, Yik Ying; Wang, Tzung-Dau; Alam, Dewan S; Di Angelantonio, Emanuele; Epstein, Steve; Nielsen, Sune F; Nordestgaard, Børge G; Tybjaerg-Hansen, Anne; Young, Robin; Benn, Marianne; Frikke-Schmidt, Ruth; Kamstrup, Pia R; Biobank, Michigan; Jukema, J Wouter; Sattar, Naveed; Smit, Roelof; Chung, Ren-Hua; Liang, Kae-Woei; Anand, Sonia; Sanghera, Dharambir K; Ripatti, Samuli; Loos, Ruth J.F.; Kooner, Jaspal S; Tai, E Shyong; Rotter, Jerome I; Chen, Yii-Der Ida; Frossard, Philippe; Maeda, Shiro; Kadowaki, Takashi; Reilly, Muredach; Pare, Guillaume; Melander, Olle; Salomaa, Veikko; Rader, Daniel J; Danesh, John; Voight, Benjamin F; Saleheen, Danish

2018-01-01

To evaluate the shared genetic etiology of type-2 diabetes (T2D) and coronary heart disease (CHD), we conducted a multi-ethnic study of genetic variation genome-wide for both diseases in up to 265,678 subjects for T2D and 260,365 subjects for CHD. We identify 16 previously unreported loci for T2D and one for CHD, including a novel T2D association at a missense variant in HLA-DRB5 (OR=1.29). We show that genetically mediated increase in T2D risk also confers higher CHD risk. Joint analysis of T2D loci demonstrated that 24% are associated with CHD, highlighting eight variants - two of which are coding - where T2D and CHD associations appear to co-localize, and a novel joint T2D/CHD association which also replicated for T2D. Variants associated with both outcomes implicate several novel pathways including cellular proliferation and cardiovascular development. PMID:28869590

Long non-coding RNAs as novel players in β cell function and type 1 diabetes

DEFF Research Database (Denmark)

Mirza, Aashiq H; Kaur, Simranjeet; Pociot, Flemming

2017-01-01

, or proteins. Accumulating body of evidence based on multitude studies has highlighted the role of lncRNAs in many autoimmune and inflammatory diseases, including type 1 diabetes (T1D). Main body of abstract This review highlights emerging roles of lncRNAs in immune and islet β cell function as well as some...... of the challenges and opportunities in understanding the pathogenesis of T1D and its complications. Conclusion We accentuate that the lncRNAs within T1D-loci regions in consort with regulatory variants and enhancer clusters orchestrate the chromatin remodeling in β cells and thereby act as cis...

Genome-wide association study identifies shared risk loci common to two malignancies in golden retrievers.

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Noriko Tonomura

2015-02-01

Full Text Available Dogs, with their breed-determined limited genetic background, are great models of human disease including cancer. Canine B-cell lymphoma and hemangiosarcoma are both malignancies of the hematologic system that are clinically and histologically similar to human B-cell non-Hodgkin lymphoma and angiosarcoma, respectively. Golden retrievers in the US show significantly elevated lifetime risk for both B-cell lymphoma (6% and hemangiosarcoma (20%. We conducted genome-wide association studies for hemangiosarcoma and B-cell lymphoma, identifying two shared predisposing loci. The two associated loci are located on chromosome 5, and together contribute ~20% of the risk of developing these cancers. Genome-wide p-values for the top SNP of each locus are 4.6×10-7 and 2.7×10-6, respectively. Whole genome resequencing of nine cases and controls followed by genotyping and detailed analysis identified three shared and one B-cell lymphoma specific risk haplotypes within the two loci, but no coding changes were associated with the risk haplotypes. Gene expression analysis of B-cell lymphoma tumors revealed that carrying the risk haplotypes at the first locus is associated with down-regulation of several nearby genes including the proximal gene TRPC6, a transient receptor Ca2+-channel involved in T-cell activation, among other functions. The shared risk haplotype in the second locus overlaps the vesicle transport and release gene STX8. Carrying the shared risk haplotype is associated with gene expression changes of 100 genes enriched for pathways involved in immune cell activation. Thus, the predisposing germ-line mutations in B-cell lymphoma and hemangiosarcoma appear to be regulatory, and affect pathways involved in T-cell mediated immune response in the tumor. This suggests that the interaction between the immune system and malignant cells plays a common role in the tumorigenesis of these relatively different cancers.

Comparative genomic analysis uncovers 3 novel loci encoding type six secretion systems differentially distributed in Salmonella serotypes

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Santiviago Carlos A

2009-08-01

Full Text Available Abstract Background The recently described Type VI Secretion System (T6SS represents a new paradigm of protein secretion in bacteria. A number of bioinformatic studies have been conducted to identify T6SS gene clusters in the available bacterial genome sequences. According to these studies, Salmonella harbors a unique T6SS encoded in the Salmonella Pathogenicity Island 6 (SPI-6. Since these studies only considered few Salmonella genomes, the present work aimed to identify novel T6SS loci by in silico analysis of every genome sequence of Salmonella available. Results The analysis of sequencing data from 44 completed or in progress Salmonella genome projects allowed the identification of 3 novel T6SS loci. These clusters are located in differentially-distributed genomic islands we designated SPI-19, SPI-20 and SPI-21, respectively. SPI-19 was identified in a subset of S. enterica serotypes including Dublin, Weltevreden, Agona, Gallinarum and Enteritidis. In the later, an internal deletion eliminated most of the island. On the other hand, SPI-20 and SPI-21 were restricted to S. enterica subspecies arizonae (IIIa serotype 62:z4,z23:-. Remarkably, SPI-21 encodes a VgrG protein containing a C-terminal extension similar to S-type pyocins of Pseudomonas aeruginosa. This is not only the first evolved VgrG described in Salmonella, but also the first evolved VgrG including a pyocin domain described so far in the literature. In addition, the data indicate that SPI-6 T6SS is widely distributed in S. enterica and absent in serotypes Enteritidis, Gallinarum, Agona, Javiana, Paratyphi B, Virchow, IIIa 62:z4,z23:- and IIIb 61:1,v:1,5,(7. Interestingly, while some serotypes harbor multiple T6SS (Dublin, Weltvreden and IIIa 62:z4,z23:- others do not encode for any (Enteritidis, Paratyphi B, Javiana, Virchow and IIIb 61:1,v:1,5,(7. Comparative and phylogenetic analyses indicate that the 4 T6SS loci in Salmonella have a distinct evolutionary history. Finally, we

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

OpenAIRE

Dastani, Z.; Hivert, M. F.; Timpson, N.; Perry, J. R.; Yuan, X.; Scott, R. A.; Henneman, P.; Heid, I. M.; Kizer, J. R.; Lyytikäinen, L. P.; Fuchsberger, C.; Tanaka, T.; Morris, A. P.; Small, K.; Isaacs, A.

2012-01-01

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a...

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

OpenAIRE

Dastani, Zari; Hivert, Marie-France; Timpson, Nicholas; Perry, John Richard; Yuan, Xin; Scott, Robert; Henneman, Peter; Heid, Iris M; Kizer, Jorge R; Lyytikäinen, Leo-Pekka; Fuchsberger, Christian; Tanaka, Toshiko; Morris, Andrew P; Small, Kerrin; Isaacs, Aaron

2012-01-01

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = \\(4.5×10^{−8}–1.2×10^{−43}\\)). U...

Clinical significance of determination of changes of serum SOD and T-cell subsets distribution type after leukocyte-deduced red blood cell transfusion in patients with lung cancer

International Nuclear Information System (INIS)

Yu Zhengqin; Li Keqin; Xiang Hengquan

2006-01-01

Objective: To investigate the changes of serum SOD contents and T-cell subsets distribution type after leukocyte-deduced red blood cell transfusion in patients with lung cancer. Methods: Serum SOD levels was measured with RIA and T-cell subsets distribution type was detected with monoclonal antibody technic both before and after leukocyte-deduced red blood cell transfusion in 32 patients with lung cancer and 35 normal controls. Results: Before treatment, the serum levels of SOD and T-cell CIM/ CD8 value were significantly lower in the patients than those in controls (P 0.05). Conclusion: Determination of serum SOD level and T-cell subsets distribution type is clinically useful in the management of patients with lung cancer. (authors)

Determination of allele frequencies in nine short tandem repeat loci ...

African Journals Online (AJOL)

SERVER

2008-04-17

Apr 17, 2008 ... out the human genome. These loci are a rich source of highly polymorphic markers that may be detected using the polymerase chain reaction (PCR). PCR is a mimic of the normal cellular process of replication of DNA molecules. Each STR is distinguished by the number of times a sequence is repeated, ...

High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry.

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Sun, Celi; Molineros, Julio E; Looger, Loren L; Zhou, Xu-Jie; Kim, Kwangwoo; Okada, Yukinori; Ma, Jianyang; Qi, Yuan-Yuan; Kim-Howard, Xana; Motghare, Prasenjeet; Bhattarai, Krishna; Adler, Adam; Bang, So-Young; Lee, Hye-Soon; Kim, Tae-Hwan; Kang, Young Mo; Suh, Chang-Hee; Chung, Won Tae; Park, Yong-Beom; Choe, Jung-Yoon; Shim, Seung Cheol; Kochi, Yuta; Suzuki, Akari; Kubo, Michiaki; Sumida, Takayuki; Yamamoto, Kazuhiko; Lee, Shin-Seok; Kim, Young Jin; Han, Bok-Ghee; Dozmorov, Mikhail; Kaufman, Kenneth M; Wren, Jonathan D; Harley, John B; Shen, Nan; Chua, Kek Heng; Zhang, Hong; Bae, Sang-Cheol; Nath, Swapan K

2016-03-01

Systemic lupus erythematosus (SLE) has a strong but incompletely understood genetic architecture. We conducted an association study with replication in 4,478 SLE cases and 12,656 controls from six East Asian cohorts to identify new SLE susceptibility loci and better localize known loci. We identified ten new loci and confirmed 20 known loci with genome-wide significance. Among the new loci, the most significant locus was GTF2IRD1-GTF2I at 7q11.23 (rs73366469, Pmeta = 3.75 × 10(-117), odds ratio (OR) = 2.38), followed by DEF6, IL12B, TCF7, TERT, CD226, PCNXL3, RASGRP1, SYNGR1 and SIGLEC6. We identified the most likely functional variants at each locus by analyzing epigenetic marks and gene expression data. Ten candidate variants are known to alter gene expression in cis or in trans. Enrichment analysis highlights the importance of these loci in B cell and T cell biology. The new loci, together with previously known loci, increase the explained heritability of SLE to 24%. The new loci share functional and ontological characteristics with previously reported loci and are possible drug targets for SLE therapeutics.

Dynamic changes in the interchromosomal interaction of early histone gene loci during development of sea urchin.

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Matsushita, Masaya; Ochiai, Hiroshi; Suzuki, Ken-Ichi T; Hayashi, Sayaka; Yamamoto, Takashi; Awazu, Akinori; Sakamoto, Naoaki

2017-12-15

The nuclear positioning and chromatin dynamics of eukaryotic genes are closely related to the regulation of gene expression, but they have not been well examined during early development, which is accompanied by rapid cell cycle progression and dynamic changes in nuclear organization, such as nuclear size and chromatin constitution. In this study, we focused on the early development of the sea urchin Hemicentrotus pulcherrimus and performed three-dimensional fluorescence in situ hybridization of gene loci encoding early histones (one of the types of histone in sea urchin). There are two non-allelic early histone gene loci per sea urchin genome. We found that during the morula stage, when the early histone gene expression levels are at their maximum, interchromosomal interactions were often formed between the early histone gene loci on separate chromosomes and that the gene loci were directed to locate to more interior positions. Furthermore, these interactions were associated with the active transcription of the early histone genes. Thus, such dynamic interchromosomal interactions may contribute to the efficient synthesis of early histone mRNA during the morula stage of sea urchin development. © 2017. Published by The Company of Biologists Ltd.

Standing genetic variation in contingency loci drives the rapid adaptation of Campylobacter jejuni to a novel host.

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John P Jerome

2011-01-01

Full Text Available The genome of the food-borne pathogen Campylobacter jejuni contains multiple highly mutable sites, or contingency loci. It has been suggested that standing variation at these loci is a mechanism for rapid adaptation to a novel environment, but this phenomenon has not been shown experimentally. In previous work we showed that the virulence of C. jejuni NCTC11168 increased after serial passage through a C57BL/6 IL-10(-/- mouse model of campylobacteriosis. Here we sought to determine the genetic basis of this adaptation during passage. Re-sequencing of the 1.64 Mb genome to 200-500 X coverage allowed us to define variation in 23 contingency loci to an unprecedented depth both before and after in vivo adaptation. Mutations in the mouse-adapted C. jejuni were largely restricted to the homopolymeric tracts of thirteen contingency loci. These changes cause significant alterations in open reading frames of genes in surface structure biosynthesis loci and in genes with only putative functions. Several loci with open reading frame changes also had altered transcript abundance. The increase in specific phases of contingency loci during in vivo passage of C. jejuni, coupled with the observed virulence increase and the lack of other types of genetic changes, is the first experimental evidence that these variable regions play a significant role in C. jejuni adaptation and virulence in a novel host.

Evaluation of customised lineage-specific sets of MIRU-VNTR loci for genotyping Mycobacterium tuberculosis complex isolates in Ghana.

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Asante-Poku, Adwoa; Nyaho, Michael Selasi; Borrell, Sonia; Comas, Iñaki; Gagneux, Sebastien; Yeboah-Manu, Dorothy

2014-01-01

Different combinations of variable number of tandem repeat (VNTR) loci have been proposed for genotyping Mycobacterium tuberculosis complex (MTBC). Existing VNTR schemes show different discriminatory capacity among the six human MTBC lineages. Here, we evaluated the discriminatory power of a "customized MIRU12" loci format proposed previously by Comas et al. based on the standard 24 loci defined by Supply et al. for VNTR-typing of MTBC in Ghana. One hundred and fifty-eight MTBC isolates classified into Lineage 4 and Lineage 5 were used to compare a customized lineage-specific panel of 12 MIRU-VNTR loci ("customized MIRU-12") to the standard MIRU-15 genotyping scheme. The resolution power of each typing method was determined based on the Hunter-Gaston- Discriminatory Index (HGDI). A minimal set of customized MIRU-VNTR loci for typing Lineages 4 (Euro-American) and 5 (M. africanum West African 1) strains from Ghana was defined based on the cumulative HGDI. Among the 106 Lineage 4 strains, the customized MIRU-12 identified a total of 104 distinct genotypes consisting of 2 clusters of 2 isolates each (clustering rate 1.8%), and 102 unique strains while standard MIRU-15 yielded a total of 105 different genotypes, including 1 cluster of 2 isolates (clustering rate: 0.9%) and 104 singletons. Among, 52 Lineage 5 isolates, customized MIRU-12 genotyping defined 51 patterns with 1 cluster of 2 isolates (clustering rate: 0.9%) and 50 unique strains whereas MIRU-15 classified all 52 strains as unique. Cumulative HGDI values for customized MIRU-12 for Lineages 4 and 5 were 0.98 respectively whilst that of standard MIRU-15 was 0.99. A union of loci from the customised MIRU-12 and standard MIRU-15 revealed a set of customized eight highly discriminatory loci: 4052, 2163B, 40, 4165, 2165, 10,16 and 26 with a cumulative HGDI of 0.99 for genotyping Lineage 4 and 5 strains from Ghana.

Evaluation of customised lineage-specific sets of MIRU-VNTR loci for genotyping Mycobacterium tuberculosis complex isolates in Ghana.

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Adwoa Asante-Poku

Full Text Available BACKGROUND: Different combinations of variable number of tandem repeat (VNTR loci have been proposed for genotyping Mycobacterium tuberculosis complex (MTBC. Existing VNTR schemes show different discriminatory capacity among the six human MTBC lineages. Here, we evaluated the discriminatory power of a "customized MIRU12" loci format proposed previously by Comas et al. based on the standard 24 loci defined by Supply et al. for VNTR-typing of MTBC in Ghana. METHOD: One hundred and fifty-eight MTBC isolates classified into Lineage 4 and Lineage 5 were used to compare a customized lineage-specific panel of 12 MIRU-VNTR loci ("customized MIRU-12" to the standard MIRU-15 genotyping scheme. The resolution power of each typing method was determined based on the Hunter-Gaston- Discriminatory Index (HGDI. A minimal set of customized MIRU-VNTR loci for typing Lineages 4 (Euro-American and 5 (M. africanum West African 1 strains from Ghana was defined based on the cumulative HGDI. RESULTS AND CONCLUSION: Among the 106 Lineage 4 strains, the customized MIRU-12 identified a total of 104 distinct genotypes consisting of 2 clusters of 2 isolates each (clustering rate 1.8%, and 102 unique strains while standard MIRU-15 yielded a total of 105 different genotypes, including 1 cluster of 2 isolates (clustering rate: 0.9% and 104 singletons. Among, 52 Lineage 5 isolates, customized MIRU-12 genotyping defined 51 patterns with 1 cluster of 2 isolates (clustering rate: 0.9% and 50 unique strains whereas MIRU-15 classified all 52 strains as unique. Cumulative HGDI values for customized MIRU-12 for Lineages 4 and 5 were 0.98 respectively whilst that of standard MIRU-15 was 0.99. A union of loci from the customised MIRU-12 and standard MIRU-15 revealed a set of customized eight highly discriminatory loci: 4052, 2163B, 40, 4165, 2165, 10,16 and 26 with a cumulative HGDI of 0.99 for genotyping Lineage 4 and 5 strains from Ghana.

TYK2, a Candidate Gene for Type 1 Diabetes, Modulates Apoptosis and the Innate Immune Response in Human Pancreatic β-Cells

DEFF Research Database (Denmark)

Marroqui, Laura; Dos Santos, Reinaldo Sousa; Fløyel, Tina

2015-01-01

histocompatibility complex (MHC) class I proteins, a hallmark of early β-cell inflammation in type 1 diabetes. Importantly, TYK2 inhibition prevented PIC-induced β-cell apoptosis via the mitochondrial pathway of cell death. The present findings suggest that TYK2 regulates apoptotic and proinflammatory pathways...... in pancreatic β-cells via modulation of IFNα signaling, subsequent increase in MHC class I protein, and modulation of chemokines such as CXCL10 that are important for recruitment of T cells to the islets.......Pancreatic β-cells are destroyed by an autoimmune attack in type 1 diabetes. Linkage and genome-wide association studies point to >50 loci that are associated with the disease in the human genome. Pathway analysis of candidate genes expressed in human islets identified a central role for interferon...

Micro-ribonucleic acid-binding site variants of type 2 diabetes candidate loci predispose to gestational diabetes mellitus in Chinese Han women.

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Wang, Xiaojing; Li, Wei; Ma, Liangkun; Ping, Fan; Liu, Juntao; Wu, Xueyan; Mao, Jiangfeng; Wang, Xi; Nie, Min

2018-01-20

Emerging evidence has suggested that the genetic background of gestational diabetes mellitus (GDM) was analogous to type 2 diabetes mellitus. In contrast to type 2 diabetes mellitus, the genetic studies for GDM were limited. Accordingly, the aim of the present study was to extensively explore the influence of micro-ribonucleic acid-binding single-nucleotide polymorphisms (SNPs) in type 2 diabetes mellitus candidate loci on GDM susceptibility in Chinese. A total of 839 GDM patients and 900 controls were enrolled. Six micro-ribonucleic acid-binding SNPs were selected from 30 type 2 diabetes mellitus susceptibility loci and genotyped using TaqMan allelic discrimination assays. The minor allele of three SNPs, PAX4 rs712699 (OR 1.366, 95% confidence interval 1.021-1.828, P = 0.036), KCNB1 rs1051295 (OR 1.579, 95% confidence interval 1.172-2.128, P = 0.003) and MFN2 rs1042842 (OR 1.398, 95% confidence interval 1.050-1.862, P = 0.022) were identified to significantly confer higher a risk of GDM in the additive model. The association between rs1051295 and increased fasting plasma glucose (b = 0.006, P = 0.008), 3-h oral glucose tolerance test plasma glucose (b = 0.058, P = 0.025) and homeostatic model assessment of insulin resistance (b = 0.065, P = 0.017) was also shown. Rs1042842 was correlated with higher 3-h oral glucose tolerance test plasma glucose (b = 0.056, P = 0.028). However, no significant correlation between the other included SNPs (LPIN1 rs1050800, VPS26A rs1802295 and NLRP3 rs10802502) and GDM susceptibility were observed. The present findings showed that micro-ribonucleic acid-binding SNPs in type 2 diabetes mellitus candidate loci were also associated with GDM susceptibility, which further highlighted the similar genetic basis underlying GDM and type 2 diabetes mellitus. © 2018 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Efficient Differentiation of Mycobacterium tuberculosis Strains of the W-Beijing Family from Russia using Highly Polymorphic VNTR Loci

International Nuclear Information System (INIS)

Surikova, O. V.; Voitech, D. S.; Kuzmicheva, G.; Tatkov, S. I.; Mokrousov, I. V.; Narvskaya, O. V.; Rot, M. A.; Soolingen, D. van; Filipenko, M. L.

2005-01-01

The W-Beijing family is a widespread Mycobacterium tuberculosis clonal lineage that frequently causes epidemic outbreaks. This family is genetically homogeneous and conserved, so ETR-VNTR (exact tandem repeat-variable number of tandem repeats) typing is insufficient for strain differentiation, due to a common ETR-A to E profile (42435). This leads to the false clustering in molecular epidemiological studies, especially in the regions of predominance of the W-Beijing family. In this study, we searched for VNTR loci with a high evolutionary rate of polymorphism in the W-Beijing genome. Here we further evaluated VNTR typing on a set of 99 Mycobacterium tuberculosis clinical isolates and reference strains. These isolates were characterized and classified into several genotype families based on three ETR loci (A, C, E) and eight additional loci [previously described as QUB (Queen's University Belfast) or MIRU (Mycobacterial Interspersed Repetitive Units) or Mtubs]. Ninety-nine strains were divided into 74 VNTR-types, 51 isolates of the W-Beijing family identified by IS6110 RFLP-typing (the restriction fragment length polymorphism-typing) and/or spoligotyping were subdivided into 30 VNTR-types. HGDI (the Hunter-Gaston discriminatory index) for all studied loci was close to that of IS6110 RFLP typing, a 'gold standard' method for subtyping M. tuberculosis complex strains. The QUB 26 and QUB 18 loci located in the PPE genes were highly polymorphic and more discriminative than other loci (HGDI is 0.8). Statistically significant increase of tandem repeats number in loci ETR-A, -E, QUB 26, QUB 18, QUB 11B, Mtub21 was revealed in the W-Beijing group compared to genetically divergent non-W-Beijing strains. Thirty-six isolates were subjected to IS6110 RFLP typing. The congruence between results of the IS6110 RFLP typing and 11-loci VNTR typing was estimated on 23 isolates of the W-Beijing family. These isolates were subdivided into 9 IS6110-RFLP types and 13 VNTR types. The poor

Combinatorial Modulation of Signaling Pathways Reveals Cell-Type-Specific Requirements for Highly Efficient and Synchronous iPSC Reprogramming

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Simon E. Vidal

2014-10-01

Full Text Available The differentiated state of somatic cells provides barriers for the derivation of induced pluripotent stem cells (iPSCs. To address why some cell types reprogram more readily than others, we studied the effect of combined modulation of cellular signaling pathways. Surprisingly, inhibition of transforming growth factor β (TGF-β together with activation of Wnt signaling in the presence of ascorbic acid allows >80% of murine fibroblasts to acquire pluripotency after 1 week of reprogramming factor expression. In contrast, hepatic and blood progenitors predominantly required only TGF-β inhibition or canonical Wnt activation, respectively, to reprogram at efficiencies approaching 100%. Strikingly, blood progenitors reactivated endogenous pluripotency loci in a highly synchronous manner, and we demonstrate that expression of specific chromatin-modifying enzymes and reduced TGF-β/mitogen-activated protein (MAP kinase activity are intrinsic properties associated with the unique reprogramming response of these cells. Our observations define cell-type-specific requirements for the rapid and synchronous reprogramming of somatic cells.

Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells.

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Sugimoto, Asuna; Miyazaki, Aya; Kawarabayashi, Keita; Shono, Masayuki; Akazawa, Yuki; Hasegawa, Tomokazu; Ueda-Yamaguchi, Kimiko; Kitamura, Takamasa; Yoshizaki, Keigo; Fukumoto, Satoshi; Iwamoto, Tsutomu

2017-12-18

The extracellular environment regulates the dynamic behaviors of cells. However, the effects of hydrostatic pressure (HP) on cell fate determination of mesenchymal stem cells (MSCs) are not clearly understood. Here, we established a cell culture chamber to control HP. Using this system, we found that the promotion of osteogenic differentiation by HP is depend on bone morphogenetic protein 2 (BMP2) expression regulated by Piezo type mechanosensitive ion channel component 1 (PIEZO1) in MSCs. The PIEZO1 was expressed and induced after HP loading in primary MSCs and MSC lines, UE7T-13 and SDP11. HP and Yoda1, an activator of PIEZO1, promoted BMP2 expression and osteoblast differentiation, whereas inhibits adipocyte differentiation. Conversely, PIEZO1 inhibition reduced osteoblast differentiation and BMP2 expression. Furthermore, Blocking of BMP2 function by noggin inhibits HP induced osteogenic maker genes expression. In addition, in an in vivo model of medaka with HP loading, HP promoted caudal fin ray development whereas inhibition of piezo1 using GsMTx4 suppressed its development. Thus, our results suggested that PIEZO1 is responsible for HP and could functions as a factor for cell fate determination of MSCs by regulating BMP2 expression.

lociNGS: a lightweight alternative for assessing suitability of next-generation loci for evolutionary analysis.

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Sarah M Hird

Full Text Available Genomic enrichment methods and next-generation sequencing produce uneven coverage for the portions of the genome (the loci they target; this information is essential for ascertaining the suitability of each locus for further analysis. lociNGS is a user-friendly accessory program that takes multi-FASTA formatted loci, next-generation sequence alignments and demographic data as input and collates, displays and outputs information about the data. Summary information includes the parameters coverage per locus, coverage per individual and number of polymorphic sites, among others. The program can output the raw sequences used to call loci from next-generation sequencing data. lociNGS also reformats subsets of loci in three commonly used formats for multi-locus phylogeographic and population genetics analyses - NEXUS, IMa2 and Migrate. lociNGS is available at https://github.com/SHird/lociNGS and is dependent on installation of MongoDB (freely available at http://www.mongodb.org/downloads. lociNGS is written in Python and is supported on MacOSX and Unix; it is distributed under a GNU General Public License.

Cell-Type Specific Determinants of NRAMP1 Expression in Professional Phagocytes

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Mathieu F. M. Cellier

2013-01-01

Full Text Available The Natural resistance-associated macrophage protein 1 (Nramp1 or Solute carrier 11 member 1, Slc11a1 transports divalent metals across the membrane of late endosomes and lysosomes in professional phagocytes. Nramp1 represents an ancient eukaryotic cell-autonomous defense whereas the gene duplication that yielded Nramp1 and Nramp2 predated the origin of Sarcopterygians (lobe-finned fishes and tetrapods. SLC11A1 genetic polymorphisms associated with human resistance to tuberculosis consist of potential regulatory variants. Herein, current knowledge of the regulation of SLC11A1 gene expression is reviewed and comprehensive analysis of ENCODE data available for hematopoietic cell-types suggests a hypothesis for the regulation of SLC11A1 expression during myeloid development and phagocyte functional polarization. SLC11A1 is part of a 34.6 kb CTCF-insulated locus scattered with predicted regulatory elements: a 3' enhancer, a large 5' enhancer domain and four elements spread around the transcription start site (TSS, including several C/EBP and PU.1 sites. SLC11A1 locus ends appear mobilized by ETS-related factors early during myelopoiesis; activation of both 5' and 3' enhancers in myelo-monocytic cells correlate with transcription factor binding at the TSS. Characterizing the corresponding cis/trans determinants functionally will establish the mechanisms involved and possibly reveal genetic variation that impacts susceptibility to infectious or immune diseases.

An evolutionary reduction principle for mutation rates at multiple Loci.

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Altenberg, Lee

2011-06-01

A model of mutation rate evolution for multiple loci under arbitrary selection is analyzed. Results are obtained using techniques from Karlin (Evolutionary Biology, vol. 14, pp. 61-204, 1982) that overcome the weak selection constraints needed for tractability in prior studies of multilocus event models.A multivariate form of the reduction principle is found: reduction results at individual loci combine topologically to produce a surface of mutation rate alterations that are neutral for a new modifier allele. New mutation rates survive if and only if they fall below this surface-a generalization of the hyperplane found by Zhivotovsky et al. (Proc. Natl. Acad. Sci. USA 91, 1079-1083, 1994) for a multilocus recombination modifier. Increases in mutation rates at some loci may evolve if compensated for by decreases at other loci. The strength of selection on the modifier scales in proportion to the number of germline cell divisions, and increases with the number of loci affected. Loci that do not make a difference to marginal fitnesses at equilibrium are not subject to the reduction principle, and under fine tuning of mutation rates would be expected to have higher mutation rates than loci in mutation-selection balance.Other results include the nonexistence of 'viability analogous, Hardy-Weinberg' modifier polymorphisms under multiplicative mutation, and the sufficiency of average transmission rates to encapsulate the effect of modifier polymorphisms on the transmission of loci under selection. A conjecture is offered regarding situations, like recombination in the presence of mutation, that exhibit departures from the reduction principle. Constraints for tractability are: tight linkage of all loci, initial fixation at the modifier locus, and mutation distributions comprising transition probabilities of reversible Markov chains.

Genetic control of yeast cell radiosensitivity modification by oxygen and hypoxic sensitizers

International Nuclear Information System (INIS)

Zhuranovskaya, G.P.; Petin, V.G.

1984-01-01

Diploid yeast cells Saccharomyces cerevisiae ''of the wild type'', individual mutants, homozygous in rad 2 and rad 54 and double mutants, containing both these loci in homozygous state are considered to prove genetic determination of radiosensitivity modification of hypoxic cells by oxygen and electron acceptor compounds previously demonstrated on yeast cells of other genotypes. It is shown that both ''oxygen effect'' and the effect of hypoxic sensitizers depend on the activity of repair systems. The possible mechanism of participation of post-radiation restoration processes in the modification of cell radiosensitivity, is discussed

Development of the 16 X-STR loci typing system and genetic analysis in a Shanghai Han population from China.

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Sun, Kuan; Zhao, Shumin; Tian, Huaizhou; Zhang, Suhua; Li, Chengtao

2013-11-01

This study developed a new multiplex PCR system that simultaneously amplifies 16 X-STR loci in the same PCR reaction, and the polymorphism and mutation rates of these 16 X-STR loci were explored in a Shanghai Han population from China. These loci included DXS10134, DXS10159, DXS6789, DXS6795, DXS6800, DXS6803, DXS6807, DXS6810, DXS7132, DXS7424, DXS8378, DXS9902, GATA165B12, GATA172D05, GATA31E08, and HPRTB. Samples from 591 unrelated individuals (293 males and 298 females) and 400 two-generation families were successfully analyzed using this multiplex system. Allele frequencies and mutation rates of the 16 loci were investigated, with the comparison of allele frequency distributions among different populations performed. Polymorphism information contents of these loci were all >0.6440 except the locus DXS6800 (0.4706). Nine cases of mutations were detected in the 16 loci from the investigation of 9232 meioses. Pairwise comparisons of allele frequency distributions showed significant differences for most loci among populations from different countries and ethnic groups but not among the Han population living in other areas of China. These results suggest that the 16 X-STR loci system provides highly informative polymorphic data for paternity testing and forensic identification in the Han population in Shanghai, China, as a complementary tool. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Evaluation of 13 short tandem repeated loci for use in personal identification applications

Energy Technology Data Exchange (ETDEWEB)

Hammond, H.A.; Caskey, C.T. (Baylor College of Medicine, Houston, TX (United States)); Jin, L.; Zhong, Y.; Chakraborty, R. (Univ. of Texas Graduate School of Biomedical Sciences, Houston, TX (United States))

1994-07-01

Personal identification by using DNA typing methodologies has been an issue in the popular and scientific press for several years. The authors present a PCR-based DNA-typing method using 13 unlinked short tandem repeat (STR) loci. Validation of the loci and methodology has been performed to meet standards set by the forensic community and the accrediting organization for parentage testing. Extensive statistical analysis has addressed the issues surrounding the presentation of [open quotes]match[close quotes] statistics. The authors have found STR loci to provide a rapid, sensitive, and reliable method of DNA typing for parentage testing, forensic identification, and medical diagnostics. Valid statistical analysis is generally simpler than similar analysis of RFLP-VNTR results and provides powerful statistical evidence of the low frequency of random multilocus genotype matching. 54 refs., 4 figs., 6 tabs.

The combination of two Sle2 lupus-susceptibility loci and Cdkn2c deficiency leads to T cell-mediated pathology in B6.Faslpr mice

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Xu, Zhiwei; Croker, Byron P.; Morel, Laurence

2013-01-01

The NZM2410 Sle2c1 lupus susceptibility locus is responsible for the expansion of the B1a cell compartment and for the induction of T-cell induced renal and skin pathology on a CD95 deficient (Faslpr)-background. We have previously shown that deficiency in cyclin-dependent kinase inhibitor p18INK4c (p18) was responsible for the B1a cell expansion but was not sufficient to account for the pathology in B6.lpr mice. This study was designed to map the additional Sle2c1 loci responsible for autoimmune pathology when co-expressed with CD95 deficiency. The production, fine-mapping and phenotypic characterization of five recombinant intervals indicated that three interacting sub-loci were responsive for inducting autoimmune pathogenesis in B6.lpr mice. One of these sub-loci corresponds most likely to p18-deficiency. Another major locus mapping to a 2 Mb region at the telomeric end of Sle2c1 is necessary to both renal and skin pathology. Finally, a third locus centromeric to p18 enhances the severity of lupus nephritis. These results provide new insights into the genetic interactions leading to SLE disease presentation, and represent a major step towards the identification of novel susceptibility genes involved in T-cell mediated organ damage. PMID:23698709

A microsatellite-based linkage map of salt tolerant tilapia (Oreochromis mossambicus x Oreochromis spp.) and mapping of sex-determining loci

Science.gov (United States)

2013-01-01

Background Tilapia is the common name for a group of cichlid fishes and is one of the most important aquacultured freshwater food fish. Mozambique tilapia and its hybrids, including red tilapia are main representatives of salt tolerant tilapias. A linkage map is an essential framework for mapping QTL for important traits, positional cloning of genes and understanding of genome evolution. Results We constructed a consensus linkage map of Mozambique tilapia and red tilapia using 95 individuals from two F1 families and 401 microsatellites including 282 EST-derived markers. In addition, we conducted comparative mapping and searched for sex-determining loci on the whole genome. These 401 microsatellites were assigned to 22 linkage groups. The map spanned 1067.6 cM with an average inter-marker distance of 3.3 cM. Comparative mapping between tilapia and stickleback, medaka, pufferfish and zebrafish revealed clear homologous relationships between chromosomes from different species. We found evidence for the fusion of two sets of two independent chromosomes forming two new chromosome pairs, leading to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex determination locus in Mozambique tilapia was mapped on LG1, and verified in five families containing 549 individuals. The major XY sex determination locus in red tilapia was located on LG22, and verified in two families containing 275 individuals. Conclusions A first-generation linkage map of salt tolerant tilapia was constructed using 401 microsatellites. Two separate fusions of two sets of two independent chromosomes may lead to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex-determining loci from Mozambique tilapia and red tilapia were mapped on LG1 and LG22, respectively. This map provides a useful resource for QTL mapping for important traits and comparative genome studies. The DNA markers linked to the sex-determining loci could be used in

A microsatellite-based linkage map of salt tolerant tilapia (Oreochromis mossambicus x Oreochromis spp. and mapping of sex-determining loci

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Liu Feng

2013-01-01

Full Text Available Abstract Background Tilapia is the common name for a group of cichlid fishes and is one of the most important aquacultured freshwater food fish. Mozambique tilapia and its hybrids, including red tilapia are main representatives of salt tolerant tilapias. A linkage map is an essential framework for mapping QTL for important traits, positional cloning of genes and understanding of genome evolution. Results We constructed a consensus linkage map of Mozambique tilapia and red tilapia using 95 individuals from two F1 families and 401 microsatellites including 282 EST-derived markers. In addition, we conducted comparative mapping and searched for sex-determining loci on the whole genome. These 401 microsatellites were assigned to 22 linkage groups. The map spanned 1067.6 cM with an average inter-marker distance of 3.3 cM. Comparative mapping between tilapia and stickleback, medaka, pufferfish and zebrafish revealed clear homologous relationships between chromosomes from different species. We found evidence for the fusion of two sets of two independent chromosomes forming two new chromosome pairs, leading to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex determination locus in Mozambique tilapia was mapped on LG1, and verified in five families containing 549 individuals. The major XY sex determination locus in red tilapia was located on LG22, and verified in two families containing 275 individuals. Conclusions A first-generation linkage map of salt tolerant tilapia was constructed using 401 microsatellites. Two separate fusions of two sets of two independent chromosomes may lead to a reduction of 24 chromosome pairs in their ancestor to 22 pairs in tilapias. The XY sex-determining loci from Mozambique tilapia and red tilapia were mapped on LG1 and LG22, respectively. This map provides a useful resource for QTL mapping for important traits and comparative genome studies. The DNA markers linked to the sex-determining

Genetic Risk Score Modelling for Disease Progression in New-Onset Type 1 Diabetes Patients

DEFF Research Database (Denmark)

Brorsson, Caroline A; Nielsen, Lotte B; Andersen, Marie-Louise

2016-01-01

Genome-wide association studies (GWAS) have identified over 40 type 1 diabetes risk loci. The clinical impact of these loci on β-cell function during disease progression is unknown. We aimed at testing whether a genetic risk score could predict glycemic control and residual β-cell function in type...... 1 diabetes (T1D). As gene expression may represent an intermediate phenotype between genetic variation and disease, we hypothesized that genes within T1D loci which are expressed in islets and transcriptionally regulated by proinflammatory cytokines would be the best predictors of disease...... constructed a genetic risk score based on the cumulative number of risk alleles carried in children with newly diagnosed T1D. With each additional risk allele carried, HbA1c levels increased significantly within first year after diagnosis. Network and gene ontology (GO) analyses revealed that several...

Cellular uptake of nanoparticles as determined by particle properties, experimental conditions, and cell type.

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Kettler, Katja; Veltman, Karin; van de Meent, Dik; van Wezel, Annemarie; Hendriks, A Jan

2014-03-01

The increased application of nanoparticles (NPs) is increasing the risk of their release into the environment. Although many toxicity studies have been conducted, the environmental risk is difficult to estimate, because uptake mechanisms are often not determined in toxicity studies. In the present study, the authors review dominant uptake mechanisms of NPs in cells, as well as the effect of NP properties, experimental conditions, and cell type on NP uptake. Knowledge of NP uptake is crucial for risk assessment and is essential to predict the behavior of NPs based on their physical-chemical properties. Important uptake mechanisms for eukaryotic cells are macropinocytosis, receptor-mediated endocytosis, and phagocytosis in specialized mammalian cells. The studies reviewed demonstrate that uptake into nonphagocytic cells depends strongly on NP size, with an uptake optimum at an NP diameter of approximately 50 nm. Increasing surface charges, either positive or negative, have been shown to increase particle uptake in comparison with uncharged NPs. Another important factor is the degree of (homo-) aggregation. Results regarding shape have been ambiguous. Difficulties in the production of NPs, with 1 property changed at a time, call for a full characterization of NP properties. Only then will it be possible to draw conclusions as to which property affected the uptake. © 2013 SETAC.

Genes and quality trait loci (QTLs) associated with firmness in Malus x domestica

KAUST Repository

Marondedze, Claudius; Thomas, Ludivine

2013-01-01

, crunchiness and crispness. Fruit firmness is affected by the inheritance of alleles at multiple loci and their possible interactions with the environment. Identification of these loci is key for the determination of genetic candidate markers that can

Mating-Type Genes and MAT Switching in Saccharomyces cerevisiae

Science.gov (United States)

Haber, James E.

2012-01-01

Mating type in Saccharomyces cerevisiae is determined by two nonhomologous alleles, MATa and MATα. These sequences encode regulators of the two different haploid mating types and of the diploids formed by their conjugation. Analysis of the MATa1, MATα1, and MATα2 alleles provided one of the earliest models of cell-type specification by transcriptional activators and repressors. Remarkably, homothallic yeast cells can switch their mating type as often as every generation by a highly choreographed, site-specific homologous recombination event that replaces one MAT allele with different DNA sequences encoding the opposite MAT allele. This replacement process involves the participation of two intact but unexpressed copies of mating-type information at the heterochromatic loci, HMLα and HMRa, which are located at opposite ends of the same chromosome-encoding MAT. The study of MAT switching has yielded important insights into the control of cell lineage, the silencing of gene expression, the formation of heterochromatin, and the regulation of accessibility of the donor sequences. Real-time analysis of MAT switching has provided the most detailed description of the molecular events that occur during the homologous recombinational repair of a programmed double-strand chromosome break. PMID:22555442

PHOTOGRAPHY AS A MEANS OF DEPICTING GENIUS LOCI?

Directory of Open Access Journals (Sweden)

Iulia DOROFTEI

2016-10-01

Full Text Available The paper aims to explore the concept of genius loci (spirit of a place starting from Christian Norberg-Schulz’s notable work “Genius Loci: Towards a Phenomenology of Architecture” and to reflect on the possibility of capturing the spirit of a place through photography. The problem arises in the context of a predominantly visual culture, where photography has become an accesible and omnipresent means of experiencing the world and, therefore, considered a convenient tool for gaining (a type of knowledge. A photographic method of exploring the spirirt of the place could serve in understanding local characteristics, in identifying the elements that make a place unique and recognizible. Norberg-Schulz’s position and other views on the concept of genius loci have been analysed. A photo-essay was employed in order to explore the spirit of the old town of Chefchaouen in Morocco and the ambiguity and dual nature of the concept. A critical reflection was conducted with respect to the results.

Genome-edited human stem cell-derived beta cells: a powerful tool for drilling down on type 2 diabetes GWAS biology.

Science.gov (United States)

Beer, Nicola L; Gloyn, Anna L

2016-01-01

Type 2 diabetes (T2D) is a disease of pandemic proportions, one defined by a complex aetiological mix of genetic, epigenetic, environmental, and lifestyle risk factors. Whilst the last decade of T2D genetic research has identified more than 100 loci showing strong statistical association with disease susceptibility, our inability to capitalise upon these signals reflects, in part, a lack of appropriate human cell models for study. This review discusses the impact of two complementary, state-of-the-art technologies on T2D genetic research: the generation of stem cell-derived, endocrine pancreas-lineage cells and the editing of their genomes. Such models facilitate investigation of diabetes-associated genomic perturbations in a physiologically representative cell context and allow the role of both developmental and adult islet dysfunction in T2D pathogenesis to be investigated. Accordingly, we interrogate the role that patient-derived induced pluripotent stem cell models are playing in understanding cellular dysfunction in monogenic diabetes, and how site-specific nucleases such as the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system are helping to confirm genes crucial to human endocrine pancreas development. We also highlight the novel biology gleaned in the absence of patient lines, including an ability to model the whole phenotypic spectrum of diabetes phenotypes occurring both in utero and in adult cells, interrogating the non-coding 'islet regulome' for disease-causing perturbations, and understanding the role of other islet cell types in aberrant glycaemia. This article aims to reinforce the importance of investigating T2D signals in cell models reflecting appropriate species, genomic context, developmental time point, and tissue type.

Determination of lower bound crystallographic yield loci of zircaloy-4 tubes

International Nuclear Information System (INIS)

Costa Viana, C.S. da

1980-01-01

The use of zircaloy-4 tubing in fuel elements of water cooled reactors is discussed with respect to its mechanisms of deformation and also its resulting anisotropic plastic behaviour. A method for obtaining lower bound crystallographic yield loci of α-Zr is presented and applied to individual crystal orientations and to a real texture described by the main components observed on a direct pole figure. (Author) [pt

Loci and candidate genes conferring resistance to soybean cyst nematode HG type 2.5.7.

Science.gov (United States)

Zhao, Xue; Teng, Weili; Li, Yinghui; Liu, Dongyuan; Cao, Guanglu; Li, Dongmei; Qiu, Lijuan; Zheng, Hongkun; Han, Yingpeng; Li, Wenbin

2017-06-14

Soybean (Glycine max L. Merr.) cyst nematode (SCN, Heterodera glycines I,) is a major pest of soybean worldwide. The most effective strategy to control this pest involves the use of resistant cultivars. The aim of the present study was to investigate the genome-wide genetic architecture of resistance to SCN HG Type 2.5.7 (race 1) in landrace and elite cultivated soybeans. A total of 200 diverse soybean accessions were screened for resistance to SCN HG Type 2.5.7 and genotyped through sequencing using the Specific Locus Amplified Fragment Sequencing (SLAF-seq) approach with a 6.14-fold average sequencing depth. A total of 33,194 SNPs were identified with minor allele frequencies (MAF) over 4%, covering 97% of all the genotypes. Genome-wide association mapping (GWAS) revealed thirteen SNPs associated with resistance to SCN HG Type 2.5.7. These SNPs were distributed on five chromosomes (Chr), including Chr7, 8, 14, 15 and 18. Four SNPs were novel resistance loci and nine SNPs were located near known QTL. A total of 30 genes were identified as candidate genes underlying SCN resistance. A total of sixteen novel soybean accessions were identified with significant resistance to HG Type 2.5.7. The beneficial alleles and candidate genes identified by GWAS might be valuable for improving marker-assisted breeding efficiency and exploring the molecular mechanisms underlying SCN resistance.

Genome-wide association study identifies novel loci associated with circulating phospho- and sphingolipid concentrations.

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Ayşe Demirkan

Full Text Available Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034 on plasma levels of 24 sphingomyelins (SPM, 9 ceramides (CER, 57 phosphatidylcholines (PC, 20 lysophosphatidylcholines (LPC, 27 phosphatidylethanolamines (PE, and 16 PE-based plasmalogens (PLPE, as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88×10(-204 and 10 loci for sphingolipids (smallest P-value = 3.10×10(-57. After a correction for multiple comparisons (P-value<2.2×10(-9, we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1 and two with sphingolipids (PLD2 and APOE explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3 suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2 to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our

Origins of amino acid transporter loci in trypanosomatid parasites

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Jackson Andrew P

2007-02-01

Full Text Available Abstract Background Large amino acid transporter gene families were identified from the genome sequences of three parasitic protists, Trypanosoma brucei, Trypanosoma cruzi and Leishmania major. These genes encode molecular sensors of the external host environment for trypanosomatid cells and are crucial to modulation of gene expression as the parasite passes through different life stages. This study provides a comprehensive phylogenetic account of the origins of these genes, redefining each locus according to a positional criterion, through the integration of phyletic identity with comparative gene order information. Results Each locus was individually specified by its surrounding gene order and associated with homologs showing the same position ('homoeologs' in other species, where available. Bayesian and maximum likelihood phylogenies were in general agreement on systematic relationships and confirmed several 'orthology sets' of genes retained since divergence from the common ancestor. Reconciliation analysis quantified the scale of duplication and gene loss, as well as identifying further apparent orthology sets, which lacked conservation of genomic position. These instances suggested substantial genomic restructuring or transposition. Other analyses identified clear instances of evolutionary rate changes post-duplication, the effects of concerted evolution within tandem gene arrays and gene conversion events between syntenic loci. Conclusion Despite their importance to cell function and parasite development, the repertoires of AAT loci in trypanosomatid parasites are relatively fluid in both complement and gene dosage. Some loci are ubiquitous and, after an ancient origin through transposition, originated through descent from the ancestral trypanosomatid. However, reconciliation analysis demonstrated that unilateral expansions of gene number through tandem gene duplication, transposition of gene duplicates to otherwise well conserved genomic

Genome-Wide Association Study Identifies Two Novel Loci with Sex-Specific Effects for Type 2 Diabetes Mellitus and Glycemic Traits in a Korean Population

Directory of Open Access Journals (Sweden)

Min Jin Go

2014-10-01

Full Text Available BackgroundUntil recently, genome-wide association study (GWAS-based findings have provided a substantial genetic contribution to type 2 diabetes mellitus (T2DM or related glycemic traits. However, identification of allelic heterogeneity and population-specific genetic variants under consideration of potential confounding factors will be very valuable for clinical applicability. To identify novel susceptibility loci for T2DM and glycemic traits, we performed a two-stage genetic association study in a Korean population.MethodsWe performed a logistic analysis for T2DM, and the first discovery GWAS was analyzed for 1,042 cases and 2,943 controls recruited from a population-based cohort (KARE, n=8,842. The second stage, de novo replication analysis, was performed in 1,216 cases and 1,352 controls selected from an independent population-based cohort (Health 2, n=8,500. A multiple linear regression analysis for glycemic traits was further performed in a total of 14,232 nondiabetic individuals consisting of 7,696 GWAS and 6,536 replication study participants. A meta-analysis was performed on the combined results using effect size and standard errors estimated for stage 1 and 2, respectively.ResultsA combined meta-analysis for T2DM identified two new (rs11065756 and rs2074356 loci reaching genome-wide significance in CCDC63 and C12orf51 on the 12q24 region. In addition, these variants were significantly associated with fasting plasma glucose and homeostasis model assessment of β-cell function. Interestingly, two independent single nucleotide polymorphisms were associated with sex-specific stratification in this study.ConclusionOur study showed a strong association between T2DM and glycemic traits. We further observed that two novel loci with multiple diverse effects were highly specific to males. Taken together, these findings may provide additional insights into the clinical assessment or subclassification of disease risk in a Korean population.

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation

Science.gov (United States)

Andlauer, Till F. M.; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A.; Loleit, Verena; Luessi, Felix; Meuth, Sven G.; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H.; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K.; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O.; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B.; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M.; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M.; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-01-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis. PMID:27386562

Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.

Science.gov (United States)

Andlauer, Till F M; Buck, Dorothea; Antony, Gisela; Bayas, Antonios; Bechmann, Lukas; Berthele, Achim; Chan, Andrew; Gasperi, Christiane; Gold, Ralf; Graetz, Christiane; Haas, Jürgen; Hecker, Michael; Infante-Duarte, Carmen; Knop, Matthias; Kümpfel, Tania; Limmroth, Volker; Linker, Ralf A; Loleit, Verena; Luessi, Felix; Meuth, Sven G; Mühlau, Mark; Nischwitz, Sandra; Paul, Friedemann; Pütz, Michael; Ruck, Tobias; Salmen, Anke; Stangel, Martin; Stellmann, Jan-Patrick; Stürner, Klarissa H; Tackenberg, Björn; Then Bergh, Florian; Tumani, Hayrettin; Warnke, Clemens; Weber, Frank; Wiendl, Heinz; Wildemann, Brigitte; Zettl, Uwe K; Ziemann, Ulf; Zipp, Frauke; Arloth, Janine; Weber, Peter; Radivojkov-Blagojevic, Milena; Scheinhardt, Markus O; Dankowski, Theresa; Bettecken, Thomas; Lichtner, Peter; Czamara, Darina; Carrillo-Roa, Tania; Binder, Elisabeth B; Berger, Klaus; Bertram, Lars; Franke, Andre; Gieger, Christian; Herms, Stefan; Homuth, Georg; Ising, Marcus; Jöckel, Karl-Heinz; Kacprowski, Tim; Kloiber, Stefan; Laudes, Matthias; Lieb, Wolfgang; Lill, Christina M; Lucae, Susanne; Meitinger, Thomas; Moebus, Susanne; Müller-Nurasyid, Martina; Nöthen, Markus M; Petersmann, Astrid; Rawal, Rajesh; Schminke, Ulf; Strauch, Konstantin; Völzke, Henry; Waldenberger, Melanie; Wellmann, Jürgen; Porcu, Eleonora; Mulas, Antonella; Pitzalis, Maristella; Sidore, Carlo; Zara, Ilenia; Cucca, Francesco; Zoledziewska, Magdalena; Ziegler, Andreas; Hemmer, Bernhard; Müller-Myhsok, Bertram

2016-06-01

We conducted a genome-wide association study (GWAS) on multiple sclerosis (MS) susceptibility in German cohorts with 4888 cases and 10,395 controls. In addition to associations within the major histocompatibility complex (MHC) region, 15 non-MHC loci reached genome-wide significance. Four of these loci are novel MS susceptibility loci. They map to the genes L3MBTL3, MAZ, ERG, and SHMT1. The lead variant at SHMT1 was replicated in an independent Sardinian cohort. Products of the genes L3MBTL3, MAZ, and ERG play important roles in immune cell regulation. SHMT1 encodes a serine hydroxymethyltransferase catalyzing the transfer of a carbon unit to the folate cycle. This reaction is required for regulation of methylation homeostasis, which is important for establishment and maintenance of epigenetic signatures. Our GWAS approach in a defined population with limited genetic substructure detected associations not found in larger, more heterogeneous cohorts, thus providing new clues regarding MS pathogenesis.

BPS Jumping Loci are Automorphic

Science.gov (United States)

Kachru, Shamit; Tripathy, Arnav

2018-06-01

We show that BPS jumping loci-loci in the moduli space of string compactifications where the number of BPS states jumps in an upper semi-continuous manner—naturally appear as Fourier coefficients of (vector space-valued) automorphic forms. For the case of T 2 compactification, the jumping loci are governed by a modular form studied by Hirzebruch and Zagier, while the jumping loci in K3 compactification appear in a story developed by Oda and Kudla-Millson in arithmetic geometry. We also comment on some curious related automorphy in the physics of black hole attractors and flux vacua.

Genetic polymorphisms of 20 autosomal STR loci in the Vietnamese population from Yunnan Province, Southwest China.

Science.gov (United States)

Zhang, Xiufeng; Hu, Liping; Du, Lei; Nie, Aiting; Rao, Min; Pang, Jing Bo; Nie, Shengjie

2017-05-01

The genetic polymorphisms of 20 autosomal short tandem repeat (STR) loci included in the PowerPlex® 21 kit were evaluated in 522 healthy unrelated Vietnamese from Yunnan, China. All of the loci reached the Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. The combined discrimination power and probability of excluding paternity of the 20 STR loci were 0.999999999999999999999991 26 and 0.999999975, respectively. Results suggested that the 20 STR loci are highly polymorphic, which is suitable for forensic personal identification and paternity testing.

Types of Stem Cells

Science.gov (United States)

... Stem Cell Glossary Search Toggle Nav Types of Stem Cells Stem cells are the foundation from which all ... Learn About Stem Cells > Types of Stem Cells Stem cells Stem cells are the foundation for every organ ...

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

DEFF Research Database (Denmark)

Zeggini, Eleftheria; Scott, Laura J; Saxena, Richa

2008-01-01

analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample......Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published...

Genome-wide association study of renal cell carcinoma identifies two susceptibility loci on 2p21 and 11q13.3

NARCIS (Netherlands)

Purdue, Mark P.; Johansson, Mattias; Zelenika, Diana; Toro, Jorge R.; Scelo, Ghislaine; Moore, Lee E.; Prokhortchouk, Egor; Wu, Xifeng; Kiemeney, Lambertus A.; Gaborieau, Valerie; Jacobs, Kevin B.; Chow, Wong-Ho; Zaridze, David; Matveev, Vsevolod; Lubinski, Jan; Trubicka, Joanna; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Foretova, Lenka; Janout, Vladimir; Boffetta, Paolo; Colt, Joanne S.; Davis, Faith G.; Schwartz, Kendra L.; Banks, Rosamonde E.; Selby, Peter J.; Harnden, Patricia; Berg, Christine D.; Hsing, Ann W.; Grubb, Robert L.; Boeing, Heiner; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; Duell, Eric J.; Quiros, Jose Ramon; Sanchez, Maria-Jose; Navarro, Carmen; Ardanaz, Eva; Dorronsoro, Miren; Khaw, Kay-Tee; Allen, Naomi E.; Bueno-de-Mesquita, H. Bas; Peeters, Petra H. M.; Trichopoulos, Dimitrios; Linseisen, Jakob; Ljungberg, Borje; Overvad, Kim; Tjonneland, Anne; Romieu, Isabelle; Riboli, Elio; Mukeria, Anush; Shangina, Oxana; Stevens, Victoria L.; Thun, Michael J.; Diver, W. Ryan; Gapstur, Susan M.; Pharoah, Paul D.; Easton, Douglas F.; Albanes, Demetrius; Weinstein, Stephanie J.; Virtamo, Jarmo; Vatten, Lars; Hveem, Kristian; Njolstad, Inger; Tell, Grethe S.; Stoltenberg, Camilla; Kumar, Rajiv; Koppova, Kvetoslava; Cussenot, Olivier; Benhamou, Simone; Oosterwijk, Egbert; Vermeulen, Sita H.; Aben, Katja K. H.; van der Marel, Saskia L.; Ye, Yuanqing; Wood, Christopher G.; Pu, Xia; Mazur, Alexander M.; Boulygina, Eugenia S.; Chekanov, Nikolai N.; Foglio, Mario; Lechner, Doris; Gut, Ivo; Heath, Simon; Blanche, Helene; Hutchinson, Amy; Thomas, Gilles; Wang, Zhaoming; Yeager, Meredith; Fraumeni, Joseph F.; Skryabin, Konstantin G.; McKay, James D.; Rothman, Nathaniel; Chanock, Stephen J.; Lathrop, Mark; Brennan, Paul

We conducted a two-stage genome-wide association study of renal cell carcinoma (RCC) in 3,772 affected individuals (cases) and 8,505 controls of European background from 11 studies and followed up 6 SNPs in 3 replication studies of 2,198 cases and 4,918 controls. Two loci on the regions of 2p21 and

Radiation effects on polyethylene foam of open cell type

International Nuclear Information System (INIS)

Tang Beilin; Kanako Kaji; Iwao Yoshizawa; Choji Kohara; Motoyoshi Hatada

1991-01-01

The effects of electron beam irradiation on polyethylene foam of open cell type have been studied. Experiments for determining of gel fraction and physical-mechanical properties of irradiated polyethylene foam of open cell type as a function of dose, respectively, were carried out. The dimensional stability of irradiated specimens at elevated temperatures was measured. It was found that tensile strength did not change and gel fraction increased when the specimen was irradiated in nitrogen atmosphere with increasing dose up to 300 kGy. The result shows that dimensional stability of polyethylene foam of open cell type after being kept in an oven at 70 deg C and 110 deg C for 22 h is improved by irradiation in nitrogen atmosphere. The similar results of irradiated EVA foam of open cell type irradiated foam of open cell type were obtained

Genotype-dependent participation of coat color gene loci in the behavioral traits of laboratory mice.

Science.gov (United States)

Yamamuro, Yutaka; Shiraishi, Aya

2011-10-01

To evaluate if loci responsible for coat color phenotypes contribute to behavioral characteristics, we specified novel gene loci associated with social exploratory behavior and examined the effects of the frequency of each allele at distinct loci on behavioral expression. We used the F2 generation, which arose from the mating of F1 mice obtained by interbreeding DBA/2 and ICR mice. Phenotypic analysis indicated that the agouti and albino loci affect behavioral traits. A genotype-based analysis revealed that novel exploratory activity was suppressed in a manner dependent on the frequency of the dominant wild-type allele at the agouti, but not albino, locus. The allele-dependent suppression was restricted to colored mice and was not seen in albino mice. The present results suggest that the agouti locus contributes to a particular behavioral trait in the presence of a wild-type allele at the albino locus, which encodes a structural gene for tyrosinase. Copyright © 2011 Elsevier B.V. All rights reserved.

Genetic mapping of xenotropic murine leukemia virus-inducing loci in five mouse strains.

Science.gov (United States)

Kozak, C A; Rowe, W P

1980-07-01

A single mendelian gene was identified for induction of the endogenous xenotropic murine leukemia virus in five mouse strains (C57BL/10, C57L, C57BR, AKR, and BALB/c). This locus, designated Bxv-1, mapped to the same site on chromosome 1 in all strains: Id-1-Pep-3-[Bxv-1-Lp]. Thus, inducibility loci for xenotropic virus are more limited in number and chromosomal distribution than ecotropic inducibility loci. Virus expression in mice with Bxv-1 was induced by treatment of fibroblasts with 5-iododeoxyuridine or by exposure of spleen cells to a B cell mitogen, bacterial lipopolysaccharide. An analysis of the hamster X mouse somatic cell hybrids indicated that chromosome 1, alone, was sufficient for virus induction.

Nine Loci for Ocular Axial Length Identified through Genome-wide Association Studies, Including Shared Loci with Refractive Error

Science.gov (United States)

Cheng, Ching-Yu; Schache, Maria; Ikram, M. Kamran; Young, Terri L.; Guggenheim, Jeremy A.; Vitart, Veronique; MacGregor, Stuart; Verhoeven, Virginie J.M.; Barathi, Veluchamy A.; Liao, Jiemin; Hysi, Pirro G.; Bailey-Wilson, Joan E.; St. Pourcain, Beate; Kemp, John P.; McMahon, George; Timpson, Nicholas J.; Evans, David M.; Montgomery, Grant W.; Mishra, Aniket; Wang, Ya Xing; Wang, Jie Jin; Rochtchina, Elena; Polasek, Ozren; Wright, Alan F.; Amin, Najaf; van Leeuwen, Elisabeth M.; Wilson, James F.; Pennell, Craig E.; van Duijn, Cornelia M.; de Jong, Paulus T.V.M.; Vingerling, Johannes R.; Zhou, Xin; Chen, Peng; Li, Ruoying; Tay, Wan-Ting; Zheng, Yingfeng; Chew, Merwyn; Rahi, Jugnoo S.; Hysi, Pirro G.; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Delcourt, Cécile; Maubaret, Cecilia; Williams, Cathy; Guggenheim, Jeremy A.; Northstone, Kate; Ring, Susan M.; Davey-Smith, George; Craig, Jamie E.; Burdon, Kathryn P.; Fogarty, Rhys D.; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Iyengar, Sudha K.; Igo, Robert P.; Chew, Emily; Janmahasathian, Sarayut; Stambolian, Dwight; Wilson, Joan E. Bailey; MacGregor, Stuart; Lu, Yi; Jonas, Jost B.; Xu, Liang; Saw, Seang-Mei; Baird, Paul N.; Rochtchina, Elena; Mitchell, Paul; Wang, Jie Jin; Jonas, Jost B.; Nangia, Vinay; Hayward, Caroline; Wright, Alan F.; Vitart, Veronique; Polasek, Ozren; Campbell, Harry; Vitart, Veronique; Rudan, Igor; Vatavuk, Zoran; Vitart, Veronique; Paterson, Andrew D.; Hosseini, S. Mohsen; Iyengar, Sudha K.; Igo, Robert P.; Fondran, Jeremy R.; Young, Terri L.; Feng, Sheng; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Metspalu, Andres; Haller, Toomas; Mihailov, Evelin; Pärssinen, Olavi; Wedenoja, Juho; Wilson, Joan E. Bailey; Wojciechowski, Robert; Baird, Paul N.; Schache, Maria; Pfeiffer, Norbert; Höhn, René; Pang, Chi Pui; Chen, Peng; Meitinger, Thomas; Oexle, Konrad; Wegner, Aharon; Yoshimura, Nagahisa; Yamashiro, Kenji; Miyake, Masahiro; Pärssinen, Olavi; Yip, Shea Ping; Ho, Daniel W.H.; Pirastu, Mario; Murgia, Federico; Portas, Laura; Biino, Genevra; Wilson, James F.; Fleck, Brian; Vitart, Veronique; Stambolian, Dwight; Wilson, Joan E. Bailey; Hewitt, Alex W.; Ang, Wei; Verhoeven, Virginie J.M.; Klaver, Caroline C.; van Duijn, Cornelia M.; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Wong, Tien-Yin; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Tai, E-Shyong; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Saw, Seang-Mei; Teo, Yik-Ying; Fan, Qiao; Cheng, Ching-Yu; Zhou, Xin; Ikram, M. Kamran; Mackey, David A.; MacGregor, Stuart; Hammond, Christopher J.; Hysi, Pirro G.; Deangelis, Margaret M.; Morrison, Margaux; Zhou, Xiangtian; Chen, Wei; Paterson, Andrew D.; Hosseini, S. Mohsen; Mizuki, Nobuhisa; Meguro, Akira; Lehtimäki, Terho; Mäkelä, Kari-Matti; Raitakari, Olli; Kähönen, Mika; Burdon, Kathryn P.; Craig, Jamie E.; Iyengar, Sudha K.; Igo, Robert P.; Lass, Jonathan H.; Reinhart, William; Belin, Michael W.; Schultze, Robert L.; Morason, Todd; Sugar, Alan; Mian, Shahzad; Soong, Hunson Kaz; Colby, Kathryn; Jurkunas, Ula; Yee, Richard; Vital, Mark; Alfonso, Eduardo; Karp, Carol; Lee, Yunhee; Yoo, Sonia; Hammersmith, Kristin; Cohen, Elisabeth; Laibson, Peter; Rapuano, Christopher; Ayres, Brandon; Croasdale, Christopher; Caudill, James; Patel, Sanjay; Baratz, Keith; Bourne, William; Maguire, Leo; Sugar, Joel; Tu, Elmer; Djalilian, Ali; Mootha, Vinod; McCulley, James; Bowman, Wayne; Cavanaugh, H. Dwight; Verity, Steven; Verdier, David; Renucci, Ann; Oliva, Matt; Rotkis, Walter; Hardten, David R.; Fahmy, Ahmad; Brown, Marlene; Reeves, Sherman; Davis, Elizabeth A.; Lindstrom, Richard; Hauswirth, Scott; Hamilton, Stephen; Lee, W. Barry; Price, Francis; Price, Marianne; Kelly, Kathleen; Peters, Faye; Shaughnessy, Michael; Steinemann, Thomas; Dupps, B.J.; Meisler, David M.; Mifflin, Mark; Olson, Randal; Aldave, Anthony; Holland, Gary; Mondino, Bartly J.; Rosenwasser, George; Gorovoy, Mark; Dunn, Steven P.; Heidemann, David G.; Terry, Mark; Shamie, Neda; Rosenfeld, Steven I.; Suedekum, Brandon; Hwang, David; Stone, Donald; Chodosh, James; Galentine, Paul G.; Bardenstein, David; Goddard, Katrina; Chin, Hemin; Mannis, Mark; Varma, Rohit; Borecki, Ingrid; Chew, Emily Y.; Haller, Toomas; Mihailov, Evelin; Metspalu, Andres; Wedenoja, Juho; Simpson, Claire L.; Wojciechowski, Robert; Höhn, René; Mirshahi, Alireza; Zeller, Tanja; Pfeiffer, Norbert; Lackner, Karl J.; Donnelly, Peter; Barroso, Ines; Blackwell, Jenefer M.; Bramon, Elvira; Brown, Matthew A.; Casas, Juan P.; Corvin, Aiden; Deloukas, Panos; Duncanson, Audrey; Jankowski, Janusz; Markus, Hugh S.; Mathew, Christopher G.; Palmer, Colin N.A.; Plomin, Robert; Rautanen, Anna; Sawcer, Stephen J.; Trembath, Richard C.; Viswanathan, Ananth C.; Wood, Nicholas W.; Spencer, Chris C.A.; Band, Gavin; Bellenguez, Céline; Freeman, Colin; Hellenthal, Garrett; Giannoulatou, Eleni; Pirinen, Matti; Pearson, Richard; Strange, Amy; Su, Zhan; Vukcevic, Damjan; Donnelly, Peter; Langford, Cordelia; Hunt, Sarah E.; Edkins, Sarah; Gwilliam, Rhian; Blackburn, Hannah; Bumpstead, Suzannah J.; Dronov, Serge; Gillman, Matthew; Gray, Emma; Hammond, Naomi; Jayakumar, Alagurevathi; McCann, Owen T.; Liddle, Jennifer; Potter, Simon C.; Ravindrarajah, Radhi; Ricketts, Michelle; Waller, Matthew; Weston, Paul; Widaa, Sara; Whittaker, Pamela; Barroso, Ines; Deloukas, Panos; Mathew, Christopher G.; Blackwell, Jenefer M.; Brown, Matthew A.; Corvin, Aiden; Spencer, Chris C.A.; Bettecken, Thomas; Meitinger, Thomas; Oexle, Konrad; Pirastu, Mario; Portas, Laura; Nag, Abhishek; Williams, Katie M.; Yonova-Doing, Ekaterina; Klein, Ronald; Klein, Barbara E.; Hosseini, S. Mohsen; Paterson, Andrew D.; Genuth, S.; Nathan, D.M.; Zinman, B.; Crofford, O.; Crandall, J.; Reid, M.; Brown-Friday, J.; Engel, S.; Sheindlin, J.; Martinez, H.; Shamoon, H.; Engel, H.; Phillips, M.; Gubitosi-Klug, R.; Mayer, L.; Pendegast, S.; Zegarra, H.; Miller, D.; Singerman, L.; Smith-Brewer, S.; Novak, M.; Quin, J.; Dahms, W.; Genuth, Saul; Palmert, M.; Brillon, D.; Lackaye, M.E.; Kiss, S.; Chan, R.; Reppucci, V.; Lee, T.; Heinemann, M.; Whitehouse, F.; Kruger, D.; Jones, J.K.; McLellan, M.; Carey, J.D.; Angus, E.; Thomas, A.; Galprin, A.; Bergenstal, R.; Johnson, M.; Spencer, M.; Morgan, K.; Etzwiler, D.; Kendall, D.; Aiello, Lloyd Paul; Golden, E.; Jacobson, A.; Beaser, R.; Ganda, O.; Hamdy, O.; Wolpert, H.; Sharuk, G.; Arrigg, P.; Schlossman, D.; Rosenzwieg, J.; Rand, L.; Nathan, D.M.; Larkin, M.; Ong, M.; Godine, J.; Cagliero, E.; Lou, P.; Folino, K.; Fritz, S.; Crowell, S.; Hansen, K.; Gauthier-Kelly, C.; Service, J.; Ziegler, G.; Luttrell, L.; Caulder, S.; Lopes-Virella, M.; Colwell, J.; Soule, J.; Fernandes, J.; Hermayer, K.; Kwon, S.; Brabham, M.; Blevins, A.; Parker, J.; Lee, D.; Patel, N.; Pittman, C.; Lindsey, P.; Bracey, M.; Lee, K.; Nutaitis, M.; Farr, A.; Elsing, S.; Thompson, T.; Selby, J.; Lyons, T.; Yacoub-Wasef, S.; Szpiech, M.; Wood, D.; Mayfield, R.; Molitch, M.; Schaefer, B.; Jampol, L.; Lyon, A.; Gill, M.; Strugula, Z.; Kaminski, L.; Mirza, R.; Simjanoski, E.; Ryan, D.; Kolterman, O.; Lorenzi, G.; Goldbaum, M.; Sivitz, W.; Bayless, M.; Counts, D.; Johnsonbaugh, S.; Hebdon, M.; Salemi, P.; Liss, R.; Donner, T.; Gordon, J.; Hemady, R.; Kowarski, A.; Ostrowski, D.; Steidl, S.; Jones, B.; Herman, W.H.; Martin, C.L.; Pop-Busui, R.; Sarma, A.; Albers, J.; Feldman, E.; Kim, K.; Elner, S.; Comer, G.; Gardner, T.; Hackel, R.; Prusak, R.; Goings, L.; Smith, A.; Gothrup, J.; Titus, P.; Lee, J.; Brandle, M.; Prosser, L.; Greene, D.A.; Stevens, M.J.; Vine, A.K.; Bantle, J.; Wimmergren, N.; Cochrane, A.; Olsen, T.; Steuer, E.; Rath, P.; Rogness, B.; Hainsworth, D.; Goldstein, D.; Hitt, S.; Giangiacomo, J.; Schade, D.S.; Canady, J.L.; Chapin, J.E.; Ketai, L.H.; Braunstein, C.S.; Bourne, P.A.; Schwartz, S.; Brucker, A.; Maschak-Carey, B.J.; Baker, L.; Orchard, T.; Silvers, N.; Ryan, C.; Songer, T.; Doft, B.; Olson, S.; Bergren, R.L.; Lobes, L.; Rath, P. Paczan; Becker, D.; Rubinstein, D.; Conrad, P.W.; Yalamanchi, S.; Drash, A.; Morrison, A.; Bernal, M.L.; Vaccaro-Kish, J.; Malone, J.; Pavan, P.R.; Grove, N.; Iyer, M.N.; Burrows, A.F.; Tanaka, E.A.; Gstalder, R.; Dagogo-Jack, S.; Wigley, C.; Ricks, H.; Kitabchi, A.; Murphy, M.B.; Moser, S.; Meyer, D.; Iannacone, A.; Chaum, E.; Yoser, S.; Bryer-Ash, M.; Schussler, S.; Lambeth, H.; Raskin, P.; Strowig, S.; Zinman, B.; Barnie, A.; Devenyi, R.; Mandelcorn, M.; Brent, M.; Rogers, S.; Gordon, A.; Palmer, J.; Catton, S.; Brunzell, J.; Wessells, H.; de Boer, I.H.; Hokanson, J.; Purnell, J.; Ginsberg, J.; Kinyoun, J.; Deeb, S.; Weiss, M.; Meekins, G.; Distad, J.; Van Ottingham, L.; Dupre, J.; Harth, J.; Nicolle, D.; Driscoll, M.; Mahon, J.; Canny, C.; May, M.; Lipps, J.; Agarwal, A.; Adkins, T.; Survant, L.; Pate, R.L.; Munn, G.E.; Lorenz, R.; Feman, S.; White, N.; Levandoski, L.; Boniuk, I.; Grand, G.; Thomas, M.; Joseph, D.D.; Blinder, K.; Shah, G.; Boniuk; Burgess; Santiago, J.; Tamborlane, W.; Gatcomb, P.; Stoessel, K.; Taylor, K.; Goldstein, J.; Novella, S.; Mojibian, H.; Cornfeld, D.; Lima, J.; Bluemke, D.; Turkbey, E.; van der Geest, R.J.; Liu, C.; Malayeri, A.; Jain, A.; Miao, C.; Chahal, H.; Jarboe, R.; Maynard, J.; Gubitosi-Klug, R.; Quin, J.; Gaston, P.; Palmert, M.; Trail, R.; Dahms, W.; Lachin, J.; Cleary, P.; Backlund, J.; Sun, W.; Braffett, B.; Klumpp, K.; Chan, K.; Diminick, L.; Rosenberg, D.; Petty, B.; Determan, A.; Kenny, D.; Rutledge, B.; Younes, Naji; Dews, L.; Hawkins, M.; Cowie, C.; Fradkin, J.; Siebert, C.; Eastman, R.; Danis, R.; Gangaputra, S.; Neill, S.; Davis, M.; Hubbard, L.; Wabers, H.; Burger, M.; Dingledine, J.; Gama, V.; Sussman, R.; Steffes, M.; Bucksa, J.; Nowicki, M.; Chavers, B.; O’Leary, D.; Polak, J.; Harrington, A.; Funk, L.; Crow, R.; Gloeb, B.; Thomas, S.; O’Donnell, C.; Soliman, E.; Zhang, Z.M.; Prineas, R.; Campbell, C.; Ryan, C.; Sandstrom, D.; Williams, T.; Geckle, M.; Cupelli, E.; Thoma, F.; Burzuk, B.; Woodfill, T.; Low, P.; Sommer, C.; Nickander, K.; Budoff, M.; Detrano, R.; Wong, N.; Fox, M.; Kim, L.; Oudiz, R.; Weir, G.; Espeland, M.; Manolio, T.; Rand, L.; Singer, D.; Stern, M.; Boulton, A.E.; Clark, C.; D’Agostino, R.; Lopes-Virella, M.; Garvey, W.T.; Lyons, T.J.; Jenkins, A.; Virella, G.; Jaffa, A.; Carter, Rickey; Lackland, D.; Brabham, M.; McGee, D.; Zheng, D.; Mayfield, R.K.; Boright, A.; Bull, S.; Sun, L.; Scherer, S.; Zinman, B.; Natarajan, R.; Miao, F.; Zhang, L.; Chen;, Z.; Nathan, D.M.; Makela, Kari-Matti; Lehtimaki, Terho; Kahonen, Mika; Raitakari, Olli; Yoshimura, Nagahisa; Matsuda, Fumihiko; Chen, Li Jia; Pang, Chi Pui; Yip, Shea Ping; Yap, Maurice K.H.; Meguro, Akira; Mizuki, Nobuhisa; Inoko, Hidetoshi; Foster, Paul J.; Zhao, Jing Hua; Vithana, Eranga; Tai, E-Shyong; Fan, Qiao; Xu, Liang; Campbell, Harry; Fleck, Brian; Rudan, Igor; Aung, Tin; Hofman, Albert; Uitterlinden, André G.; Bencic, Goran; Khor, Chiea-Chuen; Forward, Hannah; Pärssinen, Olavi; Mitchell, Paul; Rivadeneira, Fernando; Hewitt, Alex W.; Williams, Cathy; Oostra, Ben A.; Teo, Yik-Ying; Hammond, Christopher J.; Stambolian, Dwight; Mackey, David A.; Klaver, Caroline C.W.; Wong, Tien-Yin; Saw, Seang-Mei; Baird, Paul N.

2013-01-01

Refractive errors are common eye disorders of public health importance worldwide. Ocular axial length (AL) is the major determinant of refraction and thus of myopia and hyperopia. We conducted a meta-analysis of genome-wide association studies for AL, combining 12,531 Europeans and 8,216 Asians. We identified eight genome-wide significant loci for AL (RSPO1, C3orf26, LAMA2, GJD2, ZNRF3, CD55, MIP, and ALPPL2) and confirmed one previously reported AL locus (ZC3H11B). Of the nine loci, five (LAMA2, GJD2, CD55, ALPPL2, and ZC3H11B) were associated with refraction in 18 independent cohorts (n = 23,591). Differential gene expression was observed for these loci in minus-lens-induced myopia mouse experiments and human ocular tissues. Two of the AL genes, RSPO1 and ZNRF3, are involved in Wnt signaling, a pathway playing a major role in the regulation of eyeball size. This study provides evidence of shared genes between AL and refraction, but importantly also suggests that these traits may have unique pathways. PMID:24144296

Tissue-specific tagging of endogenous loci in Drosophila melanogaster

Directory of Open Access Journals (Sweden)

Kate Koles

2016-01-01

Full Text Available Fluorescent protein tags have revolutionized cell and developmental biology, and in combination with binary expression systems they enable diverse tissue-specific studies of protein function. However these binary expression systems often do not recapitulate endogenous protein expression levels, localization, binding partners and/or developmental windows of gene expression. To address these limitations, we have developed a method called T-STEP (tissue-specific tagging of endogenous proteins that allows endogenous loci to be tagged in a tissue specific manner. T-STEP uses a combination of efficient CRISPR/Cas9-enhanced gene targeting and tissue-specific recombinase-mediated tag swapping to temporally and spatially label endogenous proteins. We have employed this method to GFP tag OCRL (a phosphoinositide-5-phosphatase in the endocytic pathway and Vps35 (a Parkinson's disease-implicated component of the endosomal retromer complex in diverse Drosophila tissues including neurons, glia, muscles and hemocytes. Selective tagging of endogenous proteins allows, for the first time, cell type-specific live imaging and proteomics in complex tissues.

Comprehensive Identification of Long Non-coding RNAs in Purified Cell Types from the Brain Reveals Functional LncRNA in OPC Fate Determination.

Directory of Open Access Journals (Sweden)

Xiaomin Dong

2015-12-01

Full Text Available Long non-coding RNAs (lncRNAs (> 200 bp play crucial roles in transcriptional regulation during numerous biological processes. However, it is challenging to comprehensively identify lncRNAs, because they are often expressed at low levels and with more cell-type specificity than are protein-coding genes. In the present study, we performed ab initio transcriptome reconstruction using eight purified cell populations from mouse cortex and detected more than 5000 lncRNAs. Predicting the functions of lncRNAs using cell-type specific data revealed their potential functional roles in Central Nervous System (CNS development. We performed motif searches in ENCODE DNase I digital footprint data and Mouse ENCODE promoters to infer transcription factor (TF occupancy. By integrating TF binding and cell-type specific transcriptomic data, we constructed a novel framework that is useful for systematically identifying lncRNAs that are potentially essential for brain cell fate determination. Based on this integrative analysis, we identified lncRNAs that are regulated during Oligodendrocyte Precursor Cell (OPC differentiation from Neural Stem Cells (NSCs and that are likely to be involved in oligodendrogenesis. The top candidate, lnc-OPC, shows highly specific expression in OPCs and remarkable sequence conservation among placental mammals. Interestingly, lnc-OPC is significantly up-regulated in glial progenitors from experimental autoimmune encephalomyelitis (EAE mouse models compared to wild-type mice. OLIG2-binding sites in the upstream regulatory region of lnc-OPC were identified by ChIP (chromatin immunoprecipitation-Sequencing and validated by luciferase assays. Loss-of-function experiments confirmed that lnc-OPC plays a functional role in OPC genesis. Overall, our results substantiated the role of lncRNA in OPC fate determination and provided an unprecedented data source for future functional investigations in CNS cell types. We present our datasets and

Huntingtin-interacting protein 14 is a type 1 diabetes candidate protein regulating insulin secretion and β-cell apoptosis

DEFF Research Database (Denmark)

Berchtold, Lukas Adrian; Størling, Zenia Marian; Ortis, Fernanda

2011-01-01

Type 1 diabetes (T1D) is a complex disease characterized by the loss of insulin-secreting β-cells. Although the disease has a strong genetic component, and several loci are known to increase T1D susceptibility risk, only few causal genes have currently been identified. To identify disease...... genes in T1D, including the INS gene. An unexpected top-scoring candidate gene was huntingtin-interacting protein (HIP)-14/ZDHHC17. Immunohistochemical analysis of pancreatic sections demonstrated that HIP14 is almost exclusively expressed in insulin-positive cells in islets of Langerhans. RNAi...... knockdown experiments established that HIP14 is an antiapoptotic protein required for β-cell survival and glucose-stimulated insulin secretion. Proinflammatory cytokines (IL-1β and IFN-γ) that mediate β-cell dysfunction in T1D down-regulated HIP14 expression in insulin-secreting INS-1 cells and in isolated...

Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Science.gov (United States)

Estrada, Karol; Styrkarsdottir, Unnur; Evangelou, Evangelos; Hsu, Yi-Hsiang; Duncan, Emma L; Ntzani, Evangelia E; Oei, Ling; Albagha, Omar M E; Amin, Najaf; Kemp, John P; Koller, Daniel L; Li, Guo; Liu, Ching-Ti; Minster, Ryan L; Moayyeri, Alireza; Vandenput, Liesbeth; Willner, Dana; Xiao, Su-Mei; Yerges-Armstrong, Laura M; Zheng, Hou-Feng; Alonso, Nerea; Eriksson, Joel; Kammerer, Candace M; Kaptoge, Stephen K; Leo, Paul J; Thorleifsson, Gudmar; Wilson, Scott G; Wilson, James F; Aalto, Ville; Alen, Markku; Aragaki, Aaron K; Aspelund, Thor; Center, Jacqueline R; Dailiana, Zoe; Duggan, David J; Garcia, Melissa; Garcia-Giralt, Natàlia; Giroux, Sylvie; Hallmans, Göran; Hocking, Lynne J; Husted, Lise Bjerre; Jameson, Karen A; Khusainova, Rita; Kim, Ghi Su; Kooperberg, Charles; Koromila, Theodora; Kruk, Marcin; Laaksonen, Marika; Lacroix, Andrea Z; Lee, Seung Hun; Leung, Ping C; Lewis, Joshua R; Masi, Laura; Mencej-Bedrac, Simona; Nguyen, Tuan V; Nogues, Xavier; Patel, Millan S; Prezelj, Janez; Rose, Lynda M; Scollen, Serena; Siggeirsdottir, Kristin; Smith, Albert V; Svensson, Olle; Trompet, Stella; Trummer, Olivia; van Schoor, Natasja M; Woo, Jean; Zhu, Kun; Balcells, Susana; Brandi, Maria Luisa; Buckley, Brendan M; Cheng, Sulin; Christiansen, Claus; Cooper, Cyrus; Dedoussis, George; Ford, Ian; Frost, Morten; Goltzman, David; González-Macías, Jesús; Kähönen, Mika; Karlsson, Magnus; Khusnutdinova, Elza; Koh, Jung-Min; Kollia, Panagoula; Langdahl, Bente Lomholt; Leslie, William D; Lips, Paul; Ljunggren, Östen; Lorenc, Roman S; Marc, Janja; Mellström, Dan; Obermayer-Pietsch, Barbara; Olmos, José M; Pettersson-Kymmer, Ulrika; Reid, David M; Riancho, José A; Ridker, Paul M; Rousseau, François; Slagboom, P Eline; Tang, Nelson LS; Urreizti, Roser; Van Hul, Wim; Viikari, Jorma; Zarrabeitia, María T; Aulchenko, Yurii S; Castano-Betancourt, Martha; Grundberg, Elin; Herrera, Lizbeth; Ingvarsson, Thorvaldur; Johannsdottir, Hrefna; Kwan, Tony; Li, Rui; Luben, Robert; Medina-Gómez, Carolina; Palsson, Stefan Th; Reppe, Sjur; Rotter, Jerome I; Sigurdsson, Gunnar; van Meurs, Joyce B J; Verlaan, Dominique; Williams, Frances MK; Wood, Andrew R; Zhou, Yanhua; Gautvik, Kaare M; Pastinen, Tomi; Raychaudhuri, Soumya; Cauley, Jane A; Chasman, Daniel I; Clark, Graeme R; Cummings, Steven R; Danoy, Patrick; Dennison, Elaine M; Eastell, Richard; Eisman, John A; Gudnason, Vilmundur; Hofman, Albert; Jackson, Rebecca D; Jones, Graeme; Jukema, J Wouter; Khaw, Kay-Tee; Lehtimäki, Terho; Liu, Yongmei; Lorentzon, Mattias; McCloskey, Eugene; Mitchell, Braxton D; Nandakumar, Kannabiran; Nicholson, Geoffrey C; Oostra, Ben A; Peacock, Munro; Pols, Huibert A P; Prince, Richard L; Raitakari, Olli; Reid, Ian R; Robbins, John; Sambrook, Philip N; Sham, Pak Chung; Shuldiner, Alan R; Tylavsky, Frances A; van Duijn, Cornelia M; Wareham, Nick J; Cupples, L Adrienne; Econs, Michael J; Evans, David M; Harris, Tamara B; Kung, Annie Wai Chee; Psaty, Bruce M; Reeve, Jonathan; Spector, Timothy D; Streeten, Elizabeth A; Zillikens, M Carola; Thorsteinsdottir, Unnur; Ohlsson, Claes; Karasik, David; Richards, J Brent; Brown, Matthew A; Stefansson, Kari; Uitterlinden, André G; Ralston, Stuart H; Ioannidis, John P A; Kiel, Douglas P; Rivadeneira, Fernando

2012-01-01

Bone mineral density (BMD) is the most important predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and East Asian ancestry. We tested the top-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility. PMID:22504420

Impact of type 2 diabetes susceptibility variants on quantitative glycemic traits reveals mechanistic heterogeneity

DEFF Research Database (Denmark)

Dimas, Antigone S; Lagou, Vasiliki; Barker, Adam

2013-01-01

Patients with established type 2 diabetes display both beta-cell dysfunction and insulin resistance. To define fundamental processes leading to the diabetic state, we examined the relationship between type 2 diabetes risk variants at 37 established susceptibility loci and indices of proinsulin pr...

Mouse lysozyme-M knockout mice reveal how the self-determinant hierarchy shapes the T cell repertoire against this circulating self antigen in wild-type mice

NARCIS (Netherlands)

Sinha, Pratima; Chi, Howard H.; Kim, Hong R.; Clausen, Björn E.; Pederson, Brian; Sercarz, Eli E.; Forster, Irmgard; Moudgil, Kamal D.

2004-01-01

We have studied T cell tolerance to defined determinants within ML-M using wild-type (WT; ML-M+/+) and LysMcre (ML-M-/-) C3H (H-2(k)) mice to determine the relative contribution of ML-M-derived epitopes vs those from other self Ags in selection of the ML-M-specific T cell repertoire. ML-M was

Efficacy of DNA typing as an accurate method in forensic medicine

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Namazi H

2000-08-01

Full Text Available DNA typing is a new method with important applications in forensic medicine. In the present study, we evaluated application of DNA typing in Iran. Loci Hum LPL, Hum Tpox, Hum F13, Hum vw 31A, Hum TH01 and Hum FES/FPS of DNA short tandem repeats were studied. To determine sensitivity of the test, 85 mother-child couples (1020 chromosomes that were referred to DNA section of legal medicine organization of Iran were included and for determination of it's specificity 42 brother-sister couples (1200 chromosomes and 58 non-relative couples were examined. The results show lack of mutations in the studied loci and acceptable sensitivity of the test. Of 12 alleles of siblings, there were 2-6 differences, in contrast with 3-9 differences in non-relatives, so the test has 100% specificity in these loci. Considering polymorphism, power of exclusion of these 6 sites was 99%.

Nondetectability of restriction fragments and independence of DNA fragment sizes within and between loci in RFLP typing of DNA

Energy Technology Data Exchange (ETDEWEB)

Chakraborty, R.; Zhong, Y.; Jin, L. (Univ. of Texas Health Science Center, Houston, TX (United States)); Budowle, B. (FBI Academy, Quantico, VA (United States))

1994-08-01

The authors provide experimental evidence showing that, during the restriction-enzyme digestion of DNA samples, some of the HaeIII-digested DNA fragments are small enough to prevent their reliable sizing on a Southern gel. As a result of such nondetectability of DNA fragments, individuals who show a single-band DNA profile at a VNTR locus may not necessarily be true homozygotes. In a population database, when the presence of such nondetectable alleles is ignored, they show that a pseudodependence of alleles within as well as across loci may occur. Using a known statistical method, under the hypothesis of independence of alleles within loci, they derive an efficient estimate of null allele frequency, which may be subsequently used for testing allelic independence within and across loci. The estimates of null allele frequencies, thus derived, are shown to agree with direct experimental data on the frequencies of HaeIII-null alleles. Incorporation of null alleles into the analysis of the forensic VNTR database suggests that the assumptions of allelic independence within and between loci are appropriate. In contrast, a failure to incorporate the occurrence of null alleles would provide a wrong inference regarding the independence of alleles within and between loci. 47 refs., 2 figs., 4 tabs.

Charting improvements in US registry HLA typing ambiguity using a typing resolution score.

Science.gov (United States)

Paunić, Vanja; Gragert, Loren; Schneider, Joel; Müller, Carlheinz; Maiers, Martin

2016-07-01

Unrelated stem cell registries have been collecting HLA typing of volunteer bone marrow donors for over 25years. Donor selection for hematopoietic stem cell transplantation is based primarily on matching the alleles of donors and patients at five polymorphic HLA loci. As HLA typing technologies have continually advanced since the beginnings of stem cell transplantation, registries have accrued typings of varied HLA typing ambiguity. We present a new typing resolution score (TRS), based on the likelihood of self-match, that allows the systematic comparison of HLA typings across different methods, data sets and populations. We apply the TRS to chart improvement in HLA typing within the Be The Match Registry of the United States from the initiation of DNA-based HLA typing to the current state of high-resolution typing using next-generation sequencing technologies. In addition, we present a publicly available online tool for evaluation of any given HLA typing. This TRS objectively evaluates HLA typing methods and can help define standards for acceptable recruitment HLA typing. Copyright © 2016 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.

Characterization and Exploitation of CRISPR Loci in Bifidobacterium longum

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Claudio Hidalgo-Cantabrana

2017-09-01

Full Text Available Diverse CRISPR-Cas systems provide adaptive immunity in many bacteria and most archaea, via a DNA-encoded, RNA-mediated, nucleic-acid targeting mechanism. Over time, CRISPR loci expand via iterative uptake of invasive DNA sequences into the CRISPR array during the adaptation process. These genetic vaccination cards thus provide insights into the exposure of strains to phages and plasmids in space and time, revealing the historical predatory exposure of a strain. These genetic loci thus constitute a unique basis for genotyping of strains, with potential of resolution at the strain-level. Here, we investigate the occurrence and diversity of CRISPR-Cas systems in the genomes of various Bifidobacterium longum strains across three sub-species. Specifically, we analyzed the genomic content of 66 genomes belonging to B. longum subsp. longum, B. longum subsp. infantis and B. longum subsp. suis, and identified 25 strains that carry 29 total CRISPR-Cas systems. We identify various Type I and Type II CRISPR-Cas systems that are widespread in this species, notably I-C, I-E, and II-C. Noteworthy, Type I-C systems showed extended CRISPR arrays, with extensive spacer diversity. We show how these hypervariable loci can be used to gain insights into strain origin, evolution and phylogeny, and can provide discriminatory sequences to distinguish even clonal isolates. By investigating CRISPR spacer sequences, we reveal their origin and implicate phages and prophages as drivers of CRISPR immunity expansion in this species, with redundant targeting of select prophages. Analysis of CRISPR spacer origin also revealed novel PAM sequences. Our results suggest that CRISPR-Cas immune systems are instrumental in mounting diversified viral resistance in B. longum, and show that these sequences are useful for typing across three subspecies.

Heterosis at Allozyme Loci under Inbreeding and Crossbreeding in PINUS ATTENUATA

OpenAIRE

Strauss, Steven H.

1986-01-01

The dependence of heterosis at isozyme loci on inbreeding and crossbreeding was studied in 10-yr-old trees of knobcone pine (Pinus attenuata Lemm.). Heterozygosity was determined at 24 polymorphic isozyme loci and related to the rate of vegetative growth and cone production. The inbreds, created by selfpollination, had 46% of the heterozygosity of their mothers; the crossbreds, created by interpopulation crossing, had 155% of the heterozygosity of their mothers. Within the crossbreds, hetero...

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Directory of Open Access Journals (Sweden)

Zari Dastani

Full Text Available Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8-1.2×10(-43. Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans, we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4. We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3, n = 22,044, increased triglycerides (p = 2.6×10(-14, n = 93,440, increased waist-to-hip ratio (p = 1.8×10(-5, n = 77,167, increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3, n = 15,234, increased fasting insulin (p = 0.015, n = 48,238, but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13, n = 96,748 and decreased BMI (p = 1.4×10(-4, n = 121,335. These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

Novel loci for adiponectin levels and their influence on type 2 diabetes and metabolic traits: a multi-ethnic meta-analysis of 45,891 individuals.

Science.gov (United States)

Dastani, Zari; Hivert, Marie-France; Timpson, Nicholas; Perry, John R B; Yuan, Xin; Scott, Robert A; Henneman, Peter; Heid, Iris M; Kizer, Jorge R; Lyytikäinen, Leo-Pekka; Fuchsberger, Christian; Tanaka, Toshiko; Morris, Andrew P; Small, Kerrin; Isaacs, Aaron; Beekman, Marian; Coassin, Stefan; Lohman, Kurt; Qi, Lu; Kanoni, Stavroula; Pankow, James S; Uh, Hae-Won; Wu, Ying; Bidulescu, Aurelian; Rasmussen-Torvik, Laura J; Greenwood, Celia M T; Ladouceur, Martin; Grimsby, Jonna; Manning, Alisa K; Liu, Ching-Ti; Kooner, Jaspal; Mooser, Vincent E; Vollenweider, Peter; Kapur, Karen A; Chambers, John; Wareham, Nicholas J; Langenberg, Claudia; Frants, Rune; Willems-Vandijk, Ko; Oostra, Ben A; Willems, Sara M; Lamina, Claudia; Winkler, Thomas W; Psaty, Bruce M; Tracy, Russell P; Brody, Jennifer; Chen, Ida; Viikari, Jorma; Kähönen, Mika; Pramstaller, Peter P; Evans, David M; St Pourcain, Beate; Sattar, Naveed; Wood, Andrew R; Bandinelli, Stefania; Carlson, Olga D; Egan, Josephine M; Böhringer, Stefan; van Heemst, Diana; Kedenko, Lyudmyla; Kristiansson, Kati; Nuotio, Marja-Liisa; Loo, Britt-Marie; Harris, Tamara; Garcia, Melissa; Kanaya, Alka; Haun, Margot; Klopp, Norman; Wichmann, H-Erich; Deloukas, Panos; Katsareli, Efi; Couper, David J; Duncan, Bruce B; Kloppenburg, Margreet; Adair, Linda S; Borja, Judith B; Wilson, James G; Musani, Solomon; Guo, Xiuqing; Johnson, Toby; Semple, Robert; Teslovich, Tanya M; Allison, Matthew A; Redline, Susan; Buxbaum, Sarah G; Mohlke, Karen L; Meulenbelt, Ingrid; Ballantyne, Christie M; Dedoussis, George V; Hu, Frank B; Liu, Yongmei; Paulweber, Bernhard; Spector, Timothy D; Slagboom, P Eline; Ferrucci, Luigi; Jula, Antti; Perola, Markus; Raitakari, Olli; Florez, Jose C; Salomaa, Veikko; Eriksson, Johan G; Frayling, Timothy M; Hicks, Andrew A; Lehtimäki, Terho; Smith, George Davey; Siscovick, David S; Kronenberg, Florian; van Duijn, Cornelia; Loos, Ruth J F; Waterworth, Dawn M; Meigs, James B; Dupuis, Josee; Richards, J Brent; Voight, Benjamin F; Scott, Laura J; Steinthorsdottir, Valgerdur; Dina, Christian; Welch, Ryan P; Zeggini, Eleftheria; Huth, Cornelia; Aulchenko, Yurii S; Thorleifsson, Gudmar; McCulloch, Laura J; Ferreira, Teresa; Grallert, Harald; Amin, Najaf; Wu, Guanming; Willer, Cristen J; Raychaudhuri, Soumya; McCarroll, Steve A; Hofmann, Oliver M; Segrè, Ayellet V; van Hoek, Mandy; Navarro, Pau; Ardlie, Kristin; Balkau, Beverley; Benediktsson, Rafn; Bennett, Amanda J; Blagieva, Roza; Boerwinkle, Eric; Bonnycastle, Lori L; Boström, Kristina Bengtsson; Bravenboer, Bert; Bumpstead, Suzannah; Burtt, Noël P; Charpentier, Guillaume; Chines, Peter S; Cornelis, Marilyn; Crawford, Gabe; Doney, Alex S F; Elliott, Katherine S; Elliott, Amanda L; Erdos, Michael R; Fox, Caroline S; Franklin, Christopher S; Ganser, Martha; Gieger, Christian; Grarup, Niels; Green, Todd; Griffin, Simon; Groves, Christopher J; Guiducci, Candace; Hadjadj, Samy; Hassanali, Neelam; Herder, Christian; Isomaa, Bo; Jackson, Anne U; Johnson, Paul R V; Jørgensen, Torben; Kao, Wen H L; Kong, Augustine; Kraft, Peter; Kuusisto, Johanna; Lauritzen, Torsten; Li, Man; Lieverse, Aloysius; Lindgren, Cecilia M; Lyssenko, Valeriya; Marre, Michel; Meitinger, Thomas; Midthjell, Kristian; Morken, Mario A; Narisu, Narisu; Nilsson, Peter; Owen, Katharine R; Payne, Felicity; Petersen, Ann-Kristin; Platou, Carl; Proença, Christine; Prokopenko, Inga; Rathmann, Wolfgang; Rayner, N William; Robertson, Neil R; Rocheleau, Ghislain; Roden, Michael; Sampson, Michael J; Saxena, Richa; Shields, Beverley M; Shrader, Peter; Sigurdsson, Gunnar; Sparsø, Thomas; Strassburger, Klaus; Stringham, Heather M; Sun, Qi; Swift, Amy J; Thorand, Barbara; Tichet, Jean; Tuomi, Tiinamaija; van Dam, Rob M; van Haeften, Timon W; van Herpt, Thijs; van Vliet-Ostaptchouk, Jana V; Walters, G Bragi; Weedon, Michael N; Wijmenga, Cisca; Witteman, Jacqueline; Bergman, Richard N; Cauchi, Stephane; Collins, Francis S; Gloyn, Anna L; Gyllensten, Ulf; Hansen, Torben; Hide, Winston A; Hitman, Graham A; Hofman, Albert; Hunter, David J; Hveem, Kristian; Laakso, Markku; Morris, Andrew D; Palmer, Colin N A; Rudan, Igor; Sijbrands, Eric; Stein, Lincoln D; Tuomilehto, Jaakko; Uitterlinden, Andre; Walker, Mark; Watanabe, Richard M; Abecasis, Goncalo R; Boehm, Bernhard O; Campbell, Harry; Daly, Mark J; Hattersley, Andrew T; Pedersen, Oluf; Barroso, Inês; Groop, Leif; Sladek, Rob; Thorsteinsdottir, Unnur; Wilson, James F; Illig, Thomas; Froguel, Philippe; van Duijn, Cornelia M; Stefansson, Kari; Altshuler, David; Boehnke, Michael; McCarthy, Mark I; Soranzo, Nicole; Wheeler, Eleanor; Glazer, Nicole L; Bouatia-Naji, Nabila; Mägi, Reedik; Randall, Joshua; Elliott, Paul; Rybin, Denis; Dehghan, Abbas; Hottenga, Jouke Jan; Song, Kijoung; Goel, Anuj; Lajunen, Taina; Doney, Alex; Cavalcanti-Proença, Christine; Kumari, Meena; Timpson, Nicholas J; Zabena, Carina; Ingelsson, Erik; An, Ping; O'Connell, Jeffrey; Luan, Jian'an; Elliott, Amanda; McCarroll, Steven A; Roccasecca, Rosa Maria; Pattou, François; Sethupathy, Praveen; Ariyurek, Yavuz; Barter, Philip; Beilby, John P; Ben-Shlomo, Yoav; Bergmann, Sven; Bochud, Murielle; Bonnefond, Amélie; Borch-Johnsen, Knut; Böttcher, Yvonne; Brunner, Eric; Bumpstead, Suzannah J; Chen, Yii-Der Ida; Chines, Peter; Clarke, Robert; Coin, Lachlan J M; Cooper, Matthew N; Crisponi, Laura; Day, Ian N M; de Geus, Eco J C; Delplanque, Jerome; Fedson, Annette C; Fischer-Rosinsky, Antje; Forouhi, Nita G; Franzosi, Maria Grazia; Galan, Pilar; Goodarzi, Mark O; Graessler, Jürgen; Grundy, Scott; Gwilliam, Rhian; Hallmans, Göran; Hammond, Naomi; Han, Xijing; Hartikainen, Anna-Liisa; Hayward, Caroline; Heath, Simon C; Hercberg, Serge; Hillman, David R; Hingorani, Aroon D; Hui, Jennie; Hung, Joe; Kaakinen, Marika; Kaprio, Jaakko; Kesaniemi, Y Antero; Kivimaki, Mika; Knight, Beatrice; Koskinen, Seppo; Kovacs, Peter; Kyvik, Kirsten Ohm; Lathrop, G Mark; Lawlor, Debbie A; Le Bacquer, Olivier; Lecoeur, Cécile; Li, Yun; Mahley, Robert; Mangino, Massimo; Martínez-Larrad, María Teresa; McAteer, Jarred B; McPherson, Ruth; Meisinger, Christa; Melzer, David; Meyre, David; Mitchell, Braxton D; Mukherjee, Sutapa; Naitza, Silvia; Neville, Matthew J; Orrù, Marco; Pakyz, Ruth; Paolisso, Giuseppe; Pattaro, Cristian; Pearson, Daniel; Peden, John F; Pedersen, Nancy L; Pfeiffer, Andreas F H; Pichler, Irene; Polasek, Ozren; Posthuma, Danielle; Potter, Simon C; Pouta, Anneli; Province, Michael A; Rayner, Nigel W; Rice, Kenneth; Ripatti, Samuli; Rivadeneira, Fernando; Rolandsson, Olov; Sandbaek, Annelli; Sandhu, Manjinder; Sanna, Serena; Sayer, Avan Aihie; Scheet, Paul; Seedorf, Udo; Sharp, Stephen J; Shields, Beverley; Sigurðsson, Gunnar; Sijbrands, Eric J G; Silveira, Angela; Simpson, Laila; Singleton, Andrew; Smith, Nicholas L; Sovio, Ulla; Swift, Amy; Syddall, Holly; Syvänen, Ann-Christine; Tönjes, Anke; Uitterlinden, André G; van Dijk, Ko Willems; Varma, Dhiraj; Visvikis-Siest, Sophie; Vitart, Veronique; Vogelzangs, Nicole; Waeber, Gérard; Wagner, Peter J; Walley, Andrew; Ward, Kim L; Watkins, Hugh; Wild, Sarah H; Willemsen, Gonneke; Witteman, Jaqueline C M; Yarnell, John W G; Zelenika, Diana; Zethelius, Björn; Zhai, Guangju; Zhao, Jing Hua; Zillikens, M Carola; Borecki, Ingrid B; Meneton, Pierre; Magnusson, Patrik K E; Nathan, David M; Williams, Gordon H; Silander, Kaisa; Bornstein, Stefan R; Schwarz, Peter; Spranger, Joachim; Karpe, Fredrik; Shuldiner, Alan R; Cooper, Cyrus; Serrano-Ríos, Manuel; Lind, Lars; Palmer, Lyle J; Hu, Frank B; Franks, Paul W; Ebrahim, Shah; Marmot, Michael; Kao, W H Linda; Pramstaller, Peter Paul; Wright, Alan F; Stumvoll, Michael; Hamsten, Anders; Buchanan, Thomas A; Valle, Timo T; Rotter, Jerome I; Penninx, Brenda W J H; Boomsma, Dorret I; Cao, Antonio; Scuteri, Angelo; Schlessinger, David; Uda, Manuela; Ruokonen, Aimo; Jarvelin, Marjo-Riitta; Peltonen, Leena; Mooser, Vincent; Sladek, Robert; Musunuru, Kiran; Smith, Albert V; Edmondson, Andrew C; Stylianou, Ioannis M; Koseki, Masahiro; Pirruccello, James P; Chasman, Daniel I; Johansen, Christopher T; Fouchier, Sigrid W; Peloso, Gina M; Barbalic, Maja; Ricketts, Sally L; Bis, Joshua C; Feitosa, Mary F; Orho-Melander, Marju; Melander, Olle; Li, Xiaohui; Li, Mingyao; Cho, Yoon Shin; Go, Min Jin; Kim, Young Jin; Lee, Jong-Young; Park, Taesung; Kim, Kyunga; Sim, Xueling; Ong, Rick Twee-Hee; Croteau-Chonka, Damien C; Lange, Leslie A; Smith, Joshua D; Ziegler, Andreas; Zhang, Weihua; Zee, Robert Y L; Whitfield, John B; Thompson, John R; Surakka, Ida; Spector, Tim D; Smit, Johannes H; Sinisalo, Juha; Scott, James; Saharinen, Juha; Sabatti, Chiara; Rose, Lynda M; Roberts, Robert; Rieder, Mark; Parker, Alex N; Pare, Guillaume; O'Donnell, Christopher J; Nieminen, Markku S; Nickerson, Deborah A; Montgomery, Grant W; McArdle, Wendy; Masson, David; Martin, Nicholas G; Marroni, Fabio; Lucas, Gavin; Luben, Robert; Lokki, Marja-Liisa; Lettre, Guillaume; Launer, Lenore J; Lakatta, Edward G; Laaksonen, Reijo; Kyvik, Kirsten O; König, Inke R; Khaw, Kay-Tee; Kaplan, Lee M; Johansson, Åsa; Janssens, A Cecile J W; Igl, Wilmar; Hovingh, G Kees; Hengstenberg, Christian; Havulinna, Aki S; Hastie, Nicholas D; Harris, Tamara B; Haritunians, Talin; Hall, Alistair S; Groop, Leif C; Gonzalez, Elena; Freimer, Nelson B; Erdmann, Jeanette; Ejebe, Kenechi G; Döring, Angela; Dominiczak, Anna F; Demissie, Serkalem; Deloukas, Panagiotis; de Faire, Ulf; Crawford, Gabriel; Chen, Yii-der I; Caulfield, Mark J; Boekholdt, S Matthijs; Assimes, Themistocles L; Quertermous, Thomas; Seielstad, Mark; Wong, Tien Y; Tai, E-Shyong; Feranil, Alan B; Kuzawa, Christopher W; Taylor, Herman A; Gabriel, Stacey B; Holm, Hilma; Gudnason, Vilmundur; Krauss, Ronald M; Ordovas, Jose M; Munroe, Patricia B; Kooner, Jaspal S; Tall, Alan R; Hegele, Robert A; Kastelein, John J P; Schadt, Eric E; Strachan, David P; Reilly, Muredach P; Samani, Nilesh J; Schunkert, Heribert; Cupples, L Adrienne; Sandhu, Manjinder S; Ridker, Paul M; Rader, Daniel J; Kathiresan, Sekar

2012-01-01

Circulating levels of adiponectin, a hormone produced predominantly by adipocytes, are highly heritable and are inversely associated with type 2 diabetes mellitus (T2D) and other metabolic traits. We conducted a meta-analysis of genome-wide association studies in 39,883 individuals of European ancestry to identify genes associated with metabolic disease. We identified 8 novel loci associated with adiponectin levels and confirmed 2 previously reported loci (P = 4.5×10(-8)-1.2×10(-43)). Using a novel method to combine data across ethnicities (N = 4,232 African Americans, N = 1,776 Asians, and N = 29,347 Europeans), we identified two additional novel loci. Expression analyses of 436 human adipocyte samples revealed that mRNA levels of 18 genes at candidate regions were associated with adiponectin concentrations after accounting for multiple testing (p<3×10(-4)). We next developed a multi-SNP genotypic risk score to test the association of adiponectin decreasing risk alleles on metabolic traits and diseases using consortia-level meta-analytic data. This risk score was associated with increased risk of T2D (p = 4.3×10(-3), n = 22,044), increased triglycerides (p = 2.6×10(-14), n = 93,440), increased waist-to-hip ratio (p = 1.8×10(-5), n = 77,167), increased glucose two hours post oral glucose tolerance testing (p = 4.4×10(-3), n = 15,234), increased fasting insulin (p = 0.015, n = 48,238), but with lower in HDL-cholesterol concentrations (p = 4.5×10(-13), n = 96,748) and decreased BMI (p = 1.4×10(-4), n = 121,335). These findings identify novel genetic determinants of adiponectin levels, which, taken together, influence risk of T2D and markers of insulin resistance.

The neural stem cell fate determinant TLX promotes tumorigenesis and genesis of cells resembling glioma stem cells.

Science.gov (United States)

Park, Hyo-Jung; Kim, Jun-Kyum; Jeon, Hye-Min; Oh, Se-Yeong; Kim, Sung-Hak; Nam, Do-Hyun; Kim, Hyunggee

2010-11-01

A growing body of evidence indicates that deregulation of stem cell fate determinants is a hallmark of many types of malignancies. The neural stem cell fate determinant TLX plays a pivotal role in neurogenesis in the adult brain by maintaining neural stem cells. Here, we report a tumorigenic role of TLX in brain tumor initiation and progression. Increased TLX expression was observed in a number of glioma cells and glioma stem cells, and correlated with poor survival of patients with gliomas. Ectopic expression of TLX in the U87MG glioma cell line and Ink4a/Arf-deficient mouse astrocytes (Ink4a/Arf(-/-) astrocytes) induced cell proliferation with a concomitant increase in cyclin D expression, and accelerated foci formation in soft agar and tumor formation in in vivo transplantation assays. Furthermore, overexpression of TLX in Ink4a/Arf(-/-) astrocytes inhibited cell migration and invasion and promoted neurosphere formation and Nestin expression, which are hallmark characteristics of glioma stem cells, under stem cell culture conditions. Our results indicate that TLX is involved in glioma stem cell genesis and represents a potential therapeutic target for this type of malignancy.

Inheritance of microsatellite loci in the polyploid lake sturgeon (Acipenser fulvescens)

Science.gov (United States)

Pyatskowit, J.D.; Krueger, C.C.; Kincaid, H.L.; May, B.

2001-01-01

Inheritance in the expression of amplicons for four microsatellite primer pairs was determined using 10 families created from gametes of wild lake sturgeon (Acipenser fulvescens). Loci Afu34 and Afu68 expressed a maximum of two even-intensity bands per individual and had progeny genotype ratios that fit disomic inheritance (P > 0.05). Some variation exhibited at Afu34 and Afu68 was attributable to a null allele. Genotype expression at both loci also indicated that one female parent had transmitted unreduced gametes. Primer Afu39 amplified products that exhibited four gene doses, where genotype counts fit expected ratios for disomic inheritance (P > 0.05) indicating amplification of products from two disomic loci that share alleles. Meiotic drive was evident at the Afu39 loci based on a test for random segregation (P inheritance based on a single progeny potentially produced by a double reduction gamete. No evidence for proposed octoploid inheritance was observed.

Genomic structure and evolution of the mating type locus in the green seaweed Ulva partita.

Science.gov (United States)

Yamazaki, Tomokazu; Ichihara, Kensuke; Suzuki, Ryogo; Oshima, Kenshiro; Miyamura, Shinichi; Kuwano, Kazuyoshi; Toyoda, Atsushi; Suzuki, Yutaka; Sugano, Sumio; Hattori, Masahira; Kawano, Shigeyuki

2017-09-15

The evolution of sex chromosomes and mating loci in organisms with UV systems of sex/mating type determination in haploid phases via genes on UV chromosomes is not well understood. We report the structure of the mating type (MT) locus and its evolutionary history in the green seaweed Ulva partita, which is a multicellular organism with an isomorphic haploid-diploid life cycle and mating type determination in the haploid phase. Comprehensive comparison of a total of 12.0 and 16.6 Gb of genomic next-generation sequencing data for mt - and mt + strains identified highly rearranged MT loci of 1.0 and 1.5 Mb in size and containing 46 and 67 genes, respectively, including 23 gametologs. Molecular evolutionary analyses suggested that the MT loci diverged over a prolonged period in the individual mating types after their establishment in an ancestor. A gene encoding an RWP-RK domain-containing protein was found in the mt - MT locus but was not an ortholog of the chlorophycean mating type determination gene MID. Taken together, our results suggest that the genomic structure and its evolutionary history in the U. partita MT locus are similar to those on other UV chromosomes and that the MT locus genes are quite different from those of Chlorophyceae.

Association of Genetic Loci With Glucose Levels in Childhood and Adolescence A Meta-Analysis of Over 6,000 Children

DEFF Research Database (Denmark)

Barker, A.; Sharp, S. J.; Timpson, N. J.

2011-01-01

with fasting glucose were genotyped in six studies of children and adolescents of European origin, including over 6,000 boys and girls aged 9-16 years. We performed meta-analyses to test associations of individual SNPs and a weighted risk score of the 16 loci with fasting glucose. RESULTS-Nine loci were...... glucose loci. Children and adolescents carrying glucose-raising alleles of G6PC2, MTNR1B, GCK, and GLIS3 also showed reduced p-cell function, as indicated by homeostasis model assessment of beta-cell function. Analysis using a weighted risk score showed an increase [beta (95% CI)] in fasting glucose level....... In nondiabetic adults, fasting glucose changes little over time, and our results suggest that age-independent effects of fasting glucose loci contribute to long-term interindividual differences in glucose levels from childhood onwards. Diabetes 60:1805-1812, 2011...

Nonequivalence of classical MHC class I loci in ability to direct effective antiviral immunity.

Directory of Open Access Journals (Sweden)

Kevin D Pavelko

2012-02-01

Full Text Available Structural diversity in the peptide binding sites of the redundant classical MHC antigen presenting molecules is strongly selected in humans and mice. Although the encoded antigen presenting molecules overlap in antigen presenting function, differences in polymorphism at the MHC I A, B and C loci in humans and higher primates indicate these loci are not functionally equivalent. The structural basis of these differences is not known. We hypothesize that classical class I loci differ in their ability to direct effective immunity against intracellular pathogens. Using a picornavirus infection model and chimeric H-2 transgenes, we examined locus specific functional determinants distinguishing the ability of class I sister genes to direct effective anti viral immunity. Whereas, parental FVB and transgenic FVB mice expressing the H-2K(b gene are highly susceptible to persisting Theiler's virus infection within the CNS and subsequent demyelination, mice expressing the D(b transgene clear the virus and are protected from demyelination. Remarkably, animals expressing a chimeric transgene, comprised primarily of K(b but encoding the peptide binding domain of D(b, develop a robust anti viral CTL response yet fail to clear virus and develop significant demyelination. Differences in expression of the chimeric K(bα1α2D(b gene (low and D(b (high in the CNS of infected mice mirror expression levels of their endogenous H-2(q counterparts in FVB mice. These findings demonstrate that locus specific elements other than those specifying peptide binding and T cell receptor interaction can determine ability to clear virus infection. This finding provides a basis for understanding locus-specific differences in MHC polymorphism, characterized best in human populations.

Regulated gene expression in cultured type II cells of adult human lung

OpenAIRE

Ballard, Philip L.; Lee, Jae W.; Fang, Xiaohui; Chapin, Cheryl; Allen, Lennell; Segal, Mark R.; Fischer, Horst; Illek, Beate; Gonzales, Linda W.; Kolla, Venkatadri; Matthay, Michael A.

2010-01-01

Alveolar type II cells have multiple functions, including surfactant production and fluid clearance, which are critical for lung function. Differentiation of type II cells occurs in cultured fetal lung epithelial cells treated with dexamethasone plus cAMP and isobutylmethylxanthine (DCI) and involves increased expression of 388 genes. In this study, type II cells of human adult lung were isolated at ∼95% purity, and gene expression was determined (Affymetrix) before and after culturing 5 days...

Lineage relationship of prostate cancer cell types based on gene expression

Directory of Open Access Journals (Sweden)

Ware Carol B

2011-05-01

Full Text Available Abstract Background Prostate tumor heterogeneity is a major factor in disease management. Heterogeneity could be due to multiple cancer cell types with distinct gene expression. Of clinical importance is the so-called cancer stem cell type. Cell type-specific transcriptomes are used to examine lineage relationship among cancer cell types and their expression similarity to normal cell types including stem/progenitor cells. Methods Transcriptomes were determined by Affymetrix DNA array analysis for the following cell types. Putative prostate progenitor cell populations were characterized and isolated by expression of the membrane transporter ABCG2. Stem cells were represented by embryonic stem and embryonal carcinoma cells. The cancer cell types were Gleason pattern 3 (glandular histomorphology and pattern 4 (aglandular sorted from primary tumors, cultured prostate cancer cell lines originally established from metastatic lesions, xenografts LuCaP 35 (adenocarcinoma phenotype and LuCaP 49 (neuroendocrine/small cell carcinoma grown in mice. No detectable gene expression differences were detected among serial passages of the LuCaP xenografts. Results Based on transcriptomes, the different cancer cell types could be clustered into a luminal-like grouping and a non-luminal-like (also not basal-like grouping. The non-luminal-like types showed expression more similar to that of stem/progenitor cells than the luminal-like types. However, none showed expression of stem cell genes known to maintain stemness. Conclusions Non-luminal-like types are all representatives of aggressive disease, and this could be attributed to the similarity in overall gene expression to stem and progenitor cell types.

Seven newly identified loci for autoimmune thyroid disease.

Science.gov (United States)

Cooper, Jason D; Simmonds, Matthew J; Walker, Neil M; Burren, Oliver; Brand, Oliver J; Guo, Hui; Wallace, Chris; Stevens, Helen; Coleman, Gillian; Franklyn, Jayne A; Todd, John A; Gough, Stephen C L

2012-12-01

Autoimmune thyroid disease (AITD), including Graves' disease (GD) and Hashimoto's thyroiditis (HT), is one of the most common of the immune-mediated diseases. To further investigate the genetic determinants of AITD, we conducted an association study using a custom-made single-nucleotide polymorphism (SNP) array, the ImmunoChip. The SNP array contains all known and genotype-able SNPs across 186 distinct susceptibility loci associated with one or more immune-mediated diseases. After stringent quality control, we analysed 103 875 common SNPs (minor allele frequency >0.05) in 2285 GD and 462 HT patients and 9364 controls. We found evidence for seven new AITD risk loci (P test derived significance threshold), five at locations previously associated and two at locations awaiting confirmation, with other immune-mediated diseases.

Incorporation of covariates in simultaneous localization of two linked loci using affected relative pairs

Directory of Open Access Journals (Sweden)

Liang Kung-Yee

2010-07-01

Full Text Available Abstract Background Many dichotomous traits for complex diseases are often involved more than one locus and/or associated with quantitative biomarkers or environmental factors. Incorporating these quantitative variables into linkage analysis as well as localizing two linked disease loci simultaneously could therefore improve the efficiency in mapping genes. We extended the robust multipoint Identity-by-Descent (IBD approach with incorporation of covariates developed previously to simultaneously estimate two linked loci using different types of affected relative pairs (ARPs. Results We showed that the efficiency was enhanced by incorporating a quantitative covariate parametrically or non-parametrically while localizing two disease loci using ARPs. In addition to its help in identifying factors associated with the disease and in improving the efficiency in estimating disease loci, this extension also allows investigators to account for heterogeneity in risk-ratios for different ARPs. Data released from the collaborative study on the genetics of alcoholism (COGA for Genetic Analysis Workshop 14 (GAW 14 were used to illustrate the application of this extended method. Conclusions The simulation studies and example illustrated that the efficiency in estimating disease loci was demonstratively enhanced by incorporating a quantitative covariate and by using all relative pairs while mapping two linked loci simultaneously.

Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study

DEFF Research Database (Denmark)

Boesgaard, Trine Welløv; Gjesing, Anette Prior; Grarup, Niels

2009-01-01

BACKROUND: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been in...

Does the evolutionary conservation of microsatellite loci imply function?

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Shriver, M.D.; Deka, R.; Ferrell, R.E. [Univ. of Pittsburgh, PA (United States)] [and others

1994-09-01

Microsatellites are highly polymorphic tandem arrays of short (1-6 bp) sequence motifs which have been found widely distributed in the genomes of all eukaryotes. We have analyzed allele frequency data on 16 microsatellite loci typed in the great apes (human, chimp, orangutan, and gorilla). The majority of these loci (13) were isolated from human genomic libraries; three were cloned from chimpanzee genomic DNA. Most of these loci are not only present in all apes species, but are polymorphic with comparable levels of heterozygosity and have alleles which overlap in size. The extent of divergence of allele frequencies among these four species were studies using the stepwise-weighted genetic distance (Dsw), which was previously shown to conform to linearity with evolutionary time since divergence for loci where mutations exist in a stepwise fashion. The phylogenetic tree of the great apes constructed from this distance matrix was consistent with the expected topology, with a high bootstrap confidence (82%) for the human/chimp clade. However, the allele frequency distributions of these species are 10 times more similar to each other than expected when they were calibrated with a conservative estimate of the time since separation of humans and the apes. These results are in agreement with sequence-based surveys of microsatellites which have demonstrated that they are highly (90%) conserved over short periods of evolutionary time (< 10 million years) and moderately (30%) conserved over long periods of evolutionary time (> 60-80 million years). This evolutionary conservation has prompted some authors to speculate that there are functional constraints on microsatellite loci. In contrast, the presence of directional bias of mutations with constraints and/or selection against aberrant sized alleles can explain these results.

MLVA Typing of Streptococcus pneumoniae Isolates with Emphasis on Serotypes 14, 9N and 9V: Comparison of Previously Described Panels and Proposal of a Novel 7 VNTR Loci-Based Simplified Scheme.

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Costa, Natália S; Pinto, Tatiana C A; Merquior, Vânia L C; Castro, Luciana F S; da Rocha, Filomena S P; Morais, Jaqueline M; Peralta, José M; Teixeira, Lúcia M

2016-01-01

Streptococcus pneumoniae remains as an important cause of community-acquired bacterial infections, and the nasopharynx of asymptomatic carriers is the major reservoir of this microorganism. Pneumococcal strains of serotype 14 and serogroup 9 are among the most frequently isolated from both asymptomatic carriers and patients with invasive disease living in Brazil. Internationally disseminated clones belonging to such serotypes have been associated with the emergence and spread of antimicrobial resistance in our setting, highlighting the need for epidemiological tracking of these isolates. In this scenario, Multiple Loci VNTR Analysis (MLVA) has emerged as an alternative tool for the molecular characterization of pneumococci, in addition to more traditional techniques such as Multi-Locus Sequence Typing (MLST) and Pulsed-Field Gel Electrophoresis (PFGE). In the present study, 18 VNTR loci, as well as other previously described reduced MLVA panels (7 VNTR loci), were evaluated as tools to characterize pneumococcal strains of serotypes 14, 9N and 9V belonging to international and regional clones isolated in Brazil. The 18 VNTR loci panel was highly congruent with MLST and PFGE, being also useful for indicating the genetic relationship with international clones and for discriminating among strains with indistinguishable STs and PFGE profiles. Analysis of the results also allowed deducing a novel shorter 7 VNTR loci panel, keeping a high discriminatory power for isolates of the serotypes investigated and a high congruence level with MLST and PFGE. The newly proposed simplified panel was then evaluated for typing pneumococcal strains of other commonly isolated serotypes. The results indicate that MLVA is a faster and easier to perform, reliable approach for the molecular characterization of S. pneumoniae isolates, with potential for cost-effective application, especially in resource-limited countries.

Functional interrelationship between TFII-I and E2F transcription factors at specific cell cycle gene loci.

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Shen, Yong; Nar, Rukiye; Fan, Alex X; Aryan, Mahmoud; Hossain, Mir A; Gurumurthy, Aishwarya; Wassel, Paul C; Tang, Ming; Lu, Jianrong; Strouboulis, John; Bungert, Jörg

2018-01-01

Transcription factor TFII-I is a multifunctional protein implicated in the regulation of cell cycle and stress-response genes. Previous studies have shown that a subset of TFII-I associated genomic sites contained DNA-binding motifs for E2F family transcription factors. We analyzed the co-association of TFII-I and E2Fs in more detail using bioinformatics, chromatin immunoprecipitation, and co-immunoprecipitation experiments. The data show that TFII-I interacts with E2F transcription factors. Furthermore, TFII-I, E2F4, and E2F6 interact with DNA-regulatory elements of several genes implicated in the regulation of the cell cycle, including DNMT1, HDAC1, CDKN1C, and CDC27. Inhibition of TFII-I expression led to a decrease in gene expression and in the association of E2F4 and E2F6 with these gene loci in human erythroleukemia K562 cells. Finally, TFII-I deficiency reduced the proliferation of K562 cells and increased the sensitivity toward doxorubicin toxicity. The results uncover novel interactions between TFII-I and E2Fs and suggest that TFII-I mediates E2F function at specific cell cycle genes. © 2017 Wiley Periodicals, Inc.

Genome-wide association study identifies multiple susceptibility loci for multiple myeloma

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Mitchell, Jonathan S; Li, Ni; Weinhold, Niels

2016-01-01

Multiple myeloma (MM) is a plasma cell malignancy with a significant heritable basis. Genome-wide association studies have transformed our understanding of MM predisposition, but individual studies have had limited power to discover risk loci. Here we perform a meta-analysis of these GWAS, add a ...

Quantitative trait loci for maysin synthesis in maize (Zea mays L.) lines selected for high silk maysin content.

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Meyer, J D F; Snook, M E; Houchins, K E; Rector, B G; Widstrom, N W; McMullen, M D

2007-06-01

Maysin is a naturally occurring C-glycosyl flavone found in maize (Zea mays L.) silk tissue that confers resistance to corn earworm (Helicoverpa zea, Boddie). Recently, two new maize populations were derived for high silk maysin. The two populations were named the exotic populations of maize (EPM) and the southern inbreds of maize (SIM). Quantitative trait locus (QTL) analysis was employed to determine which loci were responsible for elevated maysin levels in inbred lines derived from the EPM and SIM populations. The candidate genes consistent with QTL position included the p (pericarp color), c2 (colorless2), whp1 (white pollen1) and in1 (intensifier1) loci. The role of these loci in controlling high maysin levels in silks was tested by expression analysis and use of the loci as genetic markers onto the QTL populations. These studies support p, c2 and whp1, but not in1, as loci controlling maysin. Through this study, we determined that the p locus regulates whp1 transcription and that increased maysin in these inbred lines was primarily due to alleles at both structural and regulatory loci promoting increased flux through the flavone pathway by increasing chalcone synthase activity.

Contribution of type 2 diabetes associated loci in the Arabic population from Tunisia: a case-control study

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Almawi Wassim Y

2009-04-01

Full Text Available Abstract Background Candidate gene and genome-wide association studies have both reproducibly identified several common Single Nucleotide Polymorphisms (SNPs that confer type 2 diabetes (T2D risk in European populations. Our aim was to evaluate the contribution to T2D of five of these established T2D-associated loci in the Arabic population from Tunisia. Methods A case-control design comprising 884 type 2 diabetic patients and 513 control subjects living in the East-Center of Tunisia was used to analyze the contribution to T2D of the following SNPs: E23K in KCNJ11/Kir6.2, K121Q in ENPP1, the -30G/A variant in the pancreatic β-cell specific promoter of Glucokinase, rs7903146 in TCF7L2 encoding transcription factor 7-like2, and rs7923837 in HHEX encoding the homeobox, hematopoietically expressed transcription factor. Results TCF7L2-rs7903146 T allele increased susceptibility to T2D (OR = 1.25 [1.06–1.47], P = 0.006 in our study population. This risk was 56% higher among subjects carrying the TT genotype in comparison to those carrying the CC genotype (OR = 1.56 [1.13–2.16], P = 0.002. No allelic or genotypic association with T2D was detected for the other studied polymorphisms. Conclusion In the Tunisian population, TCF7L2-rs7903146 T allele confers an increased risk of developing T2D as previously reported in the European population and many other ethnic groups. In contrast, none of the other tested SNPs that influence T2D risk in the European population was associated with T2D in the Tunisian Arabic population. An insufficient power to detect minor allelic contributions or genetic heterogeneity of T2D between different ethnic groups can explain these findings.

Diversity, Prevalence, and Longitudinal Occurrence of Type II Toxin-Antitoxin Systems of Pseudomonas aeruginosa Infecting Cystic Fibrosis Lungs

DEFF Research Database (Denmark)

Breum Andersen, Sandra; Ghoul, Melanie; Griffin, Ashleigh S.

2017-01-01

Type II toxin-antitoxin (TA) systems are most commonly composed of two genes encoding a stable toxin, which harms the cell, and an unstable antitoxin that can inactivate it. TA systems were initially characterized as selfish elements, but have recently gained attention for regulating general stress...... responses responsible for pathogen virulence, formation of drug-tolerant persister cells and biofilms—all implicated in causing recalcitrant chronic infections. We use a bioinformatics approach to explore the distribution and evolution of type II TA loci of the opportunistic pathogen, Pseudomonas aeruginosa...... in their core genome and a variable number of the remaining 22 on genomic islands; (2) limited mutations in core genome TA loci, suggesting they are not under negative selection; (3) no evidence for horizontal transmission of elements with TA systems between clone types within patients, despite their ability...

Stimulation of DNA synthesis in cultured rat alveolar type II cells

International Nuclear Information System (INIS)

Leslie, C.C.; McCormick-Shannon, K.; Robinson, P.C.; Mason, R.J.

1985-01-01

Restoration of the alveolar epithelium after injury is thought to be dependent on the proliferation of alveolar type II cells. To understand the factors that may be involved in promoting type II cell proliferation in vivo, we determined the effect of potential mitogens and culture substrata on DNA synthesis in rat alveolar type II cells in primary culture. Type II cells cultured in basal medium containing 10% fetal bovine serum (FBS) exhibited essentially no DNA synthesis. Factors that stimulated 3 H-thymidine incorporation included cholera toxin, epidermal growth factor, and rat serum. The greatest degree of stimulation was achieved by plating type II cells on an extracellular matrix prepared from bovine corneal endothelial cells and then by culturing the pneumocytes in medium containing rat serum, cholera toxin, insulin, and epidermal growth factor. Under conditions of stimulation of 3 H-thymidine incorporation there was an increased DNA content per culture dish but no increase in cell number. The ability of various culture conditions to promote DNA synthesis in type II cells was verified by autoradiography. Type II cells were identified by the presence of cytoplasmic inclusions, which were visualized by tannic acid staining before autoradiography. These results demonstrate the importance of soluble factors and culture substratum in stimulating DNA synthesis in rat alveolar type II cells in primary culture

Evidence of gene-gene interaction and age-at-diagnosis effects in type 1 diabetes

DEFF Research Database (Denmark)

Howson, Joanna M M; Cooper, Jason D; Smyth, Deborah J

2012-01-01

The common genetic loci that independently influence the risk of type 1 diabetes have largely been determined. Their interactions with age-at-diagnosis of type 1 diabetes, sex, or the major susceptibility locus, HLA class II, remain mostly unexplored. A large collection of more than 14,866 type 1...

Comparative analysis of the mating-type loci from Neurospora crassa and Sordaria macrospora: identification of novel transcribed ORFs.

Science.gov (United States)

Pöggeler, S; Kück, U

2000-03-01

The mating-type locus controls mating and sexual development in filamentous ascomycetes. In the heterothallic ascomycete Neurospora crassa, the genes that confer mating behavior comprise dissimilar DNA sequences (idiomorphs) in the mat a and mat A mating partners. In the homothallic fungus Sordaria macrospora, sequences corresponding to both idiomorphs are located contiguously in the mating-type locus, which contains one chimeric gene, Smt A-3, that includes sequences which are similar to sequences found at the mat A and mat a mating-type idiomorphs in N. crassa. In this study, we describe the comparative transcriptional analysis of the chimeric mating-type region of S. macrospora and the corresponding region of the N. crassa mat a idiomorph. By means of RT-PCR experiments, we identified novel intervening sequences in the mating-type loci of both ascomycetes and, hence, concluded that an additional ORF, encoding a putative polypeptide of 79 amino acids, is present in the N. crassa mat a idiomorph. Furthermore, our analysis revealed co-transcription of the novel gene with the mat a-1 gene in N. crassa. The same mode of transcription was found in the corresponding mating-type region of S. macrospora, where the chimeric Smt A-3 gene is co-transcribed with the mat a-specific Smt a-1 gene. Analysis of a Smt A-3 cDNA revealed optional splicing of two introns. We believe that this is the first report of co-transcription of protein-encoding nuclear genes in filamentous fungi. Possible functions of the novel ORFs in regulating mating-type gene expression are discussed.

Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes

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Morris, Andrew P; Voight, Benjamin F; Teslovich, Tanya M; Ferreira, Teresa; Segrè, Ayellet V; Steinthorsdottir, Valgerdur; Strawbridge, Rona J; Khan, Hassan; Grallert, Harald; Mahajan, Anubha; Prokopenko, Inga; Kang, Hyun Min; Dina, Christian; Esko, Tonu; Fraser, Ross M; Kanoni, Stavroula; Kumar, Ashish; Lagou, Vasiliki; Langenberg, Claudia; Luan, Jian'an; Lindgren, Cecilia M; Müller-Nurasyid, Martina; Pechlivanis, Sonali; Rayner, N William; Scott, Laura J; Wiltshire, Steven; Yengo, Loic; Kinnunen, Leena; Rossin, Elizabeth J; Raychaudhuri, Soumya; Johnson, Andrew D; Dimas, Antigone S; Loos, Ruth J F; Vedantam, Sailaja; Chen, Han; Florez, Jose C; Fox, Caroline; Liu, Ching-Ti; Rybin, Denis; Couper, David J; Kao, Wen Hong L; Li, Man; Cornelis, Marilyn C; Kraft, Peter; Sun, Qi; van Dam, Rob M; Stringham, Heather M; Chines, Peter S; Fischer, Krista; Fontanillas, Pierre; Holmen, Oddgeir L; Hunt, Sarah E; Jackson, Anne U; Kong, Augustine; Lawrence, Robert; Meyer, Julia; Perry, John RB; Platou, Carl GP; Potter, Simon; Rehnberg, Emil; Robertson, Neil; Sivapalaratnam, Suthesh; Stančáková, Alena; Stirrups, Kathleen; Thorleifsson, Gudmar; Tikkanen, Emmi; Wood, Andrew R; Almgren, Peter; Atalay, Mustafa; Benediktsson, Rafn; Bonnycastle, Lori L; Burtt, Noël; Carey, Jason; Charpentier, Guillaume; Crenshaw, Andrew T; Doney, Alex S F; Dorkhan, Mozhgan; Edkins, Sarah; Emilsson, Valur; Eury, Elodie; Forsen, Tom; Gertow, Karl; Gigante, Bruna; Grant, George B; Groves, Christopher J; Guiducci, Candace; Herder, Christian; Hreidarsson, Astradur B; Hui, Jennie; James, Alan; Jonsson, Anna; Rathmann, Wolfgang; Klopp, Norman; Kravic, Jasmina; Krjutškov, Kaarel; Langford, Cordelia; Leander, Karin; Lindholm, Eero; Lobbens, Stéphane; Männistö, Satu; Mirza, Ghazala; Mühleisen, Thomas W; Musk, Bill; Parkin, Melissa; Rallidis, Loukianos; Saramies, Jouko; Sennblad, Bengt; Shah, Sonia; Sigurðsson, Gunnar; Silveira, Angela; Steinbach, Gerald; Thorand, Barbara; Trakalo, Joseph; Veglia, Fabrizio; Wennauer, Roman; Winckler, Wendy; Zabaneh, Delilah; Campbell, Harry; van Duijn, Cornelia; Uitterlinden89-, Andre G; Hofman, Albert; Sijbrands, Eric; Abecasis, Goncalo R; Owen, Katharine R; Zeggini, Eleftheria; Trip, Mieke D; Forouhi, Nita G; Syvänen, Ann-Christine; Eriksson, Johan G; Peltonen, Leena; Nöthen, Markus M; Balkau, Beverley; Palmer, Colin N A; Lyssenko, Valeriya; Tuomi, Tiinamaija; Isomaa, Bo; Hunter, David J; Qi, Lu; Shuldiner, Alan R; Roden, Michael; Barroso, Ines; Wilsgaard, Tom; Beilby, John; Hovingh, Kees; Price, Jackie F; Wilson, James F; Rauramaa, Rainer; Lakka, Timo A; Lind, Lars; Dedoussis, George; Njølstad, Inger; Pedersen, Nancy L; Khaw, Kay-Tee; Wareham, Nicholas J; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Korpi-Hyövälti, Eeva; Saltevo, Juha; Laakso, Markku; Kuusisto, Johanna; Metspalu, Andres; Collins, Francis S; Mohlke, Karen L; Bergman, Richard N; Tuomilehto, Jaakko; Boehm, Bernhard O; Gieger, Christian; Hveem, Kristian; Cauchi, Stephane; Froguel, Philippe; Baldassarre, Damiano; Tremoli, Elena; Humphries, Steve E; Saleheen, Danish; Danesh, John; Ingelsson, Erik; Ripatti, Samuli; Salomaa, Veikko; Erbel, Raimund; Jöckel, Karl-Heinz; Moebus, Susanne; Peters, Annette; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Morris, Andrew D; Donnelly, Peter J; Frayling, Timothy M; Hattersley, Andrew T; Boerwinkle, Eric; Melander, Olle; Kathiresan, Sekar; Nilsson, Peter M; Deloukas, Panos; Thorsteinsdottir, Unnur; Groop, Leif C; Stefansson, Kari; Hu, Frank; Pankow, James S; Dupuis, Josée; Meigs, James B; Altshuler, David; Boehnke, Michael; McCarthy, Mark I

2012-01-01

To extend understanding of the genetic architecture and molecular basis of type 2 diabetes (T2D), we conducted a meta-analysis of genetic variants on the Metabochip involving 34,840 cases and 114,981 controls, overwhelmingly of European descent. We identified ten previously unreported T2D susceptibility loci, including two demonstrating sex-differentiated association. Genome-wide analyses of these data are consistent with a long tail of further common variant loci explaining much of the variation in susceptibility to T2D. Exploration of the enlarged set of susceptibility loci implicates several processes, including CREBBP-related transcription, adipocytokine signalling and cell cycle regulation, in diabetes pathogenesis. PMID:22885922

Modularization and epistatic hierarchy determine homeostatic actions of multiple blood pressure quantitative trait loci.

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Chauvet, Cristina; Crespo, Kimberley; Ménard, Annie; Roy, Julie; Deng, Alan Y

2013-11-15

Hypertension, the most frequently diagnosed clinical condition world-wide, predisposes individuals to morbidity and mortality, yet its underlying pathological etiologies are poorly understood. So far, a large number of quantitative trait loci (QTLs) have been identified in both humans and animal models, but how they function together in determining overall blood pressure (BP) in physiological settings is unknown. Here, we systematically and comprehensively performed pair-wise comparisons of individual QTLs to create a global picture of their functionality in an inbred rat model. Rather than each of numerous QTLs contributing to infinitesimal BP increments, a modularized pattern arises: two epistatic 'blocks' constitute basic functional 'units' for nearly all QTLs, designated as epistatic module 1 (EM1) and EM2. This modularization dictates the magnitude and scope of BP effects. Any EM1 member can contribute to BP additively to that of EM2, but not to those of the same module. Members of each EM display epistatic hierarchy, which seems to reflect a related functional pathway. Rat homologues of 11 human BP QTLs belong to either EM1 or EM2. Unique insights emerge into the novel genetic mechanism and hierarchy determining BP in the Dahl salt-sensitive SS/Jr (DSS) rat model that implicate a portion of human QTLs. Elucidating the pathways underlying EM1 and EM2 may reveal the genetic regulation of BP.

Single-channel L-type Ca2+ currents in chicken embryo semicircular canal type I and type II hair cells.

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Zampini, Valeria; Valli, Paolo; Zucca, Giampiero; Masetto, Sergio

2006-08-01

Few data are available concerning single Ca channel properties in inner ear hair cells and particularly none in vestibular type I hair cells. By using the cell-attached configuration of the patch-clamp technique in combination with the semicircular canal crista slice preparation, we determined the elementary properties of voltage-dependent Ca channels in chicken embryo type I and type II hair cells. The pipette solutions included Bay K 8644. With 70 mM Ba(2+) in the patch pipette, Ca channel activity appeared as very brief openings at -60 mV. Ca channel properties were found to be similar in type I and type II hair cells; therefore data were pooled. The mean inward current amplitude was -1.3 +/- 0.1 (SD) pA at - 30 mV (n = 16). The average slope conductance was 21 pS (n = 20). With 5 mM Ba(2+) in the patch pipette, very brief openings were already detectable at -80 mV. The mean inward current amplitude was -0.7 +/- 0.2 pA at -40 mV (n = 9). The average slope conductance was 11 pS (n = 9). The mean open time and the open probability increased significantly with depolarization. Ca channel activity was still present and unaffected when omega-agatoxin IVA (2 microM) and omega-conotoxin GVIA (3.2 microM) were added to the pipette solution. Our results show that types I and II hair cells express L-type Ca channels with similar properties. Moreover, they suggest that in vivo Ca(2+) influx might occur at membrane voltages more negative than -60 mV.

EXPRESSION OF GENETIC LOCI IN THE PERIPHERAL BLOOD MONONUCLEAR FRACTION FROM PATIENTS WITH PROSTATE CANCER

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M. I. Kogan

2014-08-01

Full Text Available The early diagnosis and radical treatment of aggressive prostate cancers (PC is an effective way of improving survival and quality of life in patients. To develop mini-invasive tests is one of the ways of solving the problem. The cells of a peripheral blood mononuclear fraction in the expression patterns of their genetic loci reflect the presence or absence of cancers, including information on therapeutic effectiveness. RT-PRC was used to study the relative expression of 15 genetic loci in a chromosome and one locus of mitochondrial DNA in the cells of the peripheral blood mononuclear fraction in patients with PC or benign prostate hyperplasia and in healthy men. The genetic locus patterns whose change may be of informative value for differential diagnosis in patients with different stages of PC were revealed. The authors studied the relationship and showed the prognostic role and non-relationship of the altered transcriptional activity of loci in the TP53, GSTP1, and IL10 genes in PC to the changes in prostate-specific antigen the level with 90 % specificity and 93 % specificity.

A revised nomenclature for transcribed human endogenous retroviral loci

Science.gov (United States)

2011-01-01

Background Endogenous retroviruses (ERVs) and ERV-like sequences comprise 8% of the human genome. A hitherto unknown proportion of ERV loci are transcribed and thus contribute to the human transcriptome. A small proportion of these loci encode functional proteins. As the role of ERVs in normal and diseased biological processes is not yet established, transcribed ERV loci are of particular interest. As more transcribed ERV loci are likely to be identified in the near future, the development of a systematic nomenclature is important to ensure that all information on each locus can be easily retrieved. Results Here we present a revised nomenclature of transcribed human endogenous retroviral loci that sorts loci into groups based on Repbase classifications. Each symbol is of the format ERV + group symbol + unique number. Group symbols are based on a mixture of Repbase designations and well-supported symbols used in the literature. The presented guidelines will allow newly identified loci to be easily incorporated into the scheme. Conclusions The naming system will be employed by the HUGO Gene Nomenclature Committee for naming transcribed human ERV loci. We hope that the system will contribute to clarifying a certain aspect of a sometimes confusing nomenclature for human endogenous retroviruses. The presented system may also be employed for naming transcribed loci of human non-ERV repeat loci. PMID:21542922

Genetic analysis of 20 autosomal STR loci in the Miao ethnic group from Yunnan Province, Southwest China.

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Zhang, Xiufeng; Hu, Liping; Du, Lei; Nie, Aiting; Rao, Min; Pang, Jing Bo; Xiran, Zeng; Nie, Shengjie

2017-05-01

The genetic polymorphisms of 20 autosomal short tandem repeat (STR) loci included in the PowerPlex ® 21 kit were evaluated from 748 unrelated healthy individuals of the Miao ethnic minority living in the Yunnan province in southwestern China. All of the loci reached Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. The genetic relationship between the Miao population and other Chinese populations were also estimated. The combined discrimination power and probability of excluding paternity of the 20 STR loci were 0.999 999 999 999 999 999 999 991 26 and 0.999 999 975, respectively. The results suggested that the 20 STR loci were highly polymorphic, which makes them suitable for forensic personal identification and paternity testing. Copyright © 2017 Elsevier B.V. All rights reserved.

Murine Lupus Susceptibility Locus Sle2 Activates DNA-Reactive B Cells through Two Sub-Loci with Distinct Phenotypes

Science.gov (United States)

Zeumer, Leilani; Sang, Allison; Niu, Haitao; Morel, Laurence

2010-01-01

The NZM2410-derived Sle2 lupus susceptibility locus induces an abnormal B cell differentiation which most prominently leads to the expansion of autoreactive B1a cells. We have mapped the expansion of B1a cells to three Sle2 sub-loci, Sle2a, Sle2b, and Sle2c. Sle2 also enhances the breach of B cell tolerance to nuclear antigens in the 56R anti-DNA immunoglobulin transgenic (Tg) model. This study used the Sle2 sub-congenic strains to map the activation of 56R Tg B cells. Sle2c strongly sustained the breach of tolerance and the activation of anti-DNA B cells. The production of Tg-encoded anti-DNA antibodies was more modest in Sle2a expressing mice, but Sle2a was responsible for the recruitment for Tg B cells to the marginal zone, a phenotype that has been found for 56R Tg B cells in mice expressing the whole Sle2 interval. In addition, Sle2a promoted the production of endogenously encoded anti-DNA antibodies. Overall, this study showed that at least two Sle2 genes are involved in the activation of anti-DNA B cells, and excluded more than two-thirds of the Sle2 interval from contributing to this phenotype. This constitutes an important step toward the identification of novel genes that play a critical role in B cell tolerance. PMID:21270826

Mammalian transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes and are predicted to act as transcriptional activator hubs.

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Joshi, Anagha

2014-12-30

Transcriptional hotspots are defined as genomic regions bound by multiple factors. They have been identified recently as cell type specific enhancers regulating developmentally essential genes in many species such as worm, fly and humans. The in-depth analysis of hotspots across multiple cell types in same species still remains to be explored and can bring new biological insights. We therefore collected 108 transcription-related factor (TF) ChIP sequencing data sets in ten murine cell types and classified the peaks in each cell type in three groups according to binding occupancy as singletons (low-occupancy), combinatorials (mid-occupancy) and hotspots (high-occupancy). The peaks in the three groups clustered largely according to the occupancy, suggesting priming of genomic loci for mid occupancy irrespective of cell type. We then characterized hotspots for diverse structural functional properties. The genes neighbouring hotspots had a small overlap with hotspot genes in other cell types and were highly enriched for cell type specific function. Hotspots were enriched for sequence motifs of key TFs in that cell type and more than 90% of hotspots were occupied by pioneering factors. Though we did not find any sequence signature in the three groups, the H3K4me1 binding profile had bimodal peaks at hotspots, distinguishing hotspots from mono-modal H3K4me1 singletons. In ES cells, differentially expressed genes after perturbation of activators were enriched for hotspot genes suggesting hotspots primarily act as transcriptional activator hubs. Finally, we proposed that ES hotspots might be under control of SetDB1 and not DNMT for silencing. Transcriptional hotspots are enriched for tissue specific enhancers near cell type specific highly expressed genes. In ES cells, they are predicted to act as transcriptional activator hubs and might be under SetDB1 control for silencing.

Synthesis of Heparan Sulfate with Cyclophilin B-binding Properties Is Determined by Cell Type-specific Expression of Sulfotransferases*

Science.gov (United States)

Deligny, Audrey; Denys, Agnès; Marcant, Adeline; Melchior, Aurélie; Mazurier, Joël; van Kuppevelt, Toin H.; Allain, Fabrice

2010-01-01

Cyclophilin B (CyPB) induces migration and adhesion of T lymphocytes via a mechanism that requires interaction with 3-O-sulfated heparan sulfate (HS). HS biosynthesis is a complex process with many sulfotransferases involved. N-Deacetylases/N-sulfotransferases are responsible for N-sulfation, which is essential for subsequent modification steps, whereas 3-O-sulfotransferases (3-OSTs) catalyze the least abundant modification. These enzymes are represented by several isoforms, which differ in term of distribution pattern, suggesting their involvement in making tissue-specific HS. To elucidate how the specificity of CyPB binding is determined, we explored the relationships between the expression of these sulfotransferases and the generation of HS motifs with CyPB-binding properties. We demonstrated that high N-sulfate density and the presence of 2-O- and 3-O-sulfates determine binding of CyPB, as evidenced by competitive experiments with heparin derivatives, soluble HS, and anti-HS antibodies. We then showed that target cells, i.e. CD4+ lymphocyte subsets, monocytes/macrophages, and related cell lines, specifically expressed high levels of NDST2 and 3-OST3 isoforms. Silencing the expression of NDST1, NDST2, 2-OST, and 3-OST3 by RNA interference efficiently decreased binding and activity of CyPB, thus confirming their involvement in the biosynthesis of binding sequences for CyPB. Moreover, we demonstrated that NDST1 was able to partially sulfate exogenous substrate in the absence of NDST2 but not vice versa, suggesting that both isoenzymes do not have redundant activities but do have rather complementary activities in making N-sulfated sequences with CyPB-binding properties. Altogether, these results suggest a regulatory mechanism in which cell type-specific expression of certain HS sulfotransferases determines the specific binding of CyPB to target cells. PMID:19940140

Synthesis of heparan sulfate with cyclophilin B-binding properties is determined by cell type-specific expression of sulfotransferases.

Science.gov (United States)

Deligny, Audrey; Denys, Agnès; Marcant, Adeline; Melchior, Aurélie; Mazurier, Joël; van Kuppevelt, Toin H; Allain, Fabrice

2010-01-15

Cyclophilin B (CyPB) induces migration and adhesion of T lymphocytes via a mechanism that requires interaction with 3-O-sulfated heparan sulfate (HS). HS biosynthesis is a complex process with many sulfotransferases involved. N-Deacetylases/N-sulfotransferases are responsible for N-sulfation, which is essential for subsequent modification steps, whereas 3-O-sulfotransferases (3-OSTs) catalyze the least abundant modification. These enzymes are represented by several isoforms, which differ in term of distribution pattern, suggesting their involvement in making tissue-specific HS. To elucidate how the specificity of CyPB binding is determined, we explored the relationships between the expression of these sulfotransferases and the generation of HS motifs with CyPB-binding properties. We demonstrated that high N-sulfate density and the presence of 2-O- and 3-O-sulfates determine binding of CyPB, as evidenced by competitive experiments with heparin derivatives, soluble HS, and anti-HS antibodies. We then showed that target cells, i.e. CD4+ lymphocyte subsets, monocytes/macrophages, and related cell lines, specifically expressed high levels of NDST2 and 3-OST3 isoforms. Silencing the expression of NDST1, NDST2, 2-OST, and 3-OST3 by RNA interference efficiently decreased binding and activity of CyPB, thus confirming their involvement in the biosynthesis of binding sequences for CyPB. Moreover, we demonstrated that NDST1 was able to partially sulfate exogenous substrate in the absence of NDST2 but not vice versa, suggesting that both isoenzymes do not have redundant activities but do have rather complementary activities in making N-sulfated sequences with CyPB-binding properties. Altogether, these results suggest a regulatory mechanism in which cell type-specific expression of certain HS sulfotransferases determines the specific binding of CyPB to target cells.

The fusion protein of wild-type canine distemper virus is a major determinant of persistent infection

International Nuclear Information System (INIS)

Plattet, Philippe; Rivals, Jean-Paul; Zuber, BenoIt; Brunner, Jean-Marc; Zurbriggen, Andreas; Wittek, Riccardo

2005-01-01

The wild-type A75/17 canine distemper virus (CDV) strain induces a persistent infection in the central nervous system but infects cell lines very inefficiently. In contrast, the genetically more distant Onderstepoort CDV vaccine strain (OP-CDV) induces extensive syncytia formation. Here, we investigated the roles of wild-type fusion (F WT ) and attachment (H WT ) proteins in Vero cells expressing, or not, the canine SLAM receptor by transfection experiments and by studying recombinants viruses expressing different combinations of wild-type and OP-CDV glycoproteins. We show that low fusogenicity is not due to a defect of the envelope proteins to reach the cell surface and that H WT determines persistent infection in a receptor-dependent manner, emphasizing the role of SLAM as a potent enhancer of fusogenicity. However, importantly, F WT reduced cell-to-cell fusion independently of the cell surface receptor, thus demonstrating that the fusion protein of the neurovirulent A75/17-CDV strain plays a key role in determining persistent infection

Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes.

Science.gov (United States)

Ackermann, Amanda M; Wang, Zhiping; Schug, Jonathan; Naji, Ali; Kaestner, Klaus H

2016-03-01

Although glucagon-secreting α-cells and insulin-secreting β-cells have opposing functions in regulating plasma glucose levels, the two cell types share a common developmental origin and exhibit overlapping transcriptomes and epigenomes. Notably, destruction of β-cells can stimulate repopulation via transdifferentiation of α-cells, at least in mice, suggesting plasticity between these cell fates. Furthermore, dysfunction of both α- and β-cells contributes to the pathophysiology of type 1 and type 2 diabetes, and β-cell de-differentiation has been proposed to contribute to type 2 diabetes. Our objective was to delineate the molecular properties that maintain islet cell type specification yet allow for cellular plasticity. We hypothesized that correlating cell type-specific transcriptomes with an atlas of open chromatin will identify novel genes and transcriptional regulatory elements such as enhancers involved in α- and β-cell specification and plasticity. We sorted human α- and β-cells and performed the "Assay for Transposase-Accessible Chromatin with high throughput sequencing" (ATAC-seq) and mRNA-seq, followed by integrative analysis to identify cell type-selective gene regulatory regions. We identified numerous transcripts with either α-cell- or β-cell-selective expression and discovered the cell type-selective open chromatin regions that correlate with these gene activation patterns. We confirmed cell type-selective expression on the protein level for two of the top hits from our screen. The "group specific protein" (GC; or vitamin D binding protein) was restricted to α-cells, while CHODL (chondrolectin) immunoreactivity was only present in β-cells. Furthermore, α-cell- and β-cell-selective ATAC-seq peaks were identified to overlap with known binding sites for islet transcription factors, as well as with single nucleotide polymorphisms (SNPs) previously identified as risk loci for type 2 diabetes. We have determined the genetic landscape of

Delicate balance among three types of T cells in concurrent regulation of tumor immunity

Science.gov (United States)

Izhak, Liat; Ambrosino, Elena; Kato, Shingo; Parish, Stanley T.; O’Konek, Jessica J.; Weber, Hannah; Xia, Zheng; Venzon, David; Berzofsky, Jay A.; Terabe, Masaki

2013-01-01

The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here we addressed this question for Tregs and type II NKT cells in syngeneic models of colorectal and renal cancer. In mice with both type I and type II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Treg cells as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in three ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we demonstrated that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As cancer patients often have deficient type I NKT cell function, managing this delicate balance among three T cell subsets may be critical for the success of immunotherapy of human cancer. PMID:23319803

[SSR loci information analysis in transcriptome of Andrographis paniculata].

Science.gov (United States)

Li, Jun-Ren; Chen, Xiu-Zhen; Tang, Xiao-Ting; He, Rui; Zhan, Ruo-Ting

2018-06-01

To study the SSR loci information and develop molecular markers, a total of 43 683 Unigenes in transcriptome of Andrographis paniculata were used to explore SSR. The distribution frequency of SSR and the basic characteristics of repeat motifs were analyzed using MicroSAtellite software, SSR primers were designed by Primer 3.0 software and then validated by PCR. Moreover, the gene function analysis of SSR Unigene was obtained by Blast. The results showed that 14 135 SSR loci were found in the transcriptome of A. paniculata, which distributed in 9 973 Unigenes with a distribution frequency of 32.36%. Di-nucleotide and Tri-nucleotide repeat were the main types, accounted for 75.54% of all SSRs. The repeat motifs of AT/AT and CCG/CGG were the predominant repeat types of Di-nucleotide and Tri-nucleotide, respectively. A total of 4 740 pairs of SSR primers with the potential to produce polymorphism were designed for maker development. Ten pairs of primers in 20 pairs of randomly picked primers produced fragments with expected molecular size. The gene function of Unigenes containing SSR were mostly related to the basic metabolism function of A. paniculata. The SSR markers in transcriptome of A. paniculata show rich type, strong specificity and high potential of polymorphism, which will benefit the candidate gene mining and marker-assisted breeding. Copyright© by the Chinese Pharmaceutical Association.

Germline mutation rates at tandem repeat loci in DNA-repair deficient mice

International Nuclear Information System (INIS)

Barber, Ruth C.; Miccoli, Laurent; Buul, Paul P.W. van; Burr, Karen L.-A.; Duyn-Goedhart, Annemarie van; Angulo, Jaime F.; Dubrova, Yuri E.

2004-01-01

Mutation rates at two expanded simple tandem repeat (ESTR) loci were studied in the germline of non-exposed and irradiated severe combined immunodeficient (scid) and poly(ADP-ribose) polymerase (PARP-1 -/- ) deficient male mice. Non-exposed scid and PARP -/- male mice showed considerably elevated ESTR mutation rates, far higher than those in wild-type isogenic mice and other inbred strains. The irradiated scid and PARP-1 -/- male mice did not show any detectable increases in their mutation rate, whereas significant ESTR mutation induction was observed in the irradiated wild-type isogenic males. ESTR mutation spectra in the scid and PARP-1 -/- strains did not differ from those in the isogenic wild-type strains. Considering these data and the results of previous studies, we propose that a delay in repair of DNA damage in scid and PARP-1 -/- mice could result in replication fork pausing which, in turn, may affect ESTR mutation rate in the non-irradiated males. The lack of mutation induction in irradiated scid and PARP-1 -/- can be explained by the high cell killing effects of irradiation on the germline of deficient mice

Quantitative trait loci associated with the tocochromanol (vitamin E) pathway in barley

Science.gov (United States)

In this study, the Genome-Wide Association Studies approach was used to detect Quantitative Trait Loci associated with tocochromanol concentrations using a panel of 1,466 barley accessions. All major tocochromanol types- alpha-, beta-, delta-, gamma-tocopherol and tocotrienol- were assayed. We found...

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

Science.gov (United States)

Scott, Robert A; Lagou, Vasiliki; Welch, Ryan P; Wheeler, Eleanor; Montasser, May E; Luan, Jian’an; Mägi, Reedik; Strawbridge, Rona J; Rehnberg, Emil; Gustafsson, Stefan; Kanoni, Stavroula; Rasmussen-Torvik, Laura J; Yengo, Loïc; Lecoeur, Cecile; Shungin, Dmitry; Sanna, Serena; Sidore, Carlo; Johnson, Paul C D; Jukema, J Wouter; Johnson, Toby; Mahajan, Anubha; Verweij, Niek; Thorleifsson, Gudmar; Hottenga, Jouke-Jan; Shah, Sonia; Smith, Albert V; Sennblad, Bengt; Gieger, Christian; Salo, Perttu; Perola, Markus; Timpson, Nicholas J; Evans, David M; Pourcain, Beate St; Wu, Ying; Andrews, Jeanette S; Hui, Jennie; Bielak, Lawrence F; Zhao, Wei; Horikoshi, Momoko; Navarro, Pau; Isaacs, Aaron; O’Connell, Jeffrey R; Stirrups, Kathleen; Vitart, Veronique; Hayward, Caroline; Esko, Tönu; Mihailov, Evelin; Fraser, Ross M; Fall, Tove; Voight, Benjamin F; Raychaudhuri, Soumya; Chen, Han; Lindgren, Cecilia M; Morris, Andrew P; Rayner, Nigel W; Robertson, Neil; Rybin, Denis; Liu, Ching-Ti; Beckmann, Jacques S; Willems, Sara M; Chines, Peter S; Jackson, Anne U; Kang, Hyun Min; Stringham, Heather M; Song, Kijoung; Tanaka, Toshiko; Peden, John F; Goel, Anuj; Hicks, Andrew A; An, Ping; Müller-Nurasyid, Martina; Franco-Cereceda, Anders; Folkersen, Lasse; Marullo, Letizia; Jansen, Hanneke; Oldehinkel, Albertine J; Bruinenberg, Marcel; Pankow, James S; North, Kari E; Forouhi, Nita G; Loos, Ruth J F; Edkins, Sarah; Varga, Tibor V; Hallmans, Göran; Oksa, Heikki; Antonella, Mulas; Nagaraja, Ramaiah; Trompet, Stella; Ford, Ian; Bakker, Stephan J L; Kong, Augustine; Kumari, Meena; Gigante, Bruna; Herder, Christian; Munroe, Patricia B; Caulfield, Mark; Antti, Jula; Mangino, Massimo; Small, Kerrin; Miljkovic, Iva; Liu, Yongmei; Atalay, Mustafa; Kiess, Wieland; James, Alan L; Rivadeneira, Fernando; Uitterlinden, Andre G; Palmer, Colin N A; Doney, Alex S F; Willemsen, Gonneke; Smit, Johannes H; Campbell, Susan; Polasek, Ozren; Bonnycastle, Lori L; Hercberg, Serge; Dimitriou, Maria; Bolton, Jennifer L; Fowkes, Gerard R; Kovacs, Peter; Lindström, Jaana; Zemunik, Tatijana; Bandinelli, Stefania; Wild, Sarah H; Basart, Hanneke V; Rathmann, Wolfgang; Grallert, Harald; Maerz, Winfried; Kleber, Marcus E; Boehm, Bernhard O; Peters, Annette; Pramstaller, Peter P; Province, Michael A; Borecki, Ingrid B; Hastie, Nicholas D; Rudan, Igor; Campbell, Harry; Watkins, Hugh; Farrall, Martin; Stumvoll, Michael; Ferrucci, Luigi; Waterworth, Dawn M; Bergman, Richard N; Collins, Francis S; Tuomilehto, Jaakko; Watanabe, Richard M; de Geus, Eco J C; Penninx, Brenda W; Hofman, Albert; Oostra, Ben A; Psaty, Bruce M; Vollenweider, Peter; Wilson, James F; Wright, Alan F; Hovingh, G Kees; Metspalu, Andres; Uusitupa, Matti; Magnusson, Patrik K E; Kyvik, Kirsten O; Kaprio, Jaakko; Price, Jackie F; Dedoussis, George V; Deloukas, Panos; Meneton, Pierre; Lind, Lars; Boehnke, Michael; Shuldiner, Alan R; van Duijn, Cornelia M; Morris, Andrew D; Toenjes, Anke; Peyser, Patricia A; Beilby, John P; Körner, Antje; Kuusisto, Johanna; Laakso, Markku; Bornstein, Stefan R; Schwarz, Peter E H; Lakka, Timo A; Rauramaa, Rainer; Adair, Linda S; Smith, George Davey; Spector, Tim D; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Gudnason, Vilmundur; Kivimaki, Mika; Hingorani, Aroon; Keinanen-Kiukaanniemi, Sirkka M; Saaristo, Timo E; Boomsma, Dorret I; Stefansson, Kari; van der Harst, Pim; Dupuis, Josée; Pedersen, Nancy L; Sattar, Naveed; Harris, Tamara B; Cucca, Francesco; Ripatti, Samuli; Salomaa, Veikko; Mohlke, Karen L; Balkau, Beverley; Froguel, Philippe; Pouta, Anneli; Jarvelin, Marjo-Riitta; Wareham, Nicholas J; Bouatia-Naji, Nabila; McCarthy, Mark I; Franks, Paul W; Meigs, James B; Teslovich, Tanya M; Florez, Jose C; Langenberg, Claudia; Ingelsson, Erik; Prokopenko, Inga; Barroso, Inês

2012-01-01

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have raised the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q fasting insulin showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional follow-up of these newly discovered loci will further improve our understanding of glycemic control. PMID:22885924

Detection of quantitative trait loci in Danish Holstein cattle affecting clinical mastitis, somatic cell score, udder conformation traits, and assessment of associated effects on milk yield

DEFF Research Database (Denmark)

Lund, M S; Guldbrandtsen, B; Buitenhuis, A J

2008-01-01

The aim of this study was to 1) detect QTL across the cattle genome that influence the incidence of clinical mastitis and somatic cell score (SCS) in Danish Holsteins, and 2) characterize these QTL for pleiotropy versus multiple linked quantitative trait loci (QTL) when chromosomal regions...... affecting clinical mastitis were also affecting other traits in the Danish udder health index or milk production traits. The chromosomes were scanned using a granddaughter design where markers were typed for 19 to 34 grandsire families and 1,373 to 2,042 sons. A total of 356 microsatellites covering all 29...... autosomes were used in the scan. Among the across-family regression analyses, 16 showed chromosome-wide significance for the primary traits incidence of clinical mastitis in first (CM1), second (CM2), and third (CM3) lactations, and SCS. Regions of chromosomes 5, 6, 9, 11, 15, and 26 were found to affect CM...

eTumorType, An Algorithm of Discriminating Cancer Types for Circulating Tumor Cells or Cell-free DNAs in Blood

Directory of Open Access Journals (Sweden)

Jinfeng Zou

2017-04-01

Full Text Available With the technology development on detecting circulating tumor cells (CTCs and cell-free DNAs (cfDNAs in blood, serum, and plasma, non-invasive diagnosis of cancer becomes promising. A few studies reported good correlations between signals from tumor tissues and CTCs or cfDNAs, making it possible to detect cancers using CTCs and cfDNAs. However, the detection cannot tell which cancer types the person has. To meet these challenges, we developed an algorithm, eTumorType, to identify cancer types based on copy number variations (CNVs of the cancer founding clone. eTumorType integrates cancer hallmark concepts and a few computational techniques such as stochastic gradient boosting, voting, centroid, and leading patterns. eTumorType has been trained and validated on a large dataset including 18 common cancer types and 5327 tumor samples. eTumorType produced high accuracies (0.86–0.96 and high recall rates (0.79–0.92 for predicting colon, brain, prostate, and kidney cancers. In addition, relatively high accuracies (0.78–0.92 and recall rates (0.58–0.95 have also been achieved for predicting ovarian, breast luminal, lung, endometrial, stomach, head and neck, leukemia, and skin cancers. These results suggest that eTumorType could be used for non-invasive diagnosis to determine cancer types based on CNVs of CTCs and cfDNAs.

Type II heat-labile enterotoxins from 50 diverse Escherichia coli isolates belong almost exclusively to the LT-IIc family and may be prophage encoded.

Directory of Open Access Journals (Sweden)

Michael G Jobling

Full Text Available Some enterotoxigenic Escherichia coli (ETEC produce a type II heat-labile enterotoxin (LT-II that activates adenylate cyclase in susceptible cells but is not neutralized by antisera against cholera toxin or type I heat-labile enterotoxin (LT-I. LT-I variants encoded by plasmids in ETEC from humans and pigs have amino acid sequences that are ≥ 95% identical. In contrast, LT-II toxins are chromosomally encoded and are much more diverse. Early studies characterized LT-IIa and LT-IIb variants, but a novel LT-IIc was reported recently. Here we characterized the LT-II encoding loci from 48 additional ETEC isolates. Two encoded LT-IIa, none encoded LT-IIb, and 46 encoded highly related variants of LT-IIc. Phylogenetic analysis indicated that the predicted LT-IIc toxins encoded by these loci could be assigned to 6 subgroups. The loci corresponding to individual toxins within each subgroup had DNA sequences that were more than 99% identical. The LT-IIc subgroups appear to have arisen by multiple recombinational events between progenitor loci encoding LT-IIc1- and LT-IIc3-like variants. All loci from representative isolates encoding the LT-IIa, LT-IIb, and each subgroup of LT-IIc enterotoxins are preceded by highly-related genes that are between 80 and 93% identical to predicted phage lysozyme genes. DNA sequences immediately following the B genes differ considerably between toxin subgroups, but all are most closely related to genomic sequences found in predicted prophages. Together these data suggest that the LT-II loci are inserted into lambdoid type prophages that may or may not be infectious. These findings raise the possibility that production of LT-II enterotoxins by ETEC may be determined by phage conversion and may be activated by induction of prophage, in a manner similar to control of production of Shiga-like toxins by converting phages in isolates of enterohemmorhagic E. coli.

CRISPR-cas loci profiling of Cronobacter sakazakii pathovars.

Science.gov (United States)

Ogrodzki, Pauline; Forsythe, Stephen James

2016-12-01

Cronobacter sakazakii sequence types 1, 4, 8 and 12 are associated with outbreaks of neonatal meningitis and necrotizing enterocolitis infections. However clonality results in strains which are indistinguishable using conventional methods. This study investigated the use of clustered regularly interspaced short palindromic repeats (CRISPR)-cas loci profiling for epidemiological investigations. Seventy whole genomes of C. sakazakii strains from four clonal complexes which were widely distributed temporally, geographically and origin of source were profiled. All strains encoded the same type I-E subtype CRISPR-cas system with a total of 12 different CRISPR spacer arrays. This study demonstrated the greater discriminatory power of CRISPR spacer array profiling compared with multilocus sequence typing, which will be of use in source attribution during Cronobacter outbreak investigations.

T-cell depleted haploidentical three loci mismatched bone-marrow and peripheral blood stem cell transplantation in acute leukaemia patients

International Nuclear Information System (INIS)

Aristei, C.; Aversa, F.; Panizza, B.M.; Perrucci, E.; Barone, V.; Marafioti, L.; Raymondi, C.; Terenzi, A.; Martelli, M.F.; Latini, P.

1996-01-01

Objectives: Allogeneic bone-marrow transplantation (BMT) is an established treatment for many haematological malignancies. Unfortunately, most patients lack an HLA geno typically identical sibling and require an alternative donor, such as an HLA-haploidentical mismatched related donor, an HLA phenotypically matched or partially mismatched unrelated donor or an HLA-similar cord blood stem cell donor. However, these types of BMT increase the risk of graft-versus-host disease (GvHD), graft failure, delayed immuno reconstitution and fatal infection that observed after a sibling matched donor. Many centers are exploring the possibility of using donors other than matched sibling. Our approach has been to employ T-cell depleted mismatched haploidentical familial donor BMT to solve the problem of GvHD, a highly immuno- and myelo-suppressive conditioning regimen to reduce the incidence of graft failure and relapse, a graft inoculum plus G-CSF donor mobilized peripheral blood stem cells (PBSC) to overcome the host-versus-graft barrier. Patients and methods: Thirty-six patients (25 male, 11 female; median age 22 years, range 2-51) were treated with an allogeneic T-depleted haploidentical three loci mismatched bone-marrow and G-CSF mobilized PBSC transplantation from a familiar donor (18 siblings, 17 parents and 1 cousin) between March 1993 and June 1995. All had high-risk or advanced stage acute myeloid (12) or acute lymphoid (24) leukaemia; 18 were in haematological complete remission (CR) and 18 in chemo resistant relapse. Patients were conditioned with 8 Gy single dose TBI administered on day -5 at an instantaneous dose-rate of 13.4-31.7 cGy/min/midplane and average of 6.7-12.12 cGy/min/midplane. Shields were used to reduce the lung dose to 7 Gy in the first 23 cases and to 6 Gy in the last 13. 10 mg/Kg thiotepa were administered on day -4, 5 mg/Kg rabbit ATG from day -4 to day -1, 60 or 50 mg/Kg/cyclophosphamide on days -3 and -2. Bone-marrow and PBSC were infused on day

Analysis of individual cells identifies cell-to-cell variability following induction of cellular senescence.

Science.gov (United States)

Wiley, Christopher D; Flynn, James M; Morrissey, Christapher; Lebofsky, Ronald; Shuga, Joe; Dong, Xiao; Unger, Marc A; Vijg, Jan; Melov, Simon; Campisi, Judith

2017-10-01

Senescent cells play important roles in both physiological and pathological processes, including cancer and aging. In all cases, however, senescent cells comprise only a small fraction of tissues. Senescent phenotypes have been studied largely in relatively homogeneous populations of cultured cells. In vivo, senescent cells are generally identified by a small number of markers, but whether and how these markers vary among individual cells is unknown. We therefore utilized a combination of single-cell isolation and a nanofluidic PCR platform to determine the contributions of individual cells to the overall gene expression profile of senescent human fibroblast populations. Individual senescent cells were surprisingly heterogeneous in their gene expression signatures. This cell-to-cell variability resulted in a loss of correlation among the expression of several senescence-associated genes. Many genes encoding senescence-associated secretory phenotype (SASP) factors, a major contributor to the effects of senescent cells in vivo, showed marked variability with a subset of highly induced genes accounting for the increases observed at the population level. Inflammatory genes in clustered genomic loci showed a greater correlation with senescence compared to nonclustered loci, suggesting that these genes are coregulated by genomic location. Together, these data offer new insights into how genes are regulated in senescent cells and suggest that single markers are inadequate to identify senescent cells in vivo. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Identification of nine new susceptibility loci for testicular cancer, including variants near DAZL and PRDM14

Science.gov (United States)

Ruark, Elise; Seal, Sheila; McDonald, Heather; Zhang, Feng; Elliot, Anna; Lau, KingWai; Perdeaux, Elizabeth; Rapley, Elizabeth; Eeles, Rosalind; Peto, Julian; Kote-Jarai, Zsofia; Muir, Kenneth; Nsengimana, Jeremie; Shipley, Janet; Bishop, D. Timothy; Stratton, Michael R; Easton, Douglas F; Huddart, Robert A; Rahman, Nazneen; Turnbull, Clare

2013-01-01

Testicular germ cell tumor (TGCT) is the most common cancer in young men and is notable for its high familial risks1,2. To date, six loci associated with TGCT have been reported3-7. From GWAS analysis of 307,291 SNPs in 986 cases and 4,946 controls, we selected for follow-up 694 SNPs, which we genotyped in a further 1,064 TGCT cases and 10,082 controls from the UK. We identified SNPs at nine new loci showing association with TGCT (P<5×10−8), at 1q22, 1q24.1, 3p24.3, 4q24, 5q31.1, 8q13.3, 16q12.1, 17q22 and 21q22.3, which together account for an additional 4-6% of the familial risk of TGCT. The loci include genes plausibly related to TGCT development. PRDM14, at 8q13.3, is essential for early germ cell specification8 whilst DAZL, at 3p24.3, is required for regulation of germ cell development9. Furthermore, PITX1, at 5q31.1 regulates TERT expression, and is the third TGCT locus implicated in telomerase regulation10. PMID:23666240

Identification of multi-loci hubs from 4C-seq demonstrates the functional importance of simultaneous interactions.

Science.gov (United States)

Jiang, Tingting; Raviram, Ramya; Snetkova, Valentina; Rocha, Pedro P; Proudhon, Charlotte; Badri, Sana; Bonneau, Richard; Skok, Jane A; Kluger, Yuval

2016-10-14

Use of low resolution single cell DNA FISH and population based high resolution chromosome conformation capture techniques have highlighted the importance of pairwise chromatin interactions in gene regulation. However, it is unlikely that associations involving regulatory elements act in isolation of other interacting partners that also influence their impact. Indeed, the influence of multi-loci interactions remains something of an enigma as beyond low-resolution DNA FISH we do not have the appropriate tools to analyze these. Here we present a method that uses standard 4C-seq data to identify multi-loci interactions from the same cell. We demonstrate the feasibility of our method using 4C-seq data sets that identify known pairwise and novel tri-loci interactions involving the Tcrb and Igk antigen receptor enhancers. We further show that the three Igk enhancers, MiEκ, 3'Eκ and Edκ, interact simultaneously in this super-enhancer cluster, which add to our previous findings showing that loss of one element decreases interactions between all three elements as well as reducing their transcriptional output. These findings underscore the functional importance of simultaneous interactions and provide new insight into the relationship between enhancer elements. Our method opens the door for studying multi-loci interactions and their impact on gene regulation in other biological settings. © The Author(s) 2016. Published by Oxford University Press on behalf of Nucleic Acids Research.

Islet β cell failure in type 2 diabetes

Science.gov (United States)

Prentki, Marc; Nolan, Christopher J.

2006-01-01

The major focus of this Review is on the mechanisms of islet β cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of β cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of β cell mass and for enhanced β cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of “susceptible” islets and overall risk for T2D is reviewed. The likely mechanisms of β cell failure are discussed within the two broad categories: those with initiation and those with progression roles. PMID:16823478

Cell Type-Specific Chromatin Signatures Underline Regulatory DNA Elements in Human Induced Pluripotent Stem Cells and Somatic Cells.

Science.gov (United States)

Zhao, Ming-Tao; Shao, Ning-Yi; Hu, Shijun; Ma, Ning; Srinivasan, Rajini; Jahanbani, Fereshteh; Lee, Jaecheol; Zhang, Sophia L; Snyder, Michael P; Wu, Joseph C

2017-11-10

Regulatory DNA elements in the human genome play important roles in determining the transcriptional abundance and spatiotemporal gene expression during embryonic heart development and somatic cell reprogramming. It is not well known how chromatin marks in regulatory DNA elements are modulated to establish cell type-specific gene expression in the human heart. We aimed to decipher the cell type-specific epigenetic signatures in regulatory DNA elements and how they modulate heart-specific gene expression. We profiled genome-wide transcriptional activity and a variety of epigenetic marks in the regulatory DNA elements using massive RNA-seq (n=12) and ChIP-seq (chromatin immunoprecipitation combined with high-throughput sequencing; n=84) in human endothelial cells (CD31 + CD144 + ), cardiac progenitor cells (Sca-1 + ), fibroblasts (DDR2 + ), and their respective induced pluripotent stem cells. We uncovered 2 classes of regulatory DNA elements: class I was identified with ubiquitous enhancer (H3K4me1) and promoter (H3K4me3) marks in all cell types, whereas class II was enriched with H3K4me1 and H3K4me3 in a cell type-specific manner. Both class I and class II regulatory elements exhibited stimulatory roles in nearby gene expression in a given cell type. However, class I promoters displayed more dominant regulatory effects on transcriptional abundance regardless of distal enhancers. Transcription factor network analysis indicated that human induced pluripotent stem cells and somatic cells from the heart selected their preferential regulatory elements to maintain cell type-specific gene expression. In addition, we validated the function of these enhancer elements in transgenic mouse embryos and human cells and identified a few enhancers that could possibly regulate the cardiac-specific gene expression. Given that a large number of genetic variants associated with human diseases are located in regulatory DNA elements, our study provides valuable resources for deciphering

Delicate balance among three types of T cells in concurrent regulation of tumor immunity.

Science.gov (United States)

Izhak, Liat; Ambrosino, Elena; Kato, Shingo; Parish, Stanley T; O'Konek, Jessica J; Weber, Hannah; Xia, Zheng; Venzon, David; Berzofsky, Jay A; Terabe, Masaki

2013-03-01

The nature of the regulatory cell types that dominate in any given tumor is not understood at present. Here, we addressed this question for regulatory T cells (Treg) and type II natural killer T (NKT) cells in syngeneic models of colorectal and renal cancer. In mice with both type I and II NKT cells, or in mice with neither type of NKT cell, Treg depletion was sufficient to protect against tumor outgrowth. Surprisingly, in mice lacking only type I NKT cells, Treg blockade was insufficient for protection. Thus, we hypothesized that type II NKT cells may be neutralized by type I NKT cells, leaving Tregs as the primary suppressor, whereas in mice lacking type I NKT cells, unopposed type II NKT cells could suppress tumor immunity even when Tregs were blocked. We confirmed this hypothesis in 3 ways by reconstituting type I NKT cells as well as selectively blocking or activating type II NKT cells with antibody or the agonist sulfatide, respectively. In this manner, we showed that blockade of both type II NKT cells and Tregs is necessary to abrogate suppression of tumor immunity, but a third cell, the type I NKT cell, determines the balance between these regulatory mechanisms. As patients with cancer often have deficient type I NKT cell function, managing this delicate balance among 3 T-cell subsets may be critical for the success of immunotherapy for human cancer. ©2012 AACR.

[Association of aggressive behaviors of schizophrenia with short tandem repeats loci].

Science.gov (United States)

Yang, Chun; Ba, Huajie; Tan, Xingqi; Zhao, Hanqing; Zhang, Shuyou; Yu, Haiying

2017-12-10

To assess the association of short tandem repeats (STRs) loci with aggressive behaviors of schizophrenia. Blood samples from 123 schizophrenic patients with aggressive behaviors and 489 schizophrenic patients without aggressive behaviors were collected. DNA from all samples was amplified with a PowerPlex 21 system and separated by electrophoresis to determine the genotypes and allelic frequencies of 20 STR loci including D3S1368, D1S1656, D6S1043, D13S317, Penta E, D16S639, D18S51, D2S1338, CSF1PO, Penta D, TH01, vWA, D21S11, D7S820, D5S818, TPOX, D8S1179, D12S391, D19S433, and FGA. All of the 20 STR loci have reached Hardy-Weinberg equilibrium in both groups. A significant difference was found in allelic and genotypic frequencies of loci Penta D between the two groups (alleles: P=0.042; genotypes: P=0.014) but not for the remaining 19 loci (P> 0.05). Univariate analysis also showed a significant difference for allele 10 and genotypes 10-12 of Penta D between the two groups (P=0.0027, P=0.0001), with the OR being 1.81 (95%CI: 1.22-2.67) and 4.33 (95%CI: 1.95-9.59), respectively. Penta D may be associated with aggressive behaviors of schizophrenia. Allele 10 and genotypes 10-12 of Penta D may confer a risk for the disease.

Radioimmunoassay of type D oncovirus from continuous J-96 cells

International Nuclear Information System (INIS)

Vlasenkova, N.K.; Altshtejn, A.D.; Zhdanov, V.M.; Kitsak, V.Ya.

1978-01-01

The radioimmunoassay of the J-96 virus and an extract of J-96 cells in the homologous and heterologous systems aimed at detecting antigenic determinants of p25 of Mason-Pfizer virus and group-specific and interspecies antigenic determinants p30 of Rauscher leukaemia virus demonstrated that (1) J-96 virus contains a major internal protein immunologically identical with p25 protein of Mason-Pfizer virus based on the antigenic determinants detectable by the radioimmunoassay used; and (2) no interspecies antigenic determinants characteristic of the major internal protein of mammalian type C viruses were detectable in the J-96 virus or the J-96 cell extract. (author)

Estimation of loci involved in non-shattering of seeds in early rice domestication.

Science.gov (United States)

Ishikawa, Ryo; Nishimura, Akinori; Htun, Than Myint; Nishioka, Ryo; Oka, Yumi; Tsujimura, Yuki; Inoue, Chizuru; Ishii, Takashige

2017-04-01

Rice (Oryza sativa L.) is widely cultivated around the world and is known to be domesticated from its wild form, O. rufipogon. A loss of seed shattering is one of the most obvious phenotypic changes selected for during rice domestication. Previously, three seed-shattering loci, qSH1, sh4, and qSH3 were reported to be involved in non-shattering of seeds of Japonica-type cultivated rice, O. sativa cv. Nipponbare. In this study, we focused on non-shattering characteristics of O. sativa Indica cv. IR36 having functional allele at qSH1. We produced backcross recombinant inbred lines having chromosomal segments from IR36 in the genetic background of wild rice, O. rufipogon W630. Histological and quantitative trait loci analyses of abscission layer formation were conducted. In the analysis of quantitative trait loci, a strong peak was observed close to sh4. We, nevertheless, found that some lines showed complete abscission layer formation despite carrying the IR36 allele at sh4, implying that non-shattering of seeds of IR36 could be regulated by the combination of mutations at sh4 and other seed-shattering loci. We also genotyped qSH3, a recently identified seed-shattering locus. Lines that have the IR36 alleles at sh4 and qSH3 showed inhibition of abscission layer formation but the degree of seed shattering was different from that of IR36. On the basis of these results, we estimated that non-shattering of seeds in early rice domestication involved mutations in at least three loci, and these genetic materials produced in this study may help to identify novel seed-shattering loci.

TRICE - A program for reconstructing 3D reciprocal space and determining unit-cell parameters

International Nuclear Information System (INIS)

Zou Xiaodong; Hovmoeller, Anders; Hovmoeller, Sven

2004-01-01

A program system-Trice-for reconstructing the 3D reciprocal lattice from an electron diffraction tilt series is described. The unit-cell parameters can be determined from electron diffraction patterns directly by Trice. The unit cell can be checked and the lattice type and crystal system can be determined from the 3D reciprocal lattice. Trice can be applied to all crystal systems and lattice types

Evaluation of white spot syndrome virus variable DNA loci as molecular markers of virus spread at intermediate spatiotemporal scales

NARCIS (Netherlands)

Bui Thi Minh Dieu,; Marks, H.; Zwart, M.P.; Vlak, J.M.

2010-01-01

Variable genomic loci have been employed in a number of molecular epidemiology studies of white spot syndrome virus (WSSV), but it is unknown which loci are suitable molecular markers for determining WSSV spread on different spatiotemporal scales. Although previous work suggests that multiple

Impact of genetic risk loci for multiple sclerosis on expression of proximal genes in patients

KAUST Repository

James, Tojo

2018-01-06

Despite advancements in genetic studies, it is difficult to understand and characterize the functional relevance of disease-associated genetic variants, especially in the context of a complex multifactorial disease such as Multiple Sclerosis (MS). Since a large proportion of expression quantitative trait loci (eQTLs) are context-specific, we performed RNA-Seq in peripheral blood mononuclear cells (PBMCs) from MS patients (n=145) to identify eQTLs in regions centered on 109 MS risk SNPs and seven associated HLA variants. We identified 77 statistically significant eQTL associations, including pseudogenes and non-coding RNAs. Thirty-eight out of 40 testable eQTL effects were colocalised with the disease association signal. Since many eQTLs are tissue specific, we aimed to detail their significance in different cell types. Approximately 70% of the eQTLs were replicated and characterized in at least one major PBMC derived cell type. Furthermore, 40% of eQTLs were found to be more pronounced in MS patients compared to noninflammatory neurological diseases patients. In addition, we found two SNPs to be significantly associated with the proportions of three different cell types. Mapping to enhancer histone marks and predicted transcription factor binding sites added additional functional evidence for eight eQTL regions. As an example, we found that rs71624119, shared with three other autoimmune diseases and located in a primed enhancer (H3K4me1) with potential binding for STAT transcription factors, significantly associates with ANKRD55 expression. This study provides many novel and validated targets for future functional characterization of MS and other diseases.

Clinical significance of determination of changes of serum IL-2, SIL-2R, TNF-α contents and T-cell subgroup distribution type in patients with psoriasis

International Nuclear Information System (INIS)

Mou Xudong

2005-01-01

Objective: To investigate the changes of serum IL-2, SIL-2R, TNF-α contents and T-cell subgroup distribution type in patients with psoriasis. Methods: Serum IL-2 and TNF-α levels were measured with RIA, SIL-2R levels was measured with ELISA and T-cell subgroup distribution type was detected with monoclonal antibody in 40 patients with psoriasis and 35 controls. Results: The serum IL-2 levels and CD 4 /CD 8 values were significantly lower in the patients than those in controls (P<0.01), while the serum SIL-2R, TNF-α levels were significantly higher (P<0.01). Conclusion: Determination of serum IL-2, SIL-2R, TNF-α contents and T-cell subgroup distribution type is clinically useful for understanding the disturbances of immuno-modulation in these patients. (authors)

Library Spirit and Genius Loci

DEFF Research Database (Denmark)

Dahlkild, Nan

2009-01-01

The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style".......The architecture and design of Nyborg Public Library in the light of the concepts "Library Spirit" and "Genius Loci", related to contemporary social and cultural movements, the development of the early welfare state and the "Scandinavian Style"....

Multi-ethnic fine-mapping of 14 central adiposity loci

NARCIS (Netherlands)

Liu, C.T.; Buchkovich, M.L.; Winkler, T.W.; Heid, I.M.; Hottenga, J.J.; Boomsma, D.I.; de Geus, E.J.C.; Willemsen, G.; Borecki, I.B.; Fox, C.S.; Mohlke, K.L.; North, K.E.; Cupples, L.A.

2014-01-01

The Genetic Investigation of Anthropometric Traits (GIANT) consortium identified 14 loci in European Ancestry (EA) individuals associated with waist-to-hip ratio (WHR) adjusted for body mass index. These loci are wide and narrowingthe signalsremains necessary. Twelve of 14 loci identified inGIANTEA

Discovery and fine mapping of serum protein loci through transethnic meta-analysis.

Science.gov (United States)

Franceschini, Nora; van Rooij, Frank J A; Prins, Bram P; Feitosa, Mary F; Karakas, Mahir; Eckfeldt, John H; Folsom, Aaron R; Kopp, Jeffrey; Vaez, Ahmad; Andrews, Jeanette S; Baumert, Jens; Boraska, Vesna; Broer, Linda; Hayward, Caroline; Ngwa, Julius S; Okada, Yukinori; Polasek, Ozren; Westra, Harm-Jan; Wang, Ying A; Del Greco M, Fabiola; Glazer, Nicole L; Kapur, Karen; Kema, Ido P; Lopez, Lorna M; Schillert, Arne; Smith, Albert V; Winkler, Cheryl A; Zgaga, Lina; Bandinelli, Stefania; Bergmann, Sven; Boban, Mladen; Bochud, Murielle; Chen, Y D; Davies, Gail; Dehghan, Abbas; Ding, Jingzhong; Doering, Angela; Durda, J Peter; Ferrucci, Luigi; Franco, Oscar H; Franke, Lude; Gunjaca, Grog; Hofman, Albert; Hsu, Fang-Chi; Kolcic, Ivana; Kraja, Aldi; Kubo, Michiaki; Lackner, Karl J; Launer, Lenore; Loehr, Laura R; Li, Guo; Meisinger, Christa; Nakamura, Yusuke; Schwienbacher, Christine; Starr, John M; Takahashi, Atsushi; Torlak, Vesela; Uitterlinden, André G; Vitart, Veronique; Waldenberger, Melanie; Wild, Philipp S; Kirin, Mirna; Zeller, Tanja; Zemunik, Tatijana; Zhang, Qunyuan; Ziegler, Andreas; Blankenberg, Stefan; Boerwinkle, Eric; Borecki, Ingrid B; Campbell, Harry; Deary, Ian J; Frayling, Timothy M; Gieger, Christian; Harris, Tamara B; Hicks, Andrew A; Koenig, Wolfgang; O' Donnell, Christopher J; Fox, Caroline S; Pramstaller, Peter P; Psaty, Bruce M; Reiner, Alex P; Rotter, Jerome I; Rudan, Igor; Snieder, Harold; Tanaka, Toshihiro; van Duijn, Cornelia M; Vollenweider, Peter; Waeber, Gerard; Wilson, James F; Witteman, Jacqueline C M; Wolffenbuttel, Bruce H R; Wright, Alan F; Wu, Qingyu; Liu, Yongmei; Jenny, Nancy S; North, Kari E; Felix, Janine F; Alizadeh, Behrooz Z; Cupples, L Adrienne; Perry, John R B; Morris, Andrew P

2012-10-05

Many disorders are associated with altered serum protein concentrations, including malnutrition, cancer, and cardiovascular, kidney, and inflammatory diseases. Although these protein concentrations are highly heritable, relatively little is known about their underlying genetic determinants. Through transethnic meta-analysis of European-ancestry and Japanese genome-wide association studies, we identified six loci at genome-wide significance (p Japanese individuals) and three loci for total protein (TNFRS13B, 6q21.3, and ELL2, in up to 25,539 European-ancestry and 10,168 Japanese individuals). We observed little evidence of heterogeneity in allelic effects at these loci between groups of European and Japanese ancestry but obtained substantial improvements in the resolution of fine mapping of potential causal variants by leveraging transethnic differences in the distribution of linkage disequilibrium. We demonstrated a functional role for the most strongly associated serum albumin locus, HPN, for which Hpn knockout mice manifest low plasma albumin concentrations. Other loci associated with serum albumin harbor genes related to ribosome function, protein translation, and proteasomal degradation, whereas those associated with serum total protein include genes related to immune function. Our results highlight the advantages of transethnic meta-analysis for the discovery and fine mapping of complex trait loci and have provided initial insights into the underlying genetic architecture of serum protein concentrations and their association with human disease. Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

Involvement of viral envelope GP2 in Ebola virus entry into cells expressing the macrophage galactose-type C-type lectin

International Nuclear Information System (INIS)

Usami, Katsuaki; Matsuno, Keita; Igarashi, Manabu; Denda-Nagai, Kaori; Takada, Ayato; Irimura, Tatsuro

2011-01-01

Highlights: → Ebola virus infection is mediated by binding to and fusion with the target cells. → Structural feature of the viral glycoprotein determines the infectivity. → Surface C-type lectin, MGL, of macrophages and dendritic cells mediate the infection. → GP2, one of glycoprotein subunits, plays an essential role in MGL-mediated infection. → There is a critical amino acid residue involved in high infectivity. -- Abstract: Ebola virus (EBOV) infection is initiated by the interaction of the viral surface envelope glycoprotein (GP) with the binding sites on target cells. Differences in the mortality among different species of the Ebola viruses, i.e., Zaire ebolavirus (ZEBOV) and Reston ebolavirus (REBOV), correspond to the in vitro infectivity of the pseudo-typed virus constructed with the GPs in cells expressing macrophage galactose-type calcium-type lectin (MGL/CD301). Through mutagenesis of GP2, the transmembrane-anchored subunit of GP, we found that residues 502-527 of the GP2 sequence determined the different infectivity between VSV-ZEBOV GP and -REBOV GP in MGL/CD301-expressing cells and a histidine residue at position 516 of ZEBOV GP2 appeared essential in the differential infectivity. These findings may provide a clue to clarify a molecular basis of different pathogenicity among EBOV species.

Involvement of viral envelope GP2 in Ebola virus entry into cells expressing the macrophage galactose-type C-type lectin

Energy Technology Data Exchange (ETDEWEB)

Usami, Katsuaki [Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033 (Japan); Matsuno, Keita; Igarashi, Manabu [Department of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020 (Japan); Denda-Nagai, Kaori [Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033 (Japan); Takada, Ayato [Department of Global Epidemiology, Hokkaido University Research Center for Zoonosis Control, Sapporo 001-0020 (Japan); Irimura, Tatsuro, E-mail: irimura@mol.f.u-tokyo.ac.jp [Laboratory of Cancer Biology and Molecular Immunology, Graduate School of Pharmaceutical Sciences, University of Tokyo, Tokyo 113-0033 (Japan)

2011-04-01

Highlights: {yields} Ebola virus infection is mediated by binding to and fusion with the target cells. {yields} Structural feature of the viral glycoprotein determines the infectivity. {yields} Surface C-type lectin, MGL, of macrophages and dendritic cells mediate the infection. {yields} GP2, one of glycoprotein subunits, plays an essential role in MGL-mediated infection. {yields} There is a critical amino acid residue involved in high infectivity. -- Abstract: Ebola virus (EBOV) infection is initiated by the interaction of the viral surface envelope glycoprotein (GP) with the binding sites on target cells. Differences in the mortality among different species of the Ebola viruses, i.e., Zaire ebolavirus (ZEBOV) and Reston ebolavirus (REBOV), correspond to the in vitro infectivity of the pseudo-typed virus constructed with the GPs in cells expressing macrophage galactose-type calcium-type lectin (MGL/CD301). Through mutagenesis of GP2, the transmembrane-anchored subunit of GP, we found that residues 502-527 of the GP2 sequence determined the different infectivity between VSV-ZEBOV GP and -REBOV GP in MGL/CD301-expressing cells and a histidine residue at position 516 of ZEBOV GP2 appeared essential in the differential infectivity. These findings may provide a clue to clarify a molecular basis of different pathogenicity among EBOV species.

Gene expression relationship between prostate cancer cells of Gleason 3, 4 and normal epithelial cells as revealed by cell type-specific transcriptomes

International Nuclear Information System (INIS)

Pascal, Laura E; Liu, Alvin Y; Vêncio, Ricardo ZN; Page, Laura S; Liebeskind, Emily S; Shadle, Christina P; Troisch, Pamela; Marzolf, Bruz; True, Lawrence D; Hood, Leroy E

2009-01-01

Prostate cancer cells in primary tumors have been typed CD10 - /CD13 - /CD24 hi /CD26 + /CD38 lo /CD44 - /CD104 - . This CD phenotype suggests a lineage relationship between cancer cells and luminal cells. The Gleason grade of tumors is a descriptive of tumor glandular differentiation. Higher Gleason scores are associated with treatment failure. CD26 + cancer cells were isolated from Gleason 3+3 (G3) and Gleason 4+4 (G4) tumors by cell sorting, and their gene expression or transcriptome was determined by Affymetrix DNA array analysis. Dataset analysis was used to determine gene expression similarities and differences between G3 and G4 as well as to prostate cancer cell lines and histologically normal prostate luminal cells. The G3 and G4 transcriptomes were compared to those of prostatic cell types of non-cancer, which included luminal, basal, stromal fibromuscular, and endothelial. A principal components analysis of the various transcriptome datasets indicated a closer relationship between luminal and G3 than luminal and G4. Dataset comparison also showed that the cancer transcriptomes differed substantially from those of prostate cancer cell lines. Genes differentially expressed in cancer are potential biomarkers for cancer detection, and those differentially expressed between G3 and G4 are potential biomarkers for disease stratification given that G4 cancer is associated with poor outcomes. Differentially expressed genes likely contribute to the prostate cancer phenotype and constitute the signatures of these particular cancer cell types

Novel association strategy with copy number variation for identifying new risk Loci of human diseases.

Directory of Open Access Journals (Sweden)

Xianfeng Chen

2010-08-01

Full Text Available Copy number variations (CNV are important causal genetic variations for human disease; however, the lack of a statistical model has impeded the systematic testing of CNVs associated with disease in large-scale cohort.Here, we developed a novel integrated strategy to test CNV-association in genome-wide case-control studies. We converted the single-nucleotide polymorphism (SNP signal to copy number states using a well-trained hidden Markov model. We mapped the susceptible CNV-loci through SNP site-specific testing to cope with the physiological complexity of CNVs. We also ensured the credibility of the associated CNVs through further window-based CNV-pattern clustering. Genome-wide data with seven diseases were used to test our strategy and, in total, we identified 36 new susceptible loci that are associated with CNVs for the seven diseases: 5 with bipolar disorder, 4 with coronary artery disease, 1 with Crohn's disease, 7 with hypertension, 9 with rheumatoid arthritis, 7 with type 1 diabetes and 3 with type 2 diabetes. Fifteen of these identified loci were validated through genotype-association and physiological function from previous studies, which provide further confidence for our results. Notably, the genes associated with bipolar disorder converged in the phosphoinositide/calcium signaling, a well-known affected pathway in bipolar disorder, which further supports that CNVs have impact on bipolar disorder.Our results demonstrated the effectiveness and robustness of our CNV-association analysis and provided an alternative avenue for discovering new associated loci of human diseases.

Surface characteristics determining the cell compatibility of ionically cross-linked alginate gels

International Nuclear Information System (INIS)

Machida-Sano, Ikuko; Hirakawa, Makoto; Matsumoto, Hiroki; Kamada, Mitsuki; Ogawa, Sakito; Satoh, Nao; Namiki, Hideo

2014-01-01

In this study we investigated differences in the characteristics determining the suitability of five types of ion (Fe 3+ , Al 3+ , Ca 2+ , Ba 2+ and Sr 2+ )-cross-linked alginate films as culture substrates for cells. Human dermal fibroblasts were cultured on each alginate film to examine the cell affinity of the alginates. Since cell behavior on the surface of a material is dependent on the proteins adsorbed to it, we investigated the protein adsorption ability and surface features (wettability, morphology and charge) related to the protein adsorption abilities of alginate films. We observed that ferric, aluminum and barium ion-cross-linked alginate films supported better cell growth and adsorbed higher amounts of serum proteins than other types. Surface wettability analysis demonstrated that ferric and aluminum ion-cross-linked alginates had moderate hydrophilic surfaces, while other types showed highly hydrophilic surfaces. The roughness was exhibited only on barium ion-cross-linked alginate surface. Surface charge measurements revealed that alginate films had negatively charged surfaces, and showed little difference among the five types of gel. These results indicate that the critical factors of ionically cross-linked alginate films determining the protein adsorption ability required for their cell compatibility may be surface wettability and morphology. (paper)

Cell type discovery using single-cell transcriptomics: implications for ontological representation.

Science.gov (United States)

Aevermann, Brian D; Novotny, Mark; Bakken, Trygve; Miller, Jeremy A; Diehl, Alexander D; Osumi-Sutherland, David; Lasken, Roger S; Lein, Ed S; Scheuermann, Richard H

2018-05-01

Cells are fundamental function units of multicellular organisms, with different cell types playing distinct physiological roles in the body. The recent advent of single-cell transcriptional profiling using RNA sequencing is producing 'big data', enabling the identification of novel human cell types at an unprecedented rate. In this review, we summarize recent work characterizing cell types in the human central nervous and immune systems using single-cell and single-nuclei RNA sequencing, and discuss the implications that these discoveries are having on the representation of cell types in the reference Cell Ontology (CL). We propose a method, based on random forest machine learning, for identifying sets of necessary and sufficient marker genes, which can be used to assemble consistent and reproducible cell type definitions for incorporation into the CL. The representation of defined cell type classes and their relationships in the CL using this strategy will make the cell type classes being identified by high-throughput/high-content technologies findable, accessible, interoperable and reusable (FAIR), allowing the CL to serve as a reference knowledgebase of information about the role that distinct cellular phenotypes play in human health and disease.

Candidate genes expressed in human islets and their role in the pathogenesis of type 1 diabetes

DEFF Research Database (Denmark)

Storling, Joachim; Brorsson, Caroline Anna

2013-01-01

In type 1 diabetes (T1D), the insulin-producing β cells are destroyed by an immune-mediated process leading to complete insulin deficiency. There is a strong genetic component in T1D. Genes located in the human leukocyte antigen (HLA) region are the most important genetic determinants of disease......, but more than 40 additional loci are known to significantly affect T1D risk. Since most of the currently known genetic candidates have annotated immune cell functions, it is generally considered that most of the genetic susceptibility in T1D is caused by variation in genes affecting immune cell function....... Recent studies, however, indicate that most T1D candidate genes are expressed in human islets suggesting that the functions of the genes are not restricted to immune cells, but also play roles in the islets and possibly the β cells. Several candidates change expression levels within the islets following...

Comparative Mapping of Seed Dormancy Loci Between Tropical and Temperate Ecotypes of Weedy Rice (Oryza sativa L.

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Lihua Zhang

2017-08-01

Full Text Available Genotypic variation at multiple loci for seed dormancy (SD contributes to plant adaptation to diverse ecosystems. Weedy rice (Oryza sativa was used as a model to address the similarity of SD genes between distinct ecotypes. A total of 12 quantitative trait loci (QTL for SD were identified in one primary and two advanced backcross (BC populations derived from a temperate ecotype of weedy rice (34.3°N Lat.. Nine (75% of the 12 loci were mapped to the same positions as those identified from a tropical ecotype of weedy rice (7.1°N Lat.. The high similarity suggested that the majority of SD genes were conserved during the ecotype differentiation. These common loci are largely those collocated/linked with the awn, hull color, pericarp color, or plant height loci. Phenotypic correlations observed in the populations support the notion that indirect selections for the wild-type morphological characteristics, together with direct selections for germination time, were major factors influencing allelic distributions of SD genes across ecotypes. Indirect selections for crop-mimic traits (e.g., plant height and flowering time could also alter allelic frequencies for some SD genes in agroecosystems. In addition, 3 of the 12 loci were collocated with segregation distortion loci, indicating that some gametophyte development genes could also influence the genetic equilibria of SD loci in hybrid populations. The SD genes with a major effect on germination across ecotypes could be used as silencing targets to develop transgene mitigation (TM strategies to reduce the risk of gene flow from genetically modified crops into weed/wild relatives.

Impact of Common Variation in Bone-Related Genes on Type 2 Diabetes and Related Traits

DEFF Research Database (Denmark)

Billings, Liana K; Hsu, Yi-Hsiang; Ackerman, Rachel J

2012-01-01

the top loci associated with type 2 diabetes, fasting insulin, β-cell function by homeostasis model assessment, and 2-h post-oral glucose tolerance test glucose and insulin levels. ITGA1 has demonstrated genetic pleiotropy in prior studies, and its suggested role in liver fibrosis, insulin secretion...

Efficient assembly of de novo human artificial chromosomes from large genomic loci

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Stromberg Gregory

2005-07-01

Full Text Available Abstract Background Human Artificial Chromosomes (HACs are potentially useful vectors for gene transfer studies and for functional annotation of the genome because of their suitability for cloning, manipulating and transferring large segments of the genome. However, development of HACs for the transfer of large genomic loci into mammalian cells has been limited by difficulties in manipulating high-molecular weight DNA, as well as by the low overall frequencies of de novo HAC formation. Indeed, to date, only a small number of large (>100 kb genomic loci have been reported to be successfully packaged into de novo HACs. Results We have developed novel methodologies to enable efficient assembly of HAC vectors containing any genomic locus of interest. We report here the creation of a novel, bimolecular system based on bacterial artificial chromosomes (BACs for the construction of HACs incorporating any defined genomic region. We have utilized this vector system to rapidly design, construct and validate multiple de novo HACs containing large (100–200 kb genomic loci including therapeutically significant genes for human growth hormone (HGH, polycystic kidney disease (PKD1 and ß-globin. We report significant differences in the ability of different genomic loci to support de novo HAC formation, suggesting possible effects of cis-acting genomic elements. Finally, as a proof of principle, we have observed sustained ß-globin gene expression from HACs incorporating the entire 200 kb ß-globin genomic locus for over 90 days in the absence of selection. Conclusion Taken together, these results are significant for the development of HAC vector technology, as they enable high-throughput assembly and functional validation of HACs containing any large genomic locus. We have evaluated the impact of different genomic loci on the frequency of HAC formation and identified segments of genomic DNA that appear to facilitate de novo HAC formation. These genomic loci

Microsatellite loci in Japanese quail and cross-species amplification in chicken and guinea fowl

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Mizutani Makoto

2002-03-01

Full Text Available Abstract In line with the Gifu University's initiative to map the Japanese quail genome, a total of 100 Japanese quail microsatellite markers isolated in our laboratory were evaluated in a population of 20 unrelated quails randomly sampled from a colony of wild quail origin. Ninety-eight markers were polymorphic with an average of 3.7 alleles per locus and a mean heterozygosity of 0.423. To determine the utility of these markers for comparative genome mapping in Phasianidae, cross-species amplification of all the markers was tested with chicken and guinea fowl DNA. Amplification products similar in size to the orthologous loci in quail were observed in 42 loci in chicken and 20 loci in guinea fowl. Of the cross-reactive markers, 57.1% in chicken and 55.0% in guinea fowl were polymorphic when tested in 20 birds from their respective populations. Five of 15 markers that could cross-amplify Japanese quail, chicken, and guinea fowl DNA were polymorphic in all three species. Amplification of orthologous loci was confirmed by sequencing 10 loci each from chicken and guinea fowl and comparing with them the corresponding quail sequence. The microsatellite markers reported would serve as a useful resource base for genetic mapping in quail and comparative mapping in Phasianidae.

Type 2 Diabetes Risk Allele Loci in the Qatari Population.

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Sarah L O'Beirne

Full Text Available The prevalence of type 2 diabetes (T2D is increasing in the Middle East. However, the genetic risk factors for T2D in the Middle Eastern populations are not known, as the majority of studies of genetic risk for T2D are in Europeans and Asians.All subjects were ≥3 generation Qataris. Cases with T2D (n = 1,124 and controls (n = 590 were randomly recruited and assigned to the 3 known Qatari genetic subpopulations [Bedouin (Q1, Persian/South Asian (Q2 and African (Q3]. Subjects underwent genotyping for 37 single nucleotide polymorphisms (SNPs in 29 genes known to be associated with T2D in Europeans and/or Asian populations, and an additional 27 tag SNPs related to these susceptibility loci. Pre-study power analysis suggested that with the known incidence of T2D in adult Qataris (22%, the study population size would be sufficient to detect significant differences if the SNPs were risk factors among Qataris, assuming that the odds ratio (OR for T2D SNPs in Qatari's is greater than or equal to the SNP with highest known OR in other populations.Haplotype analysis demonstrated that Qatari haplotypes in the region of known T2D risk alleles in Q1 and Q2 genetic subpopulations were similar to European haplotypes. After Benjamini-Hochberg adjustment for multiple testing, only two SNPs (rs7903146 and rs4506565, both associated with transcription factor 7-like 2 (TCF7L2, achieved statistical significance in the whole study population. When T2D subjects and control subjects were assigned to the known 3 Qatari subpopulations, and analyzed individually and with the Q1 and Q2 genetic subpopulations combined, one of these SNPs (rs4506565 was also significant in the admixed group. No other SNPs associated with T2D in all Qataris or individual genetic subpopulations.With the caveats of the power analysis, the European/Asian T2D SNPs do not contribute significantly to the high prevalence of T2D in the Qatari population, suggesting that the genetic risks for T2D are

Microsatellite loci isolated from the scleractinian coral, Acropora nobilis.

Science.gov (United States)

Isomura, Naoko; Hidaka, Michio

2008-05-01

We report the isolation and characterization of eight microsatellite loci from the scleractinian coral, Acropora nobilis. The microsatellite loci were obtained using compound SSR primers or an enrichment protocol. All the loci were polymorphic with four to eight alleles per locus and observed heterozygosities ranging from 0.22 to 0.76. Some of the primers developed for the two congeners, Acropora palmata and Acropora millepora were applicable to A. nobilis. These loci are useful for studying the connectivity among A. nobilis populations in Okinawa, southern Japan. © 2007 The Authors.

A powerful method for transcriptional profiling of specific cell types in eukaryotes: laser-assisted microdissection and RNA sequencing.

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Marc W Schmid

Full Text Available The acquisition of distinct cell fates is central to the development of multicellular organisms and is largely mediated by gene expression patterns specific to individual cells and tissues. A spatially and temporally resolved analysis of gene expression facilitates the elucidation of transcriptional networks linked to cellular identity and function. We present an approach that allows cell type-specific transcriptional profiling of distinct target cells, which are rare and difficult to access, with unprecedented sensitivity and resolution. We combined laser-assisted microdissection (LAM, linear amplification starting from <1 ng of total RNA, and RNA-sequencing (RNA-Seq. As a model we used the central cell of the Arabidopsis thaliana female gametophyte, one of the female gametes harbored in the reproductive organs of the flower. We estimated the number of expressed genes to be more than twice the number reported previously in a study using LAM and ATH1 microarrays, and identified several classes of genes that were systematically underrepresented in the transcriptome measured with the ATH1 microarray. Among them are many genes that are likely to be important for developmental processes and specific cellular functions. In addition, we identified several intergenic regions, which are likely to be transcribed, and describe a considerable fraction of reads mapping to introns and regions flanking annotated loci, which may represent alternative transcript isoforms. Finally, we performed a de novo assembly of the transcriptome and show that the method is suitable for studying individual cell types of organisms lacking reference sequence information, demonstrating that this approach can be applied to most eukaryotic organisms.

Secretory activity and cell cycle alteration of alveolar type II cells in the early and late phase after irradiation

International Nuclear Information System (INIS)

Willner, Jochen; Vordermark, Dirk; Schmidt, Michael; Gassel, Andreamaria; Flentje, Michael; Wirtz, Hubert

2003-01-01

Purpose: Type II cells and the surfactant system have been proposed to play a central role in pathogenesis of radiation pneumonitis. We analyzed the secretory function and proliferation parameters of alveolar type II cells in the early (until 24 h) and late phase (1-5 weeks) after irradiation (RT) in vitro and in vivo. Methods and Materials: Type II cells were isolated from rats according to the method of Dobbs. Stimulation of secretion was induced with terbutaline, adenosine triphosphate (ATP), and 12-O-tetradecanoylphorbol-13-acetate (TPA) for a 2-h period. Determination of secretion was performed using 3 H-labeled phosphatidylcholine. For the early-phase analysis, freshly isolated and adherent type II cells were irradiated in vitro with 9-21 Gy (stepwise increase of 3 Gy). Secretion stimulation was initiated 1, 6, 24, and 48 h after RT. For late-phase analysis, type II cells were isolated 1-5 weeks after 18 Gy whole lung or sham RT. Each experiment was repeated at least fivefold. Flow cytometry was used to determine cell cycle distribution and proliferating cell nuclear antigen index. Results: During the early-phase (in vitro) analysis, we found a normal stimulation of surfactant secretion in irradiated, as well as unirradiated, cells. No change in basal secretion and no dose effect were seen. During the late phase, 1-5 weeks after whole lung RT, we observed enhanced secretory activity for all secretagogues and a small increase in basal secretion in Weeks 3 and 4 (pneumonitis phase) compared with controls. The total number of isolated type II cells, as well as the rate of viable cells, decreased after the second post-RT week. Cell cycle alterations suggesting an irreversible G 2 /M block occurred in the second post-RT week and did not resolve during the observation period. The proliferating cell nuclear antigen index of type II cells from irradiated rats did not differ from that of controls. Conclusion: In contrast to literature data, we observed no direct

Genotyping of the MTL loci and susceptibility to two antifungal agents of Candida glabrata clinical isolates

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María Teresa Lavaniegos-Sobrino

2009-08-01

Full Text Available The opportunistic fungal pathogen Candida glabrata is the second most common isolate from bloodstream infections worldwide and is naturally less susceptible to the antifungal drug fluconazole than other Candida species. C. glabrata is a haploid yeast that contains three mating-type like loci (MTL, although no sexual cycle has been described. Strains containing both types of mating information at the MTL1 locus are found in clinical isolates, but it is thought that strains containing type a information are more common. Here we investigated if a particular combination of mating type information at each MTLlocus is more prevalent in clinical isolates from hospitalized patients in Mexico and if there is a correlation between mating information and resistance to fluconazole and 5-fluorocytosine. We found that while both types of information at MTL1 are equally represented in a collection of 64 clinical isolates, the vast majority of isolates contain a-type information at MTL2 and α-type at MTL3. We also found no correlation of the particular combination of mating type information at the three MTL loci and resistance to fluconazole.

Evaluating the potential roles of the Gray and Extension loci in the coat coloration of Thoroughbred racing horses.

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Sakamoto, Takahiro; Fawcett, Jeffrey A; Innan, Hideki

2017-01-01

Horses have substantial variation in coat color, and the genetic loci responsible for the coat color variations have been well investigated. It has been believed that some color variations should follow a single-locus Mendelian law. Examples include the Gray locus that causes the gray phenotype and the Extension locus that specifies the chestnut phenotype. We reevaluated the roles of the Gray and Extension loci by using a large number of mating records of Thoroughbred racing horses. We showed that the data indeed fits the Mendelian law extremely well for the two loci. Furthermore, we demonstrated that the Extension and Agouti loci might have an additional role in determining the degree of melanin that should distinguish bay, dark bay, and brown.

Glass promotes the differentiation of neuronal and non-neuronal cell types in the Drosophila eye

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Morrison, Carolyn A.; Chen, Hao; Cook, Tiffany; Brown, Stuart

2018-01-01

Transcriptional regulators can specify different cell types from a pool of equivalent progenitors by activating distinct developmental programs. The Glass transcription factor is expressed in all progenitors in the developing Drosophila eye, and is maintained in both neuronal and non-neuronal cell types. Glass is required for neuronal progenitors to differentiate as photoreceptors, but its role in non-neuronal cone and pigment cells is unknown. To determine whether Glass activity is limited to neuronal lineages, we compared the effects of misexpressing it in neuroblasts of the larval brain and in epithelial cells of the wing disc. Glass activated overlapping but distinct sets of genes in these neuronal and non-neuronal contexts, including markers of photoreceptors, cone cells and pigment cells. Coexpression of other transcription factors such as Pax2, Eyes absent, Lozenge and Escargot enabled Glass to induce additional genes characteristic of the non-neuronal cell types. Cell type-specific glass mutations generated in cone or pigment cells using somatic CRISPR revealed autonomous developmental defects, and expressing Glass specifically in these cells partially rescued glass mutant phenotypes. These results indicate that Glass is a determinant of organ identity that acts in both neuronal and non-neuronal cells to promote their differentiation into functional components of the eye. PMID:29324767

Noninvasive pulsed focused ultrasound allows spatiotemporal control of targeted homing for multiple stem cell types in murine skeletal muscle and the magnitude of cell homing can be increased through repeated applications.

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Burks, Scott R; Ziadloo, Ali; Kim, Saejeong J; Nguyen, Ben A; Frank, Joseph A

2013-11-01

Stem cells are promising therapeutics for cardiovascular diseases, and i.v. injection is the most desirable route of administration clinically. Subsequent homing of exogenous stem cells to pathological loci is frequently required for therapeutic efficacy and is mediated by chemoattractants (cell adhesion molecules, cytokines, and growth factors). Homing processes are inefficient and depend on short-lived pathological inflammation that limits the window of opportunity for cell injections. Noninvasive pulsed focused ultrasound (pFUS), which emphasizes mechanical ultrasound-tissue interactions, can be precisely targeted in the body and is a promising approach to target and maximize stem cell delivery by stimulating chemoattractant expression in pFUS-treated tissue prior to cell infusions. We demonstrate that pFUS is nondestructive to murine skeletal muscle tissue (no necrosis, hemorrhage, or muscle stem cell activation) and initiates a largely M2-type macrophage response. We also demonstrate that local upregulation of chemoattractants in pFUS-treated skeletal muscle leads to enhance homing, permeability, and retention of human mesenchymal stem cells (MSC) and human endothelial precursor cells (EPC). Furthermore, the magnitude of MSC or EPC homing was increased when pFUS treatments and cell infusions were repeated daily. This study demonstrates that pFUS defines transient "molecular zip codes" of elevated chemoattractants in targeted muscle tissue, which effectively provides spatiotemporal control and tunability of the homing process for multiple stem cell types. pFUS is a clinically translatable modality that may ultimately improve homing efficiency and flexibility of cell therapies for cardiovascular diseases. © AlphaMed Press.

Genome-Wide Progesterone Receptor Binding: Cell Type-Specific and Shared Mechanisms in T47D Breast Cancer Cells and Primary Leiomyoma Cells

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Huang, Lei; Owen, Jonas K.; Xie, Anna; Navarro, Antonia; Monsivais, Diana; Coon V, John S.; Kim, J. Julie; Dai, Yang; Bulun, Serdar E.

2012-01-01

Background Progesterone, via its nuclear receptor (PR), exerts an overall tumorigenic effect on both uterine fibroid (leiomyoma) and breast cancer tissues, whereas the antiprogestin RU486 inhibits growth of these tissues through an unknown mechanism. Here, we determined the interaction between common or cell-specific genome-wide binding sites of PR and mRNA expression in RU486-treated uterine leiomyoma and breast cancer cells. Principal Findings ChIP-sequencing revealed 31,457 and 7,034 PR-binding sites in breast cancer and uterine leiomyoma cells, respectively; 1,035 sites overlapped in both cell types. Based on the chromatin-PR interaction in both cell types, we statistically refined the consensus progesterone response element to G•ACA• • •TGT•C. We identified two striking differences between uterine leiomyoma and breast cancer cells. First, the cis-regulatory elements for HSF, TEF-1, and C/EBPα and β were statistically enriched at genomic RU486/PR-targets in uterine leiomyoma, whereas E2F, FOXO1, FOXA1, and FOXF sites were preferentially enriched in breast cancer cells. Second, 51.5% of RU486-regulated genes in breast cancer cells but only 6.6% of RU486-regulated genes in uterine leiomyoma cells contained a PR-binding site within 5 kb from their transcription start sites (TSSs), whereas 75.4% of RU486-regulated genes contained a PR-binding site farther than 50 kb from their TSSs in uterine leiomyoma cells. RU486 regulated only seven mRNAs in both cell types. Among these, adipophilin (PLIN2), a pro-differentiation gene, was induced via RU486 and PR via the same regulatory region in both cell types. Conclusions Our studies have identified molecular components in a RU486/PR-controlled gene network involved in the regulation of cell growth, cell migration, and extracellular matrix function. Tissue-specific and common patterns of genome-wide PR binding and gene regulation may determine the therapeutic effects of antiprogestins in uterine fibroids and

eTumorType, An Algorithm of Discriminating Cancer Types for Circulating Tumor Cells or Cell-free DNAs in Blood.

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Zou, Jinfeng; Wang, Edwin

2017-04-01

With the technology development on detecting circulating tumor cells (CTCs) and cell-free DNAs (cfDNAs) in blood, serum, and plasma, non-invasive diagnosis of cancer becomes promising. A few studies reported good correlations between signals from tumor tissues and CTCs or cfDNAs, making it possible to detect cancers using CTCs and cfDNAs. However, the detection cannot tell which cancer types the person has. To meet these challenges, we developed an algorithm, eTumorType, to identify cancer types based on copy number variations (CNVs) of the cancer founding clone. eTumorType integrates cancer hallmark concepts and a few computational techniques such as stochastic gradient boosting, voting, centroid, and leading patterns. eTumorType has been trained and validated on a large dataset including 18 common cancer types and 5327 tumor samples. eTumorType produced high accuracies (0.86-0.96) and high recall rates (0.79-0.92) for predicting colon, brain, prostate, and kidney cancers. In addition, relatively high accuracies (0.78-0.92) and recall rates (0.58-0.95) have also been achieved for predicting ovarian, breast luminal, lung, endometrial, stomach, head and neck, leukemia, and skin cancers. These results suggest that eTumorType could be used for non-invasive diagnosis to determine cancer types based on CNVs of CTCs and cfDNAs. Copyright © 2017 Beijing Institute of Genomics, Chinese Academy of Sciences and Genetics Society of China. Production and hosting by Elsevier B.V. All rights reserved.

Comparison of Species and Cell-Type Differences in Fraction Unbound of Liver Tissues, Hepatocytes, and Cell Lines.

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Riccardi, Keith; Ryu, Sangwoo; Lin, Jian; Yates, Phillip; Tess, David; Li, Rui; Singh, Dhirender; Holder, Brian R; Kapinos, Brendon; Chang, George; Di, Li

2018-04-01

Fraction unbound ( f u ) of liver tissue, hepatocytes, and other cell types is an essential parameter used to estimate unbound liver drug concentration and intracellular free drug concentration. f u,liver and f u,cell are frequently measured in multiple species and cell types in drug discovery and development for various applications. A comparison study of 12 matrices for f u,liver and f u,cell of hepatocytes in five different species (mouse, rat, dog, monkey, and human), as well as f u,cell of Huh7 and human embryonic kidney 293 cell lines, was conducted for 22 structurally diverse compounds with the equilibrium dialysis method. Using an average bioequivalence approach, our results show that the average difference in binding to liver tissue, hepatocytes, or different cell types was within 2-fold of that of the rat f u,liver Therefore, we recommend using rat f u,liver as a surrogate for liver binding in other species and cell types in drug discovery. This strategy offers the potential to simplify binding studies and reduce cost, thereby enabling a more effective and practical determination of f u for liver tissues, hepatocytes, and other cell types. In addition, f u under hepatocyte stability incubation conditions should not be confused with f u,cell , as one is a diluted f u and the other is an undiluted f u Cell density also plays a critical role in the accurate measurement of f u,cell . Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Cell type specific DNA methylation in cord blood: A 450K-reference data set and cell count-based validation of estimated cell type composition.

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Gervin, Kristina; Page, Christian Magnus; Aass, Hans Christian D; Jansen, Michelle A; Fjeldstad, Heidi Elisabeth; Andreassen, Bettina Kulle; Duijts, Liesbeth; van Meurs, Joyce B; van Zelm, Menno C; Jaddoe, Vincent W; Nordeng, Hedvig; Knudsen, Gunn Peggy; Magnus, Per; Nystad, Wenche; Staff, Anne Cathrine; Felix, Janine F; Lyle, Robert

2016-09-01

Epigenome-wide association studies of prenatal exposure to different environmental factors are becoming increasingly common. These studies are usually performed in umbilical cord blood. Since blood comprises multiple cell types with specific DNA methylation patterns, confounding caused by cellular heterogeneity is a major concern. This can be adjusted for using reference data consisting of DNA methylation signatures in cell types isolated from blood. However, the most commonly used reference data set is based on blood samples from adult males and is not representative of the cell type composition in neonatal cord blood. The aim of this study was to generate a reference data set from cord blood to enable correct adjustment of the cell type composition in samples collected at birth. The purity of the isolated cell types was very high for all samples (>97.1%), and clustering analyses showed distinct grouping of the cell types according to hematopoietic lineage. We explored whether this cord blood and the adult peripheral blood reference data sets impact the estimation of cell type composition in cord blood samples from an independent birth cohort (MoBa, n = 1092). This revealed significant differences for all cell types. Importantly, comparison of the cell type estimates against matched cell counts both in the cord blood reference samples (n = 11) and in another independent birth cohort (Generation R, n = 195), demonstrated moderate to high correlation of the data. This is the first cord blood reference data set with a comprehensive examination of the downstream application of the data through validation of estimated cell types against matched cell counts.

Technical note: developmental validation of a novel 6-dye typing system with 36 Y-STR loci.

Science.gov (United States)

Du, Weian; Feng, Peipei; Huang, Hongyan; Wu, Weibin; Zhang, Lei; Guo, Yulin; Liu, Changhui; Liu, Hong; Liu, Chao; Chen, Ling

2018-05-30

Y-chromosomal short tandem repeats (Y-STRs) have proven to be very useful in investigating sexual assault cases and in paternity lineage differentiation. However, currently available commercial Y-STR multiplex amplification systems bear the limitations in the identification of related males from the same paternal lineage due to there being an insufficient number of loci in any single amplification kit. The aim of this study was to establish and validate a novel 6-dye, 36-plex Y-STR multiplex amplification system that incorporated all of the loci present in the Yfiler™ Plus kit (DYS19, DYS385a/b, DYF387S1, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438, DYS439, DYS448, DYS449, DYS456, DYS458, DYS460, DYS481, DYS518, DYS533, DYS570, DYS576, DYS627, DYS635, Y_GATA_H4) as well as a further nine highly polymorphic Y-STR loci (DYS388, DYS444, DYS447, DYS522, DYS527a/b, DYS549, DYS596, DYS643). The novel system was optimized and validated by a series of studies that tested the effect of different PCR-based conditions as well as the species specificity, sensitivity, stability, stutter precision, suitability for use on DNA mixtures, reproducibility, and parallel testing of the system, as well as its performance on casework samples and population analysis, according to the SWGDAM developmental validation guidelines. A total of 246 haplotypes were found for the 36 Y-STRs among 247 Guangdong Han unrelated males. Collectively, the results demonstrate that the developed 36-plex Y-STR system is sensitive, robust, reliable, and highly informative for use in forensic genetics.

Carbon black nanoparticles induce type II epithelial cells to release chemotaxins for alveolar macrophages

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Donaldson Ken

2005-12-01

Full Text Available Abstract Background Alveolar macrophages are a key cell in dealing with particles deposited in the lungs and in determining the subsequent response to that particle exposure. Nanoparticles are considered a potential threat to the lungs and the mechanism of pulmonary response to nanoparticles is currently under intense scrutiny. The type II alveolar epithelial cell has previously been shown to release chemoattractants which can recruit alveolar macrophages to sites of particle deposition. The aim of this study was to assess the responses of a type II epithelial cell line (L-2 to both fine and nanoparticle exposure in terms of secretion of chemotactic substances capable of inducing macrophage migration. Results Exposure of type II cells to carbon black nanoparticles resulted in significant release of macrophage chemoattractant compared to the negative control and to other dusts tested (fine carbon black and TiO2 and nanoparticle TiO2 as measured by macrophage migration towards type II cell conditioned medium. SDS-PAGE analysis of the conditioned medium from particle treated type II cells revealed that a higher number of protein bands were present in the conditioned medium obtained from type II cells treated with nanoparticle carbon black compared to other dusts tested. Size-fractionation of the chemotaxin-rich supernatant determined that the chemoattractants released from the epithelial cells were between 5 and 30 kDa in size. Conclusion The highly toxic nature and reactive surface chemistry of the carbon black nanoparticles has very likely induced the type II cell line to release pro-inflammatory mediators that can potentially induce migration of macrophages. This could aid in the rapid recruitment of inflammatory cells to sites of particle deposition and the subsequent removal of the particles by phagocytic cells such as macrophages and neutrophils. Future studies in this area could focus on the exact identity of the substance(s released by the

Phylogeny of Cas9 determines functional exchangeability of dual-RNA and Cas9 among orthologous type II CRISPR-Cas systems

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Fonfara, Ines; Le Rhun, Anaïs; Chylinski, Krzysztof; Makarova, Kira S.; Lécrivain, Anne-Laure; Bzdrenga, Janek; Koonin, Eugene V.; Charpentier, Emmanuelle

2014-01-01

The CRISPR-Cas-derived RNA-guided Cas9 endonuclease is the key element of an emerging promising technology for genome engineering in a broad range of cells and organisms. The DNA-targeting mechanism of the type II CRISPR-Cas system involves maturation of tracrRNA:crRNA duplex (dual-RNA), which directs Cas9 to cleave invading DNA in a sequence-specific manner, dependent on the presence of a Protospacer Adjacent Motif (PAM) on the target. We show that evolution of dual-RNA and Cas9 in bacteria produced remarkable sequence diversity. We selected eight representatives of phylogenetically defined type II CRISPR-Cas groups to analyze possible coevolution of Cas9 and dual-RNA. We demonstrate that these two components are interchangeable only between closely related type II systems when the PAM sequence is adjusted to the investigated Cas9 protein. Comparison of the taxonomy of bacterial species that harbor type II CRISPR-Cas systems with the Cas9 phylogeny corroborates horizontal transfer of the CRISPR-Cas loci. The reported collection of dual-RNA:Cas9 with associated PAMs expands the possibilities for multiplex genome editing and could provide means to improve the specificity of the RNA-programmable Cas9 tool. PMID:24270795

A Web-Server of Cell Type Discrimination System

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Anyou Wang

2014-01-01

Full Text Available Discriminating cell types is a daily request for stem cell biologists. However, there is not a user-friendly system available to date for public users to discriminate the common cell types, embryonic stem cells (ESCs, induced pluripotent stem cells (iPSCs, and somatic cells (SCs. Here, we develop WCTDS, a web-server of cell type discrimination system, to discriminate the three cell types and their subtypes like fetal versus adult SCs. WCTDS is developed as a top layer application of our recent publication regarding cell type discriminations, which employs DNA-methylation as biomarkers and machine learning models to discriminate cell types. Implemented by Django, Python, R, and Linux shell programming, run under Linux-Apache web server, and communicated through MySQL, WCTDS provides a friendly framework to efficiently receive the user input and to run mathematical models for analyzing data and then to present results to users. This framework is flexible and easy to be expended for other applications. Therefore, WCTDS works as a user-friendly framework to discriminate cell types and subtypes and it can also be expended to detect other cell types like cancer cells.

Expression of synaptogyrin-1 in T1R2-expressing type II taste cells and type III taste cells of rat circumvallate taste buds.

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Kotani, Takeshi; Toyono, Takashi; Seta, Yuji; Kitou, Ayae; Kataoka, Shinji; Toyoshima, Kuniaki

2013-09-01

Synaptogyrins are conserved components of the exocytic apparatus and function as regulators of Ca(2+)-dependent exocytosis. The synaptogyrin family comprises three isoforms: two neuronal (synaptogyrin-1 and -3) and one ubiquitous (synaptogyrin-2) form. Although the expression patterns of the exocytic proteins synaptotagmin-1, SNAP-25, synaptobrevin-2 and synaptophysin have been elucidated in taste buds, the function and expression pattern of synaptogyrin-1 in rat gustatory tissues have not been determined. Therefore, we examined the expression patterns of synaptogyrin-1 and several cell-specific markers of type II and III cells in rat gustatory tissues. Reverse transcription/polymerase chain reaction assays and immunoblot analysis revealed the expression of synaptogyrin-1 mRNA and its protein in circumvallate papillae. In fungiform, foliate and circumvallate papillae, the antibody against synaptogyrin-1 immunolabeled a subset of taste bud cells and intra- and subgemmal nerve processes. Double-labeling experiments revealed the expression of synaptogyrin-1 in most taste cells immunoreactive for aromatic L-amino acid decarboxylase and the neural cell adhesion molecule. A subset of synaptogyrin-1-immunoreactive taste cells also expressed phospholipase Cβ2, gustducin, or sweet taste receptor (T1R2). In addition, most synaptogyrin-1-immunoreactive taste cells expressed synaptobrevin-2. These results suggest that synaptogyrin-1 plays a regulatory role in transmission at the synapses of type III cells and is involved in exocytic function with synaptobrevin-2 in a subset of type II cells in rat taste buds.

Pathogen-specific effects of quantitative trait loci affecting clinical mastitis and somatic cell count in danish holstein cattle

DEFF Research Database (Denmark)

Sørensen, Lars Peter; Guldbrandtsen, Bernt; Thomasen, J.R.

2008-01-01

The aim of this study was to investigate whether quantitative trait loci (QTL) affecting the risk of clinical mastitis (CM) and QTL affecting somatic cell score (SCS) exhibit pathogen-specific effects on the incidence of mastitis. Bacteriological data on mastitis pathogens were used to investigate...... pathogen specificity of QTL affecting treatments of mastitis in first parity (CM1), second parity (CM2), and third parity (CM3), and QTL affecting SCS. The 5 most common mastitis pathogens in the Danish dairy population were analyzed: Streptococcus dysgalactiae, Escherichia coli, coagulase...... against coagulase-negative staphylococci and Strep. uberis. Our results show that particular mastitis QTL are highly likely to exhibit pathogen-specificity. However, the results should be interpreted carefully because the results are sensitive to the sampling method and method of analysis. Field data were...

Discovery and refinement of loci associated with lipid levels

DEFF Research Database (Denmark)

Willer, C. J.; Schmidt, E. M.; Sengupta, S.

2013-01-01

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577 individ...... of using genetic data from individuals of diverse ancestry and provide insights into the biological mechanisms regulating blood lipids to guide future genetic, biological and therapeutic research.......Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188......,577 individuals using genome-wide and custom genotyping arrays. We identify and annotate 157 loci associated with lipid levels at P lipid levels in humans. Using dense genotyping in individuals of European, East Asian, South Asian and African ancestry...

A novel type of silencing factor, Clr2, is necessary for transcriptional silencing at various chromosomal locations in the fission yeast Schizosaccharomyces pombe

DEFF Research Database (Denmark)

Bjerling, Pernilla; Ekwall, Karl; Egel, Richard

2004-01-01

The mating-type region of the fission yeast Schizosaccharomyces pombe comprises three loci: mat1, mat2-P and mat3-M. mat1 is expressed and determines the mating type of the cell. mat2-P and mat3-M are two storage cassettes located in a 17 kb heterochromatic region with features identical to those...... of mammalian heterochromatin. Mutations in the swi6+, clr1+, clr2+, clr3+, clr4+ and clr6+ genes were obtained in screens for factors necessary for silencing the mat2-P-mat3-M region. swi6+ encodes a chromodomain protein, clr3+ and clr6+ histone deacetylases, and clr4+ a histone methyltransferase. Here, we...

Seventy-five genetic loci influencing the human red blood cell

NARCIS (Netherlands)

van der Harst, P.; Zhang, W.; Mateo Leach, I.; Rendon, A.; Verweij, N.; Sehmi, J.; Paul, D.S.; Elling, U.; Allayee, H.; Li, X.; Radhakrishnan, A.; Tan, S.T.; Voss, K.; Weichenberger, C.X.; Albers, C.A.; Al-Hussani, A.; Asselbergs, F.W.; Ciullo, M.; Danjou, F.; Dina, C.; Esko, T.; Evans, D.M.; Franke, L.; Gogele, M.; Hartiala, J.; Hersch, M.; Holm, H.; Hottenga, J.J.; Kanoni, S.; Kleber, M.E.; Lagou, V.; Langenberg, C.; Lopez, L.M.; Lyytikainen, L.P.; Melander, O.; Murgia, F.; Nolte, I.M.; O'Reilly, P.F.; Padmanabhan, S.; Parsa, A.; Pirastu, N.; Porcu, E.; Portas, L.; Prokopenko, I.; Ried, J.S.; Shin, S.Y.; Tang, C.S.; Teumer, A.; Traglia, M.; Ulivi, S.; Westra, H.J.; Yang, J.; Zhao, J.H.; Anni, F.; Abdellaoui, A.; Attwood, A.; Balkau, B.; Bandinelli, S.; Bastardot, F.; Benyamin, B.; Boehm, B.O.; Cookson, W.O.; Das, D; de Bakker, P.I.; de Boer, R.A.; de Geus, E.J.; de Moor, M.H.; Dimitriou, M.; Domingues, F.S.; Doring, A.; Engstrom, G.; Eyjolfsson, G.I.; Ferrucci, L.; Fischer, K.; Galanello, R.; Garner, S.F.; Genser, B.; Gibson, Q.D.; Girotto, G.; Gudbjartsson, D.F.; Harris, S.E.; Hartikainen, A.L.; Hastie, C.E.; Hedblad, B.; Illig, T.; Jolley, J.; Kahonen, M.; Kema, I.P.; Kemp, J.P.; Liang, L.; Lloyd-Jones, H.; Loos, R.J.; Meacham, S.; Medland, S.E.; Meisinger, C.; Memari, Y.; Mihailov, E.; Miller, K.; Moffatt, M.F.; Nauck, M., et al.

2012-01-01

Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related

Activation of int-1 and int-2 loci in GRf mammary tumors.

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Gray, D A; Jackson, D P; Percy, D H; Morris, V L

1986-10-30

The Mtv-2 locus is known to be associated with a high mammary tumor incidence (97%) and early development of mammary tumors (3-13 months) in GR mice. However, it was not previously known whether the provirus which resides at the Mtv-2 locus is tumorigenic in and of itself or whether reintegration of proviruses generated from Mtv-2 is required for tumorigenesis. Foster-nursing GR mice on C57/BL mice eliminates the milk-borne source of GR virus, and allows the study of Mtv-2 derived proviruses alone. Using this approach, we have tested predictions which follow from the "positional" versus "reintegrational" models of tumorigenesis. Specifically, we have examined tumors from primary foster-nursed (GRf) mice to determine if MMTV proviruses derived from Mtv-2 were scattered randomly throughout the genome or were clustered in the vicinity of the int-1 and int-2 loci, which are thought to be associated with mammary tumorigenesis. It was found that the majority of spontaneous GRf mammary tumors that were tested have MMTV proviral integrations in either or both of the int-1 and int-2 loci and have transcription of either or both of the int loci. Tumors induced by Mtv-2, therefore, appear to have arisen via a mechanism similar to the activation of the int loci by exogenous (milk-borne) MMTV proviruses.

Investigation of population structure in Gulf of Mexico Seepiophila jonesi (Polychaeta, Siboglinidae using cross-amplified microsatellite loci

Directory of Open Access Journals (Sweden)

Chunya Huang

2016-08-01

Full Text Available Background Vestimentiferan tubeworms are some of the most recognizable fauna found at deep-sea cold seeps, isolated environments where hydrocarbon rich fluids fuel biological communities. Several studies have investigated tubeworm population structure; however, much is still unknown about larval dispersal patterns at Gulf of Mexico (GoM seeps. As such, researchers have applied microsatellite markers as a measure for documenting the transport of vestimentiferan individuals. In the present study, we investigate the utility of microsatellites to be cross-amplified within the escarpiid clade of seep vestimentiferans, by determining if loci originally developed for Escarpia spp. could be amplified in the GoM seep tubeworm, Seepiophila jonesi. Additionally, we determine if cross-amplified loci can reliably uncover the same signatures of high gene flow seen in a previous investigation of S. jonesi. Methods Seventy-seven S. jonesi individuals were collected from eight seep sites across the upper Louisiana slope (<1,000 m in the GoM. Forty-eight microsatellite loci that were originally developed for Escarpia laminata (18 loci and Escarpia southwardae (30 loci were tested to determine if they were homologous and polymorphic in S. jonesi. Loci found to be both polymorphic and of high quality were used to test for significant population structuring in S. jonesi. Results Microsatellite pre-screening identified 13 (27% of the Escarpia loci were homologous and polymorphic in S. jonesi, revealing that microsatellites can be amplified within the escarpiid clade of vestimentiferans. Our findings uncovered low levels of heterozygosity and a lack of genetic differentiation amongst S. jonesi from various sites and regions, in line with previous investigations that employed species-specific polymorphic loci on S. jonesi individuals retrieved from both the same and different seep sites. The lack of genetic structure identified from these populations supports the

A global analysis of Y-chromosomal haplotype diversity for 23 STR loci

DEFF Research Database (Denmark)

Purps, Josephine; Siegert, Sabine; Willuweit, Sascha

2014-01-01

In a worldwide collaborative effort, 19,630 Y-chromosomes were sampled from 129 different populations in 51 countries. These chromosomes were typed for 23 short-tandem repeat (STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385ab, DYS437, DYS438, DYS439, DYS448, DYS456, DY...

A Laboratory Exercise to Determine Human ABO Blood Type by Noninvasive Methods

Science.gov (United States)

Martin, Michael P.; Detzel, Stephen M.

2008-01-01

Analysis of single-nucleotide polymorphisms and their association with diseases and nondisease phenotypes is of growing importance in human biology studies. In this laboratory exercise, students determine the genetic basis for their ABO blood type; however, no blood is drawn. Students isolate genomic DNA from buccal mucosa cells that are present…

Characterization of cloned cells from an immortalized fetal pulmonary type II cell line

Energy Technology Data Exchange (ETDEWEB)

Henderson, R.F.; Waide, J.J.; Lechner, J.F.

1995-12-01

A cultured cell line that maintained expression of pulmonary type II cell markers of differentiation would be advantageous to generate a large number of homogenous cells in which to study the biochemical functions of type II cells. Type II epithelial cells are the source of pulmonary surfactant and a cell of origin for pulmonary adenomas. Last year our laboratory reported the induction of expression of two phenotypic markers of pulmonary type II cells (alkaline phosphatase activity and surfactant lipid synthesis) in cultured fetal rat lung epithelial (FRLE) cells, a spontaneously immortalized cell line of fetal rat lung type II cell origin. Subsequently, the induction of the ability to synthesize surfactant lipid became difficult to repeat. We hypothesized that the cell line was heterogenuous and some cells were more like type II cells than others. The purpose of this study was to test this hypothesis and to obtain a cultured cell line with type II cell phenotypic markers by cloning several FRLE cells and characterizing them for phenotypic markers of type II cells (alkaline phosphatase activity and presence of surfactant lipids). Thirty cloned cell lines were analyzed for induced alkaline phosphatase activity (on x-axis) and for percent of phospholipids that were disaturated (i.e., surfactant).

Molecular determinants of the V3 loop of human immunodeficiency virus type 1 glycoprotein gp120 responsible for controlling cell tropism.

Science.gov (United States)

Chavda, S C; Griffin, P; Han-Liu, Z; Keys, B; Vekony, M A; Cann, A J

1994-11-01

We and others have identified the major determinant of cell tropism in human immunodeficiency virus type 1 (HIV-1) as the V3 loop of glycoprotein gp120. We have conducted a detailed study of two molecularly cloned isolates of HIV-1, HIVJR-CSF and HIVNL4-3, that differ in their tropism for immortalized CD4+ cell lines, by constructing a series of site-directed mutations within the V3 loop of HIVJR-CSF based on the sequence of HIVNL4-3. The phenotypes of these mutants fall into two classes, those which are viable and those which are not. A spontaneous mutant with significantly altered growth properties was also recovered and found to have an additional single amino acid change in the V3 loop sequence. The carboxy-terminal beta-strand part of the V3 loop is the major determinant of cell tropism. However, the results presented here indicate that the functional role of the V3 loop sequences can only be interpreted properly in the context of the original gp120 backbone from which they were derived. These findings show that over-simplistic interpretation of sequence data derived from unknown mixtures of HIV variants in infected persons may be highly misleading.

Absence of complementary sex determination in the parasitoid wasp genus Asobara (Hymenoptera: Braconidae.

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Wen-Juan Ma

Full Text Available An attractive way to improve our understanding of sex determination evolution is to study the underlying mechanisms in closely related species and in a phylogenetic perspective. Hymenopterans are well suited owing to the diverse sex determination mechanisms, including different types of Complementary Sex Determination (CSD and maternal control sex determination. We investigated different types of CSD in four species within the braconid wasp genus Asobara that exhibit diverse life-history traits. Nine to thirteen generations of inbreeding were monitored for diploid male production, brood size, offspring sex ratio, and pupal mortality as indicators for CSD. In addition, simulation models were developed to compare these observations to predicted patterns for multilocus CSD with up to ten loci. The inbreeding regime did not result in diploid male production, decreased brood sizes, substantially increased offspring sex ratios nor in increased pupal mortality. The simulations further allowed us to reject CSD with up to ten loci, which is a strong refutation of the multilocus CSD model. We discuss how the absence of CSD can be reconciled with the variation in life-history traits among Asobara species, and the ramifications for the phylogenetic distribution of sex determination mechanisms in the Hymenoptera.

Microsatellite loci discovery from next-generation sequencing data and loci characterization in the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758

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Christine Ewers-Saucedo

2016-05-01

Full Text Available Microsatellite markers remain an important tool for ecological and evolutionary research, but are unavailable for many non-model organisms. One such organism with rare ecological and evolutionary features is the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758. Chelonibia testudinaria appears to be a host generalist, and has an unusual sexual system, androdioecy. Genetic studies on host specificity and mating behavior are impeded by the lack of fine-scale, highly variable markers, such as microsatellite markers. In the present study, we discovered thousands of new microsatellite loci from next-generation sequencing data, and characterized 12 loci thoroughly. We conclude that 11 of these loci will be useful markers in future ecological and evolutionary studies on C. testudinaria.

Microsatellite loci discovery from next-generation sequencing data and loci characterization in the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758)

Science.gov (United States)

Zardus, John D.; Wares, John P.

2016-01-01

Microsatellite markers remain an important tool for ecological and evolutionary research, but are unavailable for many non-model organisms. One such organism with rare ecological and evolutionary features is the epizoic barnacle Chelonibia testudinaria (Linnaeus, 1758). Chelonibia testudinaria appears to be a host generalist, and has an unusual sexual system, androdioecy. Genetic studies on host specificity and mating behavior are impeded by the lack of fine-scale, highly variable markers, such as microsatellite markers. In the present study, we discovered thousands of new microsatellite loci from next-generation sequencing data, and characterized 12 loci thoroughly. We conclude that 11 of these loci will be useful markers in future ecological and evolutionary studies on C. testudinaria. PMID:27231653

High density genetic mapping identifies new susceptibility loci for rheumatoid arthritis

Science.gov (United States)

Eyre, Steve; Bowes, John; Diogo, Dorothée; Lee, Annette; Barton, Anne; Martin, Paul; Zhernakova, Alexandra; Stahl, Eli; Viatte, Sebastien; McAllister, Kate; Amos, Christopher I.; Padyukov, Leonid; Toes, Rene E.M.; Huizinga, Tom W.J.; Wijmenga, Cisca; Trynka, Gosia; Franke, Lude; Westra, Harm-Jan; Alfredsson, Lars; Hu, Xinli; Sandor, Cynthia; de Bakker, Paul I.W.; Davila, Sonia; Khor, Chiea Chuen; Heng, Khai Koon; Andrews, Robert; Edkins, Sarah; Hunt, Sarah E; Langford, Cordelia; Symmons, Deborah; Concannon, Pat; Onengut-Gumuscu, Suna; Rich, Stephen S; Deloukas, Panos; Gonzalez-Gay, Miguel A.; Rodriguez-Rodriguez, Luis; Ärlsetig, Lisbeth; Martin, Javier; Rantapää-Dahlqvist, Solbritt; Plenge, Robert; Raychaudhuri, Soumya; Klareskog, Lars; Gregersen, Peter K; Worthington, Jane

2012-01-01

Summary Using the Immunochip custom single nucleotide polymorphism (SNP) array, designed for dense genotyping of 186 genome wide association study (GWAS) confirmed loci we analysed 11,475 rheumatoid arthritis cases of European ancestry and 15,870 controls for 129,464 markers. The data were combined in meta-analysis with GWAS data from additional independent cases (n=2,363) and controls (n=17,872). We identified fourteen novel loci; nine were associated with rheumatoid arthritis overall and 5 specifically in anti-citrillunated peptide antibody positive disease, bringing the number of confirmed European ancestry rheumatoid arthritis loci to 46. We refined the peak of association to a single gene for 19 loci, identified secondary independent effects at six loci and association to low frequency variants (minor allele frequency <0.05) at 4 loci. Bioinformatic analysis of the data generated strong hypotheses for the causal SNP at seven loci. This study illustrates the advantages of dense SNP mapping analysis to inform subsequent functional investigations. PMID:23143596

19-VNTR loci used in genotyping Chinese clinical Mycobacterium tuberculosis complex strains and in association with spoligotyping.

Science.gov (United States)

Jiang, Yi; Liu, Hai-can; Zheng, Huajun; Dou, Xiangfeng; Tang, Biao; Zhao, Xiu-qin; Zhu, Yongqiang; Lu, Bing; Wang, Shengyue; Dong, Hai-yan; Zhang, Yuan-yuan; Zhao, Guoping; Wan, Kanglin

2013-07-01

Recently, tandem repeat typing has emerged as a rapid and easy method for the molecular epidemiology of the Mycobacterium tuberculosis (M. tuberculosis) complex. In this study, a collection of 19 VNTRs incorporating 15 previously described loci and 4 newly evaluated markers were used to genotype 206 Chinese M. tuberculosis isolates and 9 BCG strains. The discriminatory power was evaluated and compared with that obtained by Spoligotyping. It turned out that 15-locus VNTR could be very useful in M. tuberculosis complex strains genotyping in China. The 4 newly evaluated loci were proved informative and could be useful for future epidemiology studies, especially in Beijing family strains. In addition, a unique pattern of the latter 4 loci were found in Chinese BCG strains. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

[A population genetic study of 22 autosomal loci of single nucleotide polymorphisms].

Science.gov (United States)

Tang, Jian-pin; Jiang, Feng-hui; Shi, Mei-sen; Xu, Chuan-chao; Chen, Rui; Lai, Xiao-pin

2012-12-01

To evaluate polymorphisms and forensic efficiency of 22 non-binary single nucleotide polymorphism (SNP) loci. One hundred ethnic Han Chinese individuals were recruited from Dongguan, Guangdong. The 22 loci were genotyped with matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS). Nine loci were found with a single allele, 4 loci were found to be biallelic, whilst 9 loci were found to have 3 alleles. For 13 polymorphic loci, the combined discrimination power and power of exclusion were 0.999 98 and 0.9330, respectively. For the 9 non-biallelic loci, the combined discrimination power and power of exclusion were 0.9998 and 0.8956, respectively. For motherless cases, the combined power of exclusion was 0.6405 for 13 polymorphic SNPs and 0.6405 for 9 non-binary SNPs. Non-binary loci have a greater discrimination power and exclusion power per SNP.

Unraveling possible association between quantitative trait loci (QTL ...

African Journals Online (AJOL)

Unraveling possible association between quantitative trait loci (QTL) for partial resistance and nonhost resistance in food barley ( Hordeum vulgaris L.) ... Abstract. Many quantitative trait loci (QTLs) in different barley populations were discovered for resistance to Puccinia hordei and heterologous rust species. Partial ...

Population genetic analysis of the GlobalFiler STR loci in 748 individuals from the Kazakh population of Xinjiang in northwest China.

Science.gov (United States)

Zhang, Honghua; Yang, Shuping; Guo, Wei; Ren, Bo; Pu, Liwen; Ma, Teng; Xia, Mingying; Jin, Li; Li, Liming; Li, Shilin

2016-09-01

The six-dye GlobalFiler™ Express PCR amplification kit incorporates 21 commonly used autosomal short tandem repeat (STR) loci and three gender determination loci. In this study, we analyzed the GlobalFiler STR loci on 748 unrelated individuals from a Chinese Kazakh population of Xinjiang, China. No significant deviations from Hardy-Weinberg equilibrium and linkage disequilibrium were observed within and between 21 autosomal STR loci. SE33 showed the greatest power of discrimination in Kazakh population. The combined power of discrimination of Kazakh was 99.999999999999999999999996797 %. No significant differences of allele frequencies were observed between Kazakh and Uyghur at all 15 tested STR loci, as well as Mongolian. Significant differences were only observed between Kazakh and the other Chinese populations at TH01. Multiple STR loci showed significant differences between Kazakh and Arab, as well as South Portuguese. The multidimensional scaling plot (MDS) plot and neighbor-joining tree also showed Kazakh is genetically close to Uyghur.

Genius loci / Madis Kõiv

Index Scriptorium Estoniae

Kõiv, Madis, 1929-2014

2005-01-01

Ettekanne 37. Kreutzwaldi päevadel Tartu Kirjandusmuuseumis 18.-19. dets. 1993, pealkirjaga "Kus on see Valga, kus on see Tartu...: Genius loci B. Kangro ja V. Uibopuu romaanides". Varem ilmunud: Akadeemia, 1994, nr. 4

Quantitative trait loci mapping of calving and conformation traits on Bos taurus autosome 18 in the German Holstein population.

Science.gov (United States)

Brand, B; Baes, C; Mayer, M; Reinsch, N; Seidenspinner, T; Thaller, G; Kühn, Ch

2010-03-01

region previously reported to harbor QTL for somatic cell score indicated that effects of QTL for udder type traits might be correlated with effects of QTL for udder health traits on BTA18. Our results suggest that loci in the middle to telomeric region on BTA18 with effect on conformation traits may also contribute to the genetic variance of calving and udder health traits. Further analyses are required to identify the causal mutations affecting conformation and calving traits and to investigate the correlation of effects for loci associated with conformation, calving, and udder health traits.

Mapping quantitative trait loci (QTL in sheep. II. Meta-assembly and identification of novel QTL for milk production traits in sheep

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Lam Mary K

2009-10-01

Full Text Available Abstract An (Awassi × Merino × Merino backcross family of 172 ewes was used to map quantitative trait loci (QTL for different milk production traits on a framework map of 200 loci across all autosomes. From five previously proposed mathematical models describing lactation curves, the Wood model was considered the most appropriate due to its simplicity and its ability to determine ovine lactation curve characteristics. Derived milk traits for milk, fat, protein and lactose yield, as well as percentage composition and somatic cell score were used for single and two-QTL approaches using maximum likelihood estimation and regression analysis. A total of 15 significant (P P http://crcidp.vetsci.usyd.edu.au/cgi-bin/gbrowse/oaries_genome/. Many of the QTL for milk production traits have been reported on chromosomes 1, 3, 6, 16 and 20. Those on chromosomes 3 and 20 are in strong agreement with the results reported here. In addition, novel QTL were found on chromosomes 7, 8, 9, 14, 22 and 24. In a cross-species comparison, we extended the meta-assembly by comparing QTL regions of sheep and cattle, which provided strong evidence for synteny conservation of QTL regions for milk, fat, protein and somatic cell score data between cattle and sheep.

Alveolar epithelial type II cells induce T cell tolerance to specific antigen

DEFF Research Database (Denmark)

Lo, Bernice; Hansen, Søren; Evans, Kathy

2008-01-01

The lungs face the immunologic challenge of rapidly eliminating inhaled pathogens while maintaining tolerance to innocuous Ags. A break in this immune homeostasis may result in pulmonary inflammatory diseases, such as allergies or asthma. The observation that alveolar epithelial type II cells (Type...... II) constitutively express the class II MHC led us to hypothesize that Type II cells play a role in the adaptive immune response. Because Type II cells do not express detectable levels of the costimulatory molecules CD80 and CD86, we propose that Type II cells suppress activation of naive T cells...

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

DEFF Research Database (Denmark)

Demenais, Florence; Margaritte-Jeannin, Patricia; Barnes, Kathleen C

2018-01-01

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known...

Genetic variation of twenty autosomal STR loci and evaluate the ...

African Journals Online (AJOL)

SAM

2014-03-12

Mar 12, 2014 ... the second objective of the study was to evaluate the importance of these loci for forensic genetic purposes. ... of discrimination values for all tested loci was from 75 to 96%; therefore, those loci can be safely used to establish a ..... lists the frequency distribution of individual alleles within a given genetic ...

radEq Add-On Module for CFD Solver Loci-CHEM

Science.gov (United States)

McCloud, Peter

2013-01-01

Loci-CHEM to be applied to flow velocities where surface radiation due to heating from compression and friction becomes significant. The module adds a radiation equilibrium boundary condition to the computational fluid dynamics (CFD) code to produce accurate results. The module expanded the upper limit for accurate CFD solutions of Loci-CHEM from Mach 4 to Mach 10 based on Space Shuttle Orbiter Re-Entry trajectories. Loci-CHEM already has a very promising architecture and performance, but absence of radiation equilibrium boundary condition limited the application of Loci-CHEM to below Mach 4. The immediate advantage of the add-on module is that it allows Loci-CHEM to work with supersonic flows up to Mach 10. This transformed Loci-CHEM from a rocket engine- heritage CFD code with general subsonic and low-supersonic applications, to an aeroheating code with hypersonic applications. The follow-on advantage of the module is that it is a building block for additional add-on modules that will solve for the heating generated at Mach numbers higher than 10.

Development of twelve microsatellite loci in the red tree corals Primnoa resedaeformis and Primnoa pacifica

Science.gov (United States)

Morrison, Cheryl L.; Springmann, Marcus J.; Shroades, Kelsey; Stone, Robert P.

2015-01-01

A suite of tetra-, penta-, and hexa-nucleotide microsatellite loci were developed from Roche 454 pyrosequencing data for the cold-water octocorals Primnoa resedaeformis and P. pacifica. Twelve of 98 primer sets tested consistently amplified in 30 P. resedaeformis samples from Baltimore Canyon (western North Atlantic Ocean) and in 24 P. pacifica samples (Shutter Ridge, eastern Gulf of Alaska). The loci displayed moderate levels of allelic diversity (average 7.5 alleles/locus) and heterozygosity (average 47 %). Levels of genetic diversity were sufficient to produce unique multi-locus genotypes and to distinguish species. These common species are long-lived (hundreds of years) and provide essential fish habitat (P. pacifica), yet populations are provided little protection from human activities. These loci will be used to determine regional patterns of population connectivity to inform effective marine spatial planning and ecosystem-based fisheries management.

Sex chromosome differentiation and the W- and Z-specific loci in Xenopus laevis.

Science.gov (United States)

Mawaribuchi, Shuuji; Takahashi, Shuji; Wada, Mikako; Uno, Yoshinobu; Matsuda, Yoichi; Kondo, Mariko; Fukui, Akimasa; Takamatsu, Nobuhiko; Taira, Masanori; Ito, Michihiko

2017-06-15

Genetic sex-determining systems in vertebrates include two basic types of heterogamety; XX (female)/XY (male) and ZZ (male)/ZW (female) types. The African clawed frog Xenopus laevis has a ZZ/ZW-type sex-determining system. In this species, we previously identified a W-specific sex (female)-determining gene dmw, and specified W and Z chromosomes, which could be morphologically indistinguishable (homomorphic). In addition to dmw, we most recently discovered two genes, named scanw and ccdc69w, and one gene, named capn5z in the W- and Z-specific regions, respectively. In this study, we revealed the detail structures of the W/Z-specific loci and genes. Sequence analysis indicated that there is almost no sequence similarity between 278kb W-specific and 83kb Z-specific sequences on chromosome 2Lq32-33, where both the transposable elements are abundant. Synteny and phylogenic analyses indicated that all the W/Z-specific genes might have emerged independently. Expression analysis demonstrated that scanw and ccdc69w or capn5z are expressed in early differentiating ZW gonads or testes, thereby suggesting possible roles in female or male development, respectively. Importantly, the sex-determining gene (SDG) dmw might have been generated after allotetraploidization, thereby indicating the construction of the new sex-determining system by dmw after species hybridization. Furthermore, by direct genotyping, we confirmed that diploid WW embryos developed into normal female frogs, which indicate that the Z-specific region is not essential for female development. Overall, these findings indicate that sex chromosome differentiation has started, although no heteromorphic sex chromosomes are evident yet, in X. laevis. Homologous recombination suppression might have promoted the accumulation of mutations and transposable elements, and enlarged the W/Z-specific regions, thereby resulting in differentiation of the W/Z chromosomes. Copyright © 2016 Elsevier Inc. All rights reserved.

Cytokine-induced killer cells are type II natural killer T cells

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Schmidt-Wolf, Ingo G.H.

2007-09-01

Full Text Available Background: Until now, cytokine-induced killer (CIK cells were assumed to be part of the type I natural killer T (NKT cell population, but it was not yet investigated if this is correct. Methods: For analysis, CIK cells were generated by various culture conditions. Human type I NKT cells express a T cell receptor (TCR composed of an invariant Vα24-JαQ chain combined with one of several Vβ chains. The Vα24 is a reliable marker for the presence of these TCRs. Results: While comparing cultures stimulated with different substances, we observed the lack of any Vα24 on the surface of CIK culture cells. Conclusion: We conclude that CIK cells do not belong to the type I NKT cells.

Inhibition of type I NKT cells by retinoids or following sulfatide-mediated activation of type II NKT cells attenuates alcoholic liver disease

Science.gov (United States)

Maricic, Igor; Sheng, Huiming; Marrero, Idania; Seki, Ehikiro; Kisseleva, Tatiana; Chaturvedi, Som; Molle, Natasha; Mathews, K. Stephanie; Gao, Bin; Kumar, Vipin

2015-01-01

Innate immune mechanisms leading to liver injury following chronic alcohol ingestion are poorly understood. Natural killer T (NKT) cells, enriched in the liver and comprised of at least two distinct subsets, type I and type II, recognize different lipid antigens presented by CD1d molecules. We have investigated whether differential activation of NKT cell subsets orchestrates inflammatory events leading to alcoholic liver disease (ALD). We found that following chronic plus binge feeding of Lieber-DeCarli liquid diet in male C57BL/6 mice, type I but not type II NKT cells are activated leading to recruitment of inflammatory Gr-1highCD11b+ cells into liver. A central finding is that liver injury following alcohol feeding is dependent upon type I NKT cells. Thus liver injury is significantly inhibited in Jα18−/− mice deficient in type I NKT cells as well as following their inactivation by sulfatide-mediated activation of type II NKT cells. Furthermore we have identified a novel pathway involving all-trans retinoic acid (ATRA) and its receptor RARγ signaling that inhibits type I NKT cells and consequently ALD. A semi-quantitative PCR analysis of hepatic gene expression of some of the key proinflammatory molecules shared in human disease indicated that their upregulation in ALD is dependent upon type I NKT cells. Conclusion Type I but not type II NKT cells become activated following alcohol feeding. Type I NKT cells-induced inflammation and neutrophil recruitment results in liver tissue damage while type II NKT cells protect from injury in ALD. Inhibition of type I NKT cells by retinoids or by sulfatide prevents ALD. Since the CD1d pathway is highly conserved between mice and humans, NKT cell subsets might be targeted for potential therapeutic intervention in ALD. PMID:25477000

Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks

NARCIS (Netherlands)

Demenais, Florence; Margaritte-Jeannin, Patricia; Barnes, Kathleen C; Cookson, William O C; Altmüller, Janine; Ang, Wei; Barr, R Graham; Beaty, Terri H; Becker, Allan B; Beilby, John; Bisgaard, Hans; Bjornsdottir, Unnur Steina; Bleecker, Eugene; Bønnelykke, Klaus; Boomsma, Dorret I; Bouzigon, Emmanuelle; Brightling, Christopher E; Brossard, Myriam; Brusselle, Guy G; Burchard, Esteban; Burkart, Kristin M; Bush, Andrew; Chan-Yeung, Moira; Chung, Kian Fan; Couto Alves, Alexessander; Curtin, John A; Custovic, Adnan; Daley, Denise; de Jongste, Johan C; Del-Rio-Navarro, Blanca E; Donohue, Kathleen M; Duijts, Liesbeth; Eng, Celeste; Eriksson, Johan G; Farrall, Martin; Fedorova, Yuliya; Feenstra, Bjarke; Ferreira, Manuel A; Freidin, Maxim B; Gajdos, Zofia; Gauderman, Jim; Gehring, Ulrike; Geller, Frank; Genuneit, Jon; Gharib, Sina A; Gilliland, Frank; Granell, Raquel; Graves, Penelope E; Gudbjartsson, Daniel F; Haahtela, Tari; Heckbert, Susan R; Heederik, Dick; Heinrich, Joachim; Heliövaara, Markku; Henderson, John; Himes, Blanca E; Hirose, Hiroshi; Hirschhorn, Joel N; Hofman, Albert; Holt, Patrick; Hottenga, Jouke; Hudson, Thomas J; Hui, Jennie; Imboden, Medea; Ivanov, Vladimir; Jaddoe, Vincent W V; James, Alan; Janson, Christer; Jarvelin, Marjo-Riitta; Jarvis, Deborah; Jones, Graham; Jonsdottir, Ingileif; Jousilahti, Pekka; Kabesch, Michael; Kähönen, Mika; Kantor, David B; Karunas, Alexandra S; Khusnutdinova, Elza; Koppelman, Gerard H; Kozyrskyj, Anita L; Kreiner, Eskil; Kubo, Michiaki; Kumar, Rajesh; Kumar, Ashish; Kuokkanen, Mikko; Lahousse, Lies; Laitinen, Tarja; Laprise, Catherine; Lathrop, Mark; Lau, Susanne; Lee, Young-Ae; Lehtimäki, Terho; Letort, Sébastien; Levin, Albert M; Li, Guo; Liang, Liming; Loehr, Laura R; London, Stephanie J; Loth, Daan W; Manichaikul, Ani; Marenholz, Ingo; Martinez, Fernando J; Matheson, Melanie C; Mathias, Rasika A; Matsumoto, Kenji; Mbarek, Hamdi; McArdle, Wendy L; Melbye, Mads; Melén, Erik; Meyers, Deborah; Michel, Sven; Mohamdi, Hamida; Musk, Arthur W; Myers, Rachel A; Nieuwenhuis, Maartje A E; Noguchi, Emiko; O'Connor, George T; Ogorodova, Ludmila M; Palmer, Cameron D; Palotie, Aarno; Park, Julie E; Pennell, Craig E; Pershagen, Göran; Polonikov, Alexey; Postma, Dirkje S; Probst-Hensch, Nicole; Puzyrev, Valery P; Raby, Benjamin A; Raitakari, Olli T; Ramasamy, Adaikalavan; Rich, Stephen S; Robertson, Colin F; Romieu, Isabelle; Salam, Muhammad T; Salomaa, Veikko; Schlünssen, Vivi; Scott, Robert; Selivanova, Polina A; Sigsgaard, Torben; Simpson, Angela; Siroux, Valérie; Smith, Lewis J; Solodilova, Maria; Standl, Marie; Stefansson, Kari; Strachan, David P; Stricker, Bruno H; Takahashi, Atsushi; Thompson, Philip J; Thorleifsson, Gudmar; Thorsteinsdottir, Unnur; Tiesler, Carla M T; Torgerson, Dara G; Tsunoda, Tatsuhiko; Uitterlinden, André G; van der Valk, Ralf J P; Vaysse, Amaury; Vedantam, Sailaja; von Berg, Andrea; von Mutius, Erika; Vonk, Judith M; Waage, Johannes; Wareham, Nick J; Weiss, Scott T; White, Wendy B; Wickman, Magnus; Widén, Elisabeth; Willemsen, Gonneke; Williams, L Keoki; Wouters, Inge M; Yang, James J; Zhao, Jing Hua; Moffatt, Miriam F; Ober, Carole; Nicolae, Dan L

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma

Glycotoxin and Autoantibodies Are Additive Environmentally Determined Predictors of Type 1 Diabetes

Science.gov (United States)

Beyan, Huriya; Riese, Harriette; Hawa, Mohammed I.; Beretta, Guisi; Davidson, Howard W.; Hutton, John C.; Burger, Huibert; Schlosser, Michael; Snieder, Harold; Boehm, Bernhard O.; Leslie, R. David

2012-01-01

In type 1 diabetes, diabetes-associated autoantibodies, including islet cell antibodies (ICAs), reflect adaptive immunity, while increased serum Nε-carboxymethyl-lysine (CML), an advanced glycation end product, is associated with proinflammation. We assessed whether serum CML and autoantibodies predicted type 1 diabetes and to what extent they were determined by genetic or environmental factors. Of 7,287 unselected schoolchildren screened, 115 were ICA+ and were tested for baseline CML and diabetes autoantibodies and followed (for median 7 years), whereas a random selection (n = 2,102) had CML tested. CML and diabetes autoantibodies were determined in a classic twin study of twin pairs discordant for type 1 diabetes (32 monozygotic, 32 dizygotic pairs). CML was determined by enzyme-linked immunosorbent assay, autoantibodies were determined by radioimmunoprecipitation, ICA was determined by indirect immunofluorescence, and HLA class II genotyping was determined by sequence-specific oligonucleotides. CML was increased in ICA+ and prediabetic schoolchildren and in diabetic and nondiabetic twins (all P < 0.001). Elevated levels of CML in ICA+ children were a persistent, independent predictor of diabetes progression, in addition to autoantibodies and HLA risk. In twins model fitting, familial environment explained 75% of CML variance, and nonshared environment explained all autoantibody variance. Serum CML, a glycotoxin, emerged as an environmentally determined diabetes risk factor, in addition to autoimmunity and HLA genetic risk, and a potential therapeutic target. PMID:22396204

Multiple var2csa-type PfEMP1 genes located at different chromosomal loci occur in many Plasmodium falciparum isolates

DEFF Research Database (Denmark)

Sander, Adam F; Salanti, Ali; Lavstsen, Thomas

2009-01-01

in the VAR2CSA protein, sequence variation in the DBL2X region of var2csa genes in 54 P.falciparum samples was analyzed. Chromosome mapping of var2csa loci was carried out and a quantitative PCR assay was developed to estimate the number of var2csa genes in P.falciparum isolates from the placenta of pregnant....... falciparum isolates. One gene is on chromosome 12 but additional var2csa-type genes are on different chromosomes in different isolates. Multiplicity of var2csa genes appears more common in infected placentae than in samples from non-pregnant donors indicating a possible advantage of this genotype...

Sulfatide-activated type II NKT cells prevent allergic airway inflammation by inhibiting type I NKT cell function in a mouse model of asthma.

Science.gov (United States)

Zhang, Guqin; Nie, Hanxiang; Yang, Jiong; Ding, Xuhong; Huang, Yi; Yu, Hongying; Li, Ruyou; Yuan, Zhuqing; Hu, Suping

2011-12-01

Asthma is a common chronic inflammatory disease involving many different cell types. Recently, type I natural killer T (NKT) cells have been demonstrated to play a crucial role in the development of asthma. However, the roles of type II NKT cells in asthma have not been investigated before. Interestingly, type I and type II NKT cells have been shown to have opposing roles in antitumor immunity, antiparasite immunity, and autoimmunity. We hypothesized that sulfatide-activated type II NKT cells could prevent allergic airway inflammation by inhibiting type I NKT cell function in asthma. Strikingly, in our mouse model, activation of type II NKT cells by sulfatide administration and adoptive transfer of sulfatide-activated type II NKT cells result in reduced-inflammation cell infiltration in the lung and bronchoalveolar lavage fluid, decreased levels of IL-4 and IL-5 in the BALF; and decreased serum levels of ovalbumin-specific IgE and IgG1. Furthermore, it is found that the activation of sulfatide-reactive type II NKT cells leads to the functional inactivation of type I NKT cells, including the proliferation and cytokine secretion. Our data reveal that type II NKT cells activated by glycolipids, such as sulfatide, may serve as a novel approach to treat allergic diseases and other disorders characterized by inappropriate type I NKT cell activation.

Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

DEFF Research Database (Denmark)

Zuber, Verena; Bettella, Francesco; Witoelar, Aree

2017-01-01

progression. Although previous approaches have been tried to explain risk associated with SNPs in regulatory DNA elements, so far epigenetic readers such as bromodomain containing protein 4 (BRD4) and super-enhancers have not been used to annotate SNPs. In prostate cancer (PC), androgen receptor (AR) binding......Background: Epigenetic information can be used to identify clinically relevant genomic variants single nucleotide polymorphisms (SNPs) of functional importance in cancer development. Super-enhancers are cell-specific DNA elements, acting to determine tissue or cell identity and driving tumor...... the differential enrichment of SNPs mapping to specific categories of enhancers. We find that BRD4 is the key discriminant of tissue-specific enhancers, showing that it is more powerful than AR binding information to capture PC specific risk loci, and can be used with similar effect in breast cancer (BC...

Multiple loci associated with renal function in African Americans.

Directory of Open Access Journals (Sweden)

Daniel Shriner

Full Text Available The incidence of chronic kidney disease varies by ethnic group in the USA, with African Americans displaying a two-fold higher rate than European Americans. One of the two defining variables underlying staging of chronic kidney disease is the glomerular filtration rate. Meta-analysis in individuals of European ancestry has identified 23 genetic loci associated with the estimated glomerular filtration rate (eGFR. We conducted a follow-up study of these 23 genetic loci using a population-based sample of 1,018 unrelated admixed African Americans. We included in our follow-up study two variants in APOL1 associated with end-stage kidney disease discovered by admixture mapping in admixed African Americans. To address confounding due to admixture, we estimated local ancestry at each marker and global ancestry. We performed regression analysis stratified by local ancestry and combined the resulting regression estimates across ancestry strata using an inverse variance-weighted fixed effects model. We found that 11 of the 24 loci were significantly associated with eGFR in our sample. The effect size estimates were not significantly different between the subgroups of individuals with two copies of African ancestry vs. two copies of European ancestry for any of the 11 loci. In contrast, allele frequencies were significantly different at 10 of the 11 loci. Collectively, the 11 loci, including four secondary signals revealed by conditional analyses, explained 14.2% of the phenotypic variance in eGFR, in contrast to the 1.4% explained by the 24 loci in individuals of European ancestry. Our findings provide insight into the genetic basis of variation in renal function among admixed African Americans.

Industrial n-type solar cells with >20% cell efficiency

Energy Technology Data Exchange (ETDEWEB)

Romijn, I.G.; Anker, J.; Burgers, A.R.; Gutjahr, A.; Koppes, M.; Kossen, E.J.; Lamers, M.W.P.E.; Heurtault, Benoit; Saynova-Oosterling, D.S.; Tool, C.J.J. [ECN Solar Energy, Petten (Netherlands)

2013-03-15

To realize high efficiencies at low costs, ECN has developed the n-Pasha solar cell concept. The n-Pasha cell concept is a bifacial solar cell concept on n-Cz base material, with which average efficiencies of above 20% have been demonstrated. In this paper recent developments at ECN to improve the cost of ownership (lower Euro/Wp) of the n-Pasha cell concept are discussed. Two main drivers for the manufacturing costs of n-type solar cells are addressed: the n-type Cz silicon material and the silver consumption. We show that a large resistivity range between 2 and 8 cm can be tolerated for high cell efficiency, and that the costs due to the silver metallization can be significantly reduced while increasing the solar cell efficiency. Combining the improved efficiency and cost reduction makes the n-Pasha cell concept a very cost effective solution to manufacture high efficient solar cells and modules.

A critical re-evaluation of multilocus sequence typing (MLST) efforts in Wolbachia.

Science.gov (United States)

Bleidorn, Christoph; Gerth, Michael

2018-01-01

Wolbachia (Alphaproteobacteria, Rickettsiales) is the most common, and arguably one of the most important inherited symbionts. Molecular differentiation of Wolbachia strains is routinely performed with a set of five multilocus sequence typing (MLST) markers. However, since its inception in 2006, the performance of MLST in Wolbachia strain typing has not been assessed objectively. Here, we evaluate the properties of Wolbachia MLST markers and compare it to 252 other single copy loci present in the genome of most Wolbachia strains. Specifically, we investigated how well MLST performs at strain differentiation, at reflecting genetic diversity of strains, and as phylogenetic marker. We find that MLST loci are outperformed by other loci at all tasks they are currently employed for, and thus that they do not reflect the properties of a Wolbachia strain very well. We argue that whole genome typing approaches should be used for Wolbachia typing in the future. Alternatively, if few loci approaches are necessary, we provide a characterisation of 252 single copy loci for a number a criteria, which may assist in designing specific typing systems or phylogenetic studies. © FEMS 2017. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

The preventive role of type 2 NKT cells in the development of type 1 diabetes.

Science.gov (United States)

Sørensen, Jakob Ørskov; Buschard, Karsten; Brogren, Carl-Henrik

2014-03-01

In the last two decades, natural killer T (NKT) cells have emerged as an important factor in preventing type 1 diabetes (T1D) when investigated in the experimental non-obese diabetic (NOD) mouse model. So far, investigations have largely focused on type 1 NKT cells with invariant T-cell receptors, whereas the role of type 2 NKT cells with diverse T-cell receptors is less well understood. However, there have been several findings which indicate that in fact type 2 NKT cells may regulate the progression of type 1 diabetes in NOD mice, including a fraction of these cells which recognize β-cell-enriched sulfatide. Therefore, the focus for this review is to present the current evidence of the effect of type 2 NKT cells on the development of T1D. In general, there is still uncertainty surrounding the mechanism of activation and function of NKT cells. Here, we present two models of the effector mechanisms, respectively, Th1/Th2 polarization and the induction of tolerogenic dendritic cells (DC). In conclusion, this review points to the importance of immunoregulation by type 2 NKT cells in preventing the development of T1D and highlights the induction of tolerogenic DC as a likely mechanism. The possible therapeutic role of type 1 and type 2 NKT cells are evaluated and future experiments concerning type 2 NKT cells and T1D are proposed. © 2013 APMIS. Published by John Wiley & Sons Ltd.

DNA Methylation Patterns in Cord Blood of Neonates Across Gestational Age: Association With Cell-Type Proportions.

Science.gov (United States)

Braid, Susan M; Okrah, Kwame; Shetty, Amol; Corrada Bravo, Hector

A statistical methodology is available to estimate the proportion of cell types (cellular heterogeneity) in adult whole blood specimens used in epigenome-wide association studies (EWAS). However, there is no methodology to estimate the proportion of cell types in umbilical cord blood (also a heterogeneous tissue) used in EWAS. The objectives of this study were to determine whether differences in DNA methylation (DNAm) patterns in umbilical cord blood are the result of blood cell type proportion changes that typically occur across gestational age and to demonstrate the effect of cell type proportion confounding by comparing preterm infants exposed and not exposed to antenatal steroids. We obtained DNAm profiles of cord blood using the Illumina HumanMethylation27k BeadChip array for 385 neonates from the Boston Birth Cohort. We estimated cell type proportions for six cell types using the deconvolution method developed by . The cell type proportion estimates segregated into two groups that were significantly different by gestational age, indicating that gestational age was associated with cell type proportion. Among infants exposed to antenatal steroids, the number of differentially methylated CpGs dropped from 127 to 1 after controlling for cell type proportion. EWAS utilizing cord blood are confounded by cell type proportion. Careful study design including correction for cell type proportion and interpretation of results of EWAS using cord blood are critical.

Identification of variant alleles at AmpFlSTR SGM Plus STR loci in a ...

African Journals Online (AJOL)

STORAGESEVER

2008-10-20

Oct 20, 2008 ... origin. It is therefore important that forensic science community shares information on the occurrence of these variants and reduces complications during STR typing. In this study, we report 5 variant alleles at AmpFlSTR SGM. Plus loci in a sample population of Bangladesh. MATERIALS AND METHODS.

Linkage of DNA Methylation Quantitative Trait Loci to Human Cancer Risk

Directory of Open Access Journals (Sweden)

Holger Heyn

2014-04-01

Full Text Available Epigenetic regulation and, in particular, DNA methylation have been linked to the underlying genetic sequence. DNA methylation quantitative trait loci (meQTL have been identified through significant associations between the genetic and epigenetic codes in physiological and pathological contexts. We propose that interrogating the interplay between polymorphic alleles and DNA methylation is a powerful method for improving our interpretation of risk alleles identified in genome-wide association studies that otherwise lack mechanistic explanation. We integrated patient cancer risk genotype data and genome-scale DNA methylation profiles of 3,649 primary human tumors, representing 13 solid cancer types. We provide a comprehensive meQTL catalog containing DNA methylation associations for 21% of interrogated cancer risk polymorphisms. Differentially methylated loci harbor previously reported and as-yet-unidentified cancer genes. We suggest that such regulation at the DNA level can provide a considerable amount of new information about the biology of cancer-risk alleles.

Enteroendocrine cell types revisited

DEFF Research Database (Denmark)

Engelstoft, Maja S; Egerod, Kristoffer Lihme; Lund, Mari L

2013-01-01

The GI-tract is profoundly involved in the control of metabolism through peptide hormones secreted from enteroendocrine cells scattered throughout the gut mucosa. A large number of recently generated transgenic reporter mice have allowed for direct characterization of biochemical and cell...... biological properties of these previously highly elusive enteroendocrine cells. In particular the surprisingly broad co-expression of six functionally related hormones in the intestinal enteroendocrine cells indicates that it should be possible to control not only the hormone secretion but also the type...... and number of enteroendocrine cells. However, this will require a more deep understanding of the factors controlling differentiation, gene expression and specification of the enteroendocrine cells during their weekly renewal from progenitor cells in the crypts of the mucosa....

Replication and meta-analysis of GWAS identified susceptibility loci in Kawasaki disease confirm the importance of B lymphoid tyrosine kinase (BLK in disease susceptibility.

Directory of Open Access Journals (Sweden)

Chia-Jung Chang

Full Text Available The BLK and CD40 loci have been associated with Kawasaki disease (KD in two genome-wide association studies (GWAS conducted in a Taiwanese population of Han Chinese ancestry (Taiwanese and in Japanese cohorts. Here we build on these findings with replication studies of the BLK and CD40 loci in populations of Korean and European descent. The BLK region was significantly associated with KD susceptibility in both populations. Within the BLK gene the rs2736340-located linkage disequilibrium (LD comprising the promoter and first intron was strongly associated with KD, with the combined results of Asian studies including Taiwanese, Japanese, and Korean populations (2,539 KD patients and 7,021 controls providing very compelling evidence of association (rs2736340, OR = 1.498, 1.354-1.657; P = 4.74×10(-31. We determined the percentage of B cells present in the peripheral blood mononuclear cell (PBMC population and the expression of BLK in the peripheral blood leukocytes (leukocytes of KD patients during the acute and convalescent stages. The percentage of B cells in the PBMC population and the expression of BLK in leukocytes were induced in patients in the acute stage of KD. In B cell lines derived from KD patients, and in purified B cells from KD patients obtained during the acute stage, those with the risk allele of rs2736340 expressed significantly lower levels of BLK. These results suggest that peripheral B cells play a pathogenic role during the acute stage of KD. Decreased BLK expression in peripheral blood B cells may alter B cell function and predispose individuals to KD. These associative data suggest a role for B cells during acute KD. Understanding the functional implications may facilitate the development of B cell-mediated therapy for KD.

Construction of an external electrode for determination of electrochemical corrosion potential in normal operational conditions of an BWR type reactor for hot cells

International Nuclear Information System (INIS)

Aguilar T, J.A.; Rivera M, H.; Hernandez C, R.

2001-01-01

The behavior of the corrosion processes at high temperature requires of external devices that being capable to resist a temperature of 288 Centigrade and a pressure of 80 Kg/cm 2 , to give stable and reproducible results of some variable and resisting physically and chemically the radiation. The external electrode of Ag/AgCl fulfils all the requirements in the determination of the electrochemical corrosion potential under normal operational conditions of a BWR type reactor in hot cells. (Author)

Outlier Loci and Selection Signatures of Simple Sequence Repeats (SSRs) in Flax (Linum usitatissimum L.).

Science.gov (United States)

Soto-Cerda, Braulio J; Cloutier, Sylvie

2013-01-01

Genomic microsatellites (gSSRs) and expressed sequence tag-derived SSRs (EST-SSRs) have gained wide application for elucidating genetic diversity and population structure in plants. Both marker systems are assumed to be selectively neutral when making demographic inferences, but this assumption is rarely tested. In this study, three neutrality tests were assessed for identifying outlier loci among 150 SSRs (85 gSSRs and 65 EST-SSRs) that likely influence estimates of population structure in three differentiated flax sub-populations ( F ST  = 0.19). Moreover, the utility of gSSRs, EST-SSRs, and the combined sets of SSRs was also evaluated in assessing genetic diversity and population structure in flax. Six outlier loci were identified by at least two neutrality tests showing footprints of balancing selection. After removing the outlier loci, the STRUCTURE analysis and the dendrogram topology of EST-SSRs improved. Conversely, gSSRs and combined SSRs results did not change significantly, possibly as a consequence of the higher number of neutral loci assessed. Taken together, the genetic structure analyses established the superiority of gSSRs to determine the genetic relationships among flax accessions, although the combined SSRs produced the best results. Genetic diversity parameters did not differ statistically ( P  > 0.05) between gSSRs and EST-SSRs, an observation partially explained by the similar number of repeat motifs. Our study provides new insights into the ability of gSSRs and EST-SSRs to measure genetic diversity and structure in flax and confirms the importance of testing for the occurrence of outlier loci to properly assess natural and breeding populations, particularly in studies considering only few loci.

Single-trait and multi-trait genome-wide association analyses identify novel loci for blood pressure in African-ancestry populations.

Directory of Open Access Journals (Sweden)

Jingjing Liang

2017-05-01

Full Text Available Hypertension is a leading cause of global disease, mortality, and disability. While individuals of African descent suffer a disproportionate burden of hypertension and its complications, they have been underrepresented in genetic studies. To identify novel susceptibility loci for blood pressure and hypertension in people of African ancestry, we performed both single and multiple-trait genome-wide association analyses. We analyzed 21 genome-wide association studies comprised of 31,968 individuals of African ancestry, and validated our results with additional 54,395 individuals from multi-ethnic studies. These analyses identified nine loci with eleven independent variants which reached genome-wide significance (P < 1.25×10-8 for either systolic and diastolic blood pressure, hypertension, or for combined traits. Single-trait analyses identified two loci (TARID/TCF21 and LLPH/TMBIM4 and multiple-trait analyses identified one novel locus (FRMD3 for blood pressure. At these three loci, as well as at GRP20/CDH17, associated variants had alleles common only in African-ancestry populations. Functional annotation showed enrichment for genes expressed in immune and kidney cells, as well as in heart and vascular cells/tissues. Experiments driven by these findings and using angiotensin-II induced hypertension in mice showed altered kidney mRNA expression of six genes, suggesting their potential role in hypertension. Our study provides new evidence for genes related to hypertension susceptibility, and the need to study African-ancestry populations in order to identify biologic factors contributing to hypertension.

Ancient conservation of trinucleotide microsatellite loci in polistine wasps

DEFF Research Database (Denmark)

Ezenwa, V O; Peters, J M; Zhu, Y

1998-01-01

Microsatellites have proven to be very useful genetic markers for studies of kinship, parentage, and gene mapping. If microsatellites are conserved among species, then those developed for one species can be used on related species, which would save the time and effort of developing new loci. We...... evaluated conservation of 27 trinucleotide loci that were derived from 2 species of Polistes wasps in cross-species applications on 27 species chosen from the major lineages of the Vespidae, which diverged as much as 144 million years ago. We further investigated cross-species polymorphism levels for 18...... of the loci. There was a clear relationship between cladistic distance and both conservation of the priming sites and heterozygosity. However the loci derived from P. bellicosus were much more widely conserved and polymorphic than were those derived from P. annularis. The disparity in cross-species utility...

Biology and applications of human minisatellite loci.

Science.gov (United States)

Armour, J A; Jeffreys, A J

1992-12-01

Highly repetitive minisatellites' include the most variable human loci described to date. They have proved invaluable in a wide variety of genetic analyses, and despite some controversies surrounding their practical implementation, have been extensively adopted in civil and forensic casework. Molecular analysis of internal allelic structure has provided detailed insights into the repeat-unit turnover mechanisms operating in germline mutations, which are ultimately responsible for the extreme variability seen at these loci.

Population data and mutation rates of 20 autosomal STR loci in a Chinese Han population from Yunnan Province, Southwest China.

Science.gov (United States)

Zhang, Xiufeng; Liu, Linlin; Xie, Runfang; Wang, Guiyi; Shi, Yuan; Gu, Tao; Hu, Liping; Nie, Shengjie

2018-07-01

The genetic polymorphisms of 20 autosomal short tandem repeat (STR) loci included in the PowerPlex® 21 kit were evaluated from 2068 unrelated, healthy individuals from the Chinese Han population of Yunnan Province in southwest China. All of the loci reached Hardy-Weinberg equilibrium. These loci were examined to determine allele frequencies and forensic statistical parameters. The genetic relationships among the Yunnan Han and other Chinese populations were also estimated. The combined discrimination power and probability of excluding paternity of the 20 STR loci were 0.99999999999999999999999126 and 0.999999975, respectively. In addition, mutation rates from 4363 parentage cases (2215 trios and 2148 duos) were investigated in this study. A total of 164 mutations were observed in 6578 meioses from the 20 loci. The highest mutation rate was observed in D12S391 (0.30%), and the lowest mutation rates were observed in D13S317 (0.03%) and TPOX (0.03%). The average mutation rate for the 20 loci was estimated to be 1.246 × 10 -3 per meiosis. The mutations were primarily single-step and paternal mutations.

Choline Deficiency Causes Colonic Type II Natural Killer T (NKT) Cell Loss and Alleviates Murine Colitis under Type I NKT Cell Deficiency.

Science.gov (United States)

Sagami, Shintaro; Ueno, Yoshitaka; Tanaka, Shinji; Fujita, Akira; Niitsu, Hiroaki; Hayashi, Ryohei; Hyogo, Hideyuki; Hinoi, Takao; Kitadai, Yasuhiko; Chayama, Kazuaki

2017-01-01

Serum levels of choline and its derivatives are lower in patients with inflammatory bowel disease (IBD) than in healthy individuals. However, the effect of choline deficiency on the severity of colitis has not been investigated. In the present study, we investigated the role of choline deficiency in dextran sulfate sodium (DSS)-induced colitis in mice. Methionine-choline-deficient (MCD) diet lowered the levels of type II natural killer T (NKT) cells in the colonic lamina propria, peritoneal cavity, and mesenteric lymph nodes, and increased the levels of type II NKT cells in the livers of wild-type B6 mice compared with that in mice fed a control (CTR) diet. The gene expression pattern of the chemokine receptor CXCR6, which promotes NKT cell accumulation, varied between colon and liver in a manner dependent on the changes in the type II NKT cell levels. To examine the role of type II NKT cells in colitis under choline-deficient conditions, we assessed the severity of DSS-induced colitis in type I NKT cell-deficient (Jα18-/-) or type I and type II NKT cell-deficient (CD1d-/-) mice fed the MCD or CTR diets. The MCD diet led to amelioration of inflammation, decreases in interferon (IFN)-γ and interleukin (IL)-4 secretion, and a decrease in the number of IFN-γ and IL-4-producing NKT cells in Jα18-/- mice but not in CD1d-/- mice. Finally, adaptive transfer of lymphocytes with type II NKT cells exacerbated DSS-induced colitis in Jα18-/- mice with MCD diet. These results suggest that choline deficiency causes proinflammatory type II NKT cell loss and alleviates DSS-induced colitis. Thus, inflammation in DSS-induced colitis under choline deficiency is caused by type II NKT cell-dependent mechanisms, including decreased type II NKT cell and proinflammatory cytokine levels.

"Byrummets ånd. Genius Loci/The Spirit of Urban Spaces"

DEFF Research Database (Denmark)

Reeh, Henrik

2004-01-01

byrum, Genius loci, Christian Norberg-Schulz, Sønder Boulevard, Berlin, nykultur, fortove, barndomserindringer......byrum, Genius loci, Christian Norberg-Schulz, Sønder Boulevard, Berlin, nykultur, fortove, barndomserindringer...

Discovery and refinement of loci associated with lipid levels

NARCIS (Netherlands)

Willer, Cristen J.; Schmidt, Ellen M.; Sengupta, Sebanti; Peloso, Gina M.; Gustafsson, Stefan; Kanoni, Stavroula; Ganna, Andrea; Chen, Jin; Buchkovich, Martin L.; Mora, Samia; Beckmann, Jacques S.; Bragg-Gresham, Jennifer L.; Chang, Hsing-Yi; Demirkan, Ayşe; den Hertog, Heleen M.; Do, Ron; Donnelly, Louise A.; Ehret, Georg B.; Esko, Tõnu; Feitosa, Mary F.; Ferreira, Teresa; Fischer, Krista; Fontanillas, Pierre; Fraser, Ross M.; Freitag, Daniel F.; Gurdasani, Deepti; Heikkilä, Kauko; Hyppönen, Elina; Isaacs, Aaron; Jackson, Anne U.; Johansson, Asa; Johnson, Toby; Kaakinen, Marika; Kettunen, Johannes; Kleber, Marcus E.; Li, Xiaohui; Luan, Jian'an; Lyytikäinen, Leo-Pekka; Magnusson, Patrik K. E.; Mangino, Massimo; Mihailov, Evelin; Montasser, May E.; Müller-Nurasyid, Martina; Nolte, Ilja M.; O'Connell, Jeffrey R.; Palmer, Cameron D.; Perola, Markus; Petersen, Ann-Kristin; Sanna, Serena; Saxena, Richa; Service, Susan K.; Shah, Sonia; Shungin, Dmitry; Sidore, Carlo; Song, Ci; Strawbridge, Rona J.; Surakka, Ida; Tanaka, Toshiko; Teslovich, Tanya M.; Thorleifsson, Gudmar; van den Herik, Evita G.; Voight, Benjamin F.; Volcik, Kelly A.; Waite, Lindsay L.; Wong, Andrew; Wu, Ying; Zhang, Weihua; Absher, Devin; Asiki, Gershim; Barroso, Inês; Been, Latonya F.; Bolton, Jennifer L.; Bonnycastle, Lori L.; Brambilla, Paolo; Burnett, Mary S.; Cesana, Giancarlo; Dimitriou, Maria; Doney, Alex S. F.; Döring, Angela; Elliott, Paul; Epstein, Stephen E.; Eyjolfsson, Gudmundur Ingi; Gigante, Bruna; Goodarzi, Mark O.; Grallert, Harald; Gravito, Martha L.; Groves, Christopher J.; Hallmans, Göran; Hartikainen, Anna-Liisa; Hayward, Caroline; Hernandez, Dena; Hicks, Andrew A.; Holm, Hilma; Hung, Yi-Jen; Illig, Thomas; Jones, Michelle R.; Kaleebu, Pontiano; Kastelein, John J. P.; Khaw, Kay-Tee; Kim, Eric; Klopp, Norman; Komulainen, Pirjo; Kumari, Meena; Langenberg, Claudia; Lehtimäki, Terho; Lin, Shih-Yi; Lindström, Jaana; Loos, Ruth J. F.; Mach, François; McArdle, Wendy L.; Meisinger, Christa; Mitchell, Braxton D.; Müller, Gabrielle; Nagaraja, Ramaiah; Narisu, Narisu; Nieminen, Tuomo V. M.; Nsubuga, Rebecca N.; Olafsson, Isleifur; Ong, Ken K.; Palotie, Aarno; Papamarkou, Theodore; Pomilla, Cristina; Pouta, Anneli; Rader, Daniel J.; Reilly, Muredach P.; Ridker, Paul M.; Rivadeneira, Fernando; Rudan, Igor; Ruokonen, Aimo; Samani, Nilesh; Scharnagl, Hubert; Seeley, Janet; Silander, Kaisa; Stancáková, Alena; Stirrups, Kathleen; Swift, Amy J.; Tiret, Laurence; Uitterlinden, Andre G.; van Pelt, L. Joost; Vedantam, Sailaja; Wainwright, Nicholas; Wijmenga, Cisca; Wild, Sarah H.; Willemsen, Gonneke; Wilsgaard, Tom; Wilson, James F.; Young, Elizabeth H.; Zhao, Jing Hua; Adair, Linda S.; Arveiler, Dominique; Assimes, Themistocles L.; Bandinelli, Stefania; Bennett, Franklyn; Bochud, Murielle; Boehm, Bernhard O.; Boomsma, Dorret I.; Borecki, Ingrid B.; Bornstein, Stefan R.; Bovet, Pascal; Burnier, Michel; Campbell, Harry; Chakravarti, Aravinda; Chambers, John C.; Chen, Yii-Der Ida; Collins, Francis S.; Cooper, Richard S.; Danesh, John; Dedoussis, George; de Faire, Ulf; Feranil, Alan B.; Ferrières, Jean; Ferrucci, Luigi; Freimer, Nelson B.; Gieger, Christian; Groop, Leif C.; Gudnason, Vilmundur; Gyllensten, Ulf; Hamsten, Anders; Harris, Tamara B.; Hingorani, Aroon; Hirschhorn, Joel N.; Hofman, Albert; Hovingh, G. Kees; Hsiung, Chao Agnes; Humphries, Steve E.; Hunt, Steven C.; Hveem, Kristian; Iribarren, Carlos; Järvelin, Marjo-Riitta; Jula, Antti; Kähönen, Mika; Kaprio, Jaakko; Kesäniemi, Antero; Kivimaki, Mika; Kooner, Jaspal S.; Koudstaal, Peter J.; Krauss, Ronald M.; Kuh, Diana; Kuusisto, Johanna; Kyvik, Kirsten O.; Laakso, Markku; Lakka, Timo A.; Lind, Lars; Lindgren, Cecilia M.; Martin, Nicholas G.; März, Winfried; McCarthy, Mark I.; McKenzie, Colin A.; Meneton, Pierre; Metspalu, Andres; Moilanen, Leena; Morris, Andrew D.; Munroe, Patricia B.; Njølstad, Inger; Pedersen, Nancy L.; Power, Chris; Pramstaller, Peter P.; Price, Jackie F.; Psaty, Bruce M.; Quertermous, Thomas; Rauramaa, Rainer; Saleheen, Danish; Salomaa, Veikko; Sanghera, Dharambir K.; Saramies, Jouko; Schwarz, Peter E. H.; Sheu, Wayne H.-H.; Shuldiner, Alan R.; Siegbahn, Agneta; Spector, Tim D.; Stefansson, Kari; Strachan, David P.; Tayo, Bamidele O.; Tremoli, Elena; Tuomilehto, Jaakko; Uusitupa, Matti; van Duijn, Cornelia M.; Vollenweider, Peter; Wallentin, Lars; Wareham, Nicholas J.; Whitfield, John B.; Wolffenbuttel, Bruce H. R.; Ordovas, Jose M.; Boerwinkle, Eric; Palmer, Colin N. A.; Thorsteinsdottir, Unnur; Chasman, Daniel I.; Rotter, Jerome I.; Franks, Paul W.; Ripatti, Samuli; Cupples, L. Adrienne; Sandhu, Manjinder S.; Rich, Stephen S.; Boehnke, Michael; Deloukas, Panos; Kathiresan, Sekar; Mohlke, Karen L.; Ingelsson, Erik; Abecasis, Gonçalo R.

2013-01-01

Levels of low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides and total cholesterol are heritable, modifiable risk factors for coronary artery disease. To identify new loci and refine known loci influencing these lipids, we examined 188,577

Major histocompatibility complex-restricted self-recognition in responses to trinitrophenyl-Ficoll. A novel cell interaction pathway requiring self-recognition of accessory cell H-2 determinants by both T cells and B cells

International Nuclear Information System (INIS)

Hodes, R.J.; Hathcock, K.S.; Singer, A.

1983-01-01

In vitro primary antibody responses to limiting concentrations of trinitrophenyl (TNP)-Ficoll were shown to be T cell dependent, requiring the cooperation of T helper (TH) cells, B cells, and accessory cells. Under these conditions, TH cells derived from long-term radiation bone marrow chimeras were major histocompatibility complex (MHC) restricted in their ability to cooperate with accessory cells expressing host-type MHC determinants. The requirement for MHC-restricted self-recognition by TNP-Ficoll-reactive B cells was assessed under these T-dependent conditions. In the presence of competent TH cells, chimeric B cells were found to be MHC restricted, cooperating only with accessory cells that expressed host-type MHC products. In contrast, the soluble products of certain monoclonal T cell lines were able to directly activate B cells in response to TNP-Ficoll, bypassing any requirement for MHC-restricted self-recognition. These findings demonstrate the existence of a novel cell interaction pathway in which B cells as well as TH cells are each required to recognize self-MHC determinants on accessory cells, but are not required to recognize each other. They further demonstrate that the requirement for self-recognition by B cells may be bypassed in certain T-dependent activation pathways

Cell elasticity with altered cytoskeletal architectures across multiple cell types.

Science.gov (United States)

Grady, Martha E; Composto, Russell J; Eckmann, David M

2016-08-01

The cytoskeleton is primarily responsible for providing structural support, localization and transport of organelles, and intracellular trafficking. The structural support is supplied by actin filaments, microtubules, and intermediate filaments, which contribute to overall cell elasticity to varying degrees. We evaluate cell elasticity in five different cell types with drug-induced cytoskeletal derangements to probe how actin filaments and microtubules contribute to cell elasticity and whether it is conserved across cell type. Specifically, we measure elastic stiffness in primary chondrocytes, fibroblasts, endothelial cells (HUVEC), hepatocellular carcinoma cells (HUH-7), and fibrosarcoma cells (HT 1080) subjected to two cytoskeletal destabilizers: cytochalasin D and nocodazole, which disrupt actin and microtubule polymerization, respectively. Elastic stiffness is measured by atomic force microscopy (AFM) and the disruption of the cytoskeleton is confirmed using fluorescence microscopy. The two cancer cell lines showed significantly reduced elastic moduli values (~0.5kPa) when compared to the three healthy cell lines (~2kPa). Non-cancer cells whose actin filaments were disrupted using cytochalasin D showed a decrease of 60-80% in moduli values compared to untreated cells of the same origin, whereas the nocodazole-treated cells showed no change in elasticity. Overall, we demonstrate actin filaments contribute more to elastic stiffness than microtubules but this result is cell type dependent. Cancer cells behaved differently, exhibiting increased stiffness as well as stiffness variability when subjected to nocodazole. We show that disruption of microtubule dynamics affects cancer cell elasticity, suggesting therapeutic drugs targeting microtubules be monitored for significant elastic changes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Retrospective genetic study of germinative mutations in Str loci of individuals potentially exposed to ionizing radiation;Estudo genetico retrospectivo de mutacoes germinativas em Loci Str de individuos potencialmente expostos a radiacao ionizante

Energy Technology Data Exchange (ETDEWEB)

Costa, Emilia Oliveira Alves

2010-07-01

The Brazilian radiological accident that occurred in 1987, in Goiania, it was a terrible radiation episode. As a consequence, hundreds of people were contaminated due to the Cesium-137 radiation. Recently, many studies had shown that genome instabilities, such as, mutations, chromosomal aberrations, micronuclei formation and micro satellite instability and a delay on cellular death are usually reported on mammal cells exposed to ionizing radiation, being considered as a manly risk to humans. Mutations can be spontaneous, and the occurrence is dependent on the organism, or, induced, being associated to mutagenic exposition. Ionizing radiations are an example of physical and mutagenic agents that could harm the cell repair and could cause the development of many types of cancer. The evaluation of the biological effects of the ionizing radiation, in somatic and germ line cells, with a consequent determination of the radio-induced mutations, it is extremely important to estimate the genetic risks, manly in population exposed to radiation. The analyses of repetitive DNA sequences have been demonstrated that such sequences are prone to high rates of spontaneous mutations. The minisatellites and microsatellites have been used to demonstrate the induction of germ line mutation rates on mouse, humans, among others organisms. The aim of the present study was to analyze the frequency of microsatellite alterations to determine the mutation rates occurred in germ cells of the parents exposed to the ionizing radiation of the Cesium-137. The studied group was constitute of 10 families of individuals accidentally exposed to Cesium-137 and by the control group constituted by 645 healthy individuals who carried out paternity tests on 2009. We found only one mutation of paternal origin in the D8S1179 locus on the exposed group, being the mutation rate of 0.002. In the control group, we found 01 mutation on D16S539 loei and on D3S1358; 02 mutations on Penta E loeus; 04 mutations on D

Genome-wide mapping in a house mouse hybrid zone reveals hybrid sterility loci and Dobzhansky-Muller interactions.

Science.gov (United States)

Turner, Leslie M; Harr, Bettina

2014-12-09

Mapping hybrid defects in contact zones between incipient species can identify genomic regions contributing to reproductive isolation and reveal genetic mechanisms of speciation. The house mouse features a rare combination of sophisticated genetic tools and natural hybrid zones between subspecies. Male hybrids often show reduced fertility, a common reproductive barrier between incipient species. Laboratory crosses have identified sterility loci, but each encompasses hundreds of genes. We map genetic determinants of testis weight and testis gene expression using offspring of mice captured in a hybrid zone between M. musculus musculus and M. m. domesticus. Many generations of admixture enables high-resolution mapping of loci contributing to these sterility-related phenotypes. We identify complex interactions among sterility loci, suggesting multiple, non-independent genetic incompatibilities contribute to barriers to gene flow in the hybrid zone.

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese

Science.gov (United States)

Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

2015-01-01

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10−13, BCAS3), 9p24.2 (rs12236871, P=1.48 × 10−10, RFX3) and 11p15.5 (rs179785, P=1.28 × 10−8, KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis. PMID:25967671

Genome-wide association analysis identifies three new risk loci for gout arthritis in Han Chinese.

Science.gov (United States)

Li, Changgui; Li, Zhiqiang; Liu, Shiguo; Wang, Can; Han, Lin; Cui, Lingling; Zhou, Jingguo; Zou, Hejian; Liu, Zhen; Chen, Jianhua; Cheng, Xiaoyu; Zhou, Zhaowei; Ding, Chengcheng; Wang, Meng; Chen, Tong; Cui, Ying; He, Hongmei; Zhang, Keke; Yin, Congcong; Wang, Yunlong; Xing, Shichao; Li, Baojie; Ji, Jue; Jia, Zhaotong; Ma, Lidan; Niu, Jiapeng; Xin, Ying; Liu, Tian; Chu, Nan; Yu, Qing; Ren, Wei; Wang, Xuefeng; Zhang, Aiqing; Sun, Yuping; Wang, Haili; Lu, Jie; Li, Yuanyuan; Qing, Yufeng; Chen, Gang; Wang, Yangang; Zhou, Li; Niu, Haitao; Liang, Jun; Dong, Qian; Li, Xinde; Mi, Qing-Sheng; Shi, Yongyong

2015-05-13

Gout is one of the most common types of inflammatory arthritis, caused by the deposition of monosodium urate crystals in and around the joints. Previous genome-wide association studies (GWASs) have identified many genetic loci associated with raised serum urate concentrations. However, hyperuricemia alone is not sufficient for the development of gout arthritis. Here we conduct a multistage GWAS in Han Chinese using 4,275 male gout patients and 6,272 normal male controls (1,255 cases and 1,848 controls were genome-wide genotyped), with an additional 1,644 hyperuricemic controls. We discover three new risk loci, 17q23.2 (rs11653176, P=1.36 × 10(-13), BCAS3), 9p24.2 (rs12236871, P=1.48 × 10(-10), RFX3) and 11p15.5 (rs179785, P=1.28 × 10(-8), KCNQ1), which contain inflammatory candidate genes. Our results suggest that these loci are most likely related to the progression from hyperuricemia to inflammatory gout, which will provide new insights into the pathogenesis of gout arthritis.

Quantitative Trait Loci Analysis of Seed Quality Characteristics in Lentil using Single Nucleotide Polymorphism Markers

Directory of Open Access Journals (Sweden)

Michael J. Fedoruk

2013-11-01

Full Text Available Seed shape, color, and pattern of lentil ( Medik. subsp. are important quality traits as they determine market class and possible end uses. A recombinant inbred line population was phenotyped for seed dimensions over multiple site–years and classified according to cotyledon and seed coat color and pattern. The objectives were to determine the heritability of seed dimensions, identify genomic regions controlling these dimensions, and map seed coat and cotyledon color genes. A genetic linkage map consisting of 563 single nucleotide polymorphisms, 10 simple sequence repeats, and four seed color loci was developed for quantitative trait loci (QTL analysis. Loci for seed coat color and pattern mapped to linkage groups 2 (, 3 (, and 6 ( while the cotyledon color locus ( mapped to linkage group 1. The broad sense heritability estimates were high for seed diameter (broad-sense heritability [] = 0.92 and seed plumpness ( = 0.94 while seed thickness ( = 0.60 and days to flowering ( = 0.45 were more moderate. There were significant seed dimension QTL on six of the seven linkage groups. The most significant QTL for diameter and plumpness was found at the cotyledon color locus (. The markers identified in this study can be used to help enrich breeding populations for desired seed quality characteristics, thereby increasing efficiency in the lentil breeding program.

Regeneration of alveolar type I and II cells from Scgb1a1-expressing cells following severe pulmonary damage induced by bleomycin and influenza.

Directory of Open Access Journals (Sweden)

Dahai Zheng

Full Text Available The lung comprises an extensive surface of epithelia constantly exposed to environmental insults. Maintaining the integrity of the alveolar epithelia is critical for lung function and gaseous exchange. However, following severe pulmonary damage, what progenitor cells give rise to alveolar type I and II cells during the regeneration of alveolar epithelia has not been fully determined. In this study, we have investigated this issue by using transgenic mice in which Scgb1a1-expressing cells and their progeny can be genetically labeled with EGFP. We show that following severe alveolar damage induced either by bleomycin or by infection with influenza virus, the majority of the newly generated alveolar type II cells in the damaged parenchyma were labeled with EGFP. A large proportion of EGFP-expressing type I cells were also observed among the type II cells. These findings strongly suggest that Scgb1a1-expressing cells, most likely Clara cells, are a major cell type that gives rise to alveolar type I and II cells during the regeneration of alveolar epithelia in response to severe pulmonary damage in mice.

Complex heterogeneous tissue constructs containing multiple cell types prepared by inkjet printing technology.

Science.gov (United States)

Xu, Tao; Zhao, Weixin; Zhu, Jian-Ming; Albanna, Mohammad Z; Yoo, James J; Atala, Anthony

2013-01-01

This study was designed to develop a versatile method for fabricating complex and heterogeneous three-dimensional (3D) tissue constructs using simultaneous ink-jetting of multiple cell types. Human amniotic fluid-derived stem cells (hAFSCs), canine smooth muscle cells (dSMCs), and bovine aortic endothelial cells (bECs), were separately mixed with ionic cross-linker calcium chloride (CaCl(2)), loaded into separate ink cartridges and printed using a modified thermal inkjet printer. The three cell types were delivered layer-by-layer to pre-determined locations in a sodium alginate-collagen composite located in a chamber under the printer. The reaction between CaCl(2) and sodium alginate resulted in a rapid formation of a solid composite gel and the printed cells were anchored in designated areas within the gel. The printing process was repeated for several cycles leading to a complex 3D multi-cell hybrid construct. The biological functions of the 3D printed constructs were evaluated in vitro and in vivo. Each of the printed cell types maintained their viability and normal proliferation rates, phenotypic expression, and physiological functions within the heterogeneous constructs. The bioprinted constructs were able to survive and mature into functional tissues with adequate vascularization in vivo. These findings demonstrate the feasibility of fabricating complex heterogeneous tissue constructs containing multiple cell types using inkjet printing technology. Copyright © 2012 Elsevier Ltd. All rights reserved.

Molecular distribution of deafness loci in variou ethnic groups of the punjab, pakistan

International Nuclear Information System (INIS)

Ullah, S.; Aslam, K.M.

2015-01-01

To determine the existence of autosomal recessive deafness loci in different ethnic tribes of the Punjab. Study Design: Descriptive observational study. Place and Duration of Study: Department of Human Genetics and Centre of Excellence in Molecular Biology, University of Health Sciences, Lahore, from July 2009 to March 2012. Methodology: Healthy willing subjects with autosomal recessive deafness loci were studied for selected deafness loci. Those who were unhealthy and gave history of infectious disease were excluded. DNA extraction was carried out using the inorganic method. Fluorescently labeled microsatellite markers were used for amplification of desired regions by PCR (Polymerase Chain Reaction). Automated allele assignment was performed using the ABI PRISM GeneScan Analysis Software Version 3.7 for Windows NT Platform. Two-point LOD scores were calculated using the FASTLINK computer package (Schaffer 1996) and MLINK was used for calculation and 95% CI (confidence intervals) were calculated. Results: One hundred and thirty two individuals of 8 families were analyzed. Three families (SAPun-03, SAPun-10 and SAPun-15) were found linked to DFNB12; two families (SAPun-05 and SAPun-17) were found linked to DFNB8/10, while three families (SAPun-06, SAPun-13 and SAPun-19) were found linked to DFNB29, DFNB36 and DFNB37 respectively. Conclusion: The genotyping results revealed that DFNB12 locus was the most common followed by DFNB8/10 locus, while the Loci DFNB29, DFNB36 and DFNB37 were less common. (author)

Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson's disease etiology.

Science.gov (United States)

Coetzee, Simon G; Pierce, Steven; Brundin, Patrik; Brundin, Lena; Hazelett, Dennis J; Coetzee, Gerhard A

2016-07-27

Recent genome-wide association studies (GWAS) of Parkinson's disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r(2) ≥ 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (-logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development.

Enrichment of risk SNPs in regulatory regions implicate diverse tissues in Parkinson’s disease etiology

Science.gov (United States)

Coetzee, Simon G.; Pierce, Steven; Brundin, Patrik; Brundin, Lena; Hazelett, Dennis J.; Coetzee, Gerhard A.

2016-01-01

Recent genome-wide association studies (GWAS) of Parkinson’s disease (PD) revealed at least 26 risk loci, with associated single nucleotide polymorphisms (SNPs) located in non-coding DNA having unknown functions in risk. In order to explore in which cell types these SNPs (and their correlated surrogates at r2 ≥ 0.8) could alter cellular function, we assessed their location overlap with histone modification regions that indicate transcription regulation in 77 diverse cell types. We found statistically significant enrichment of risk SNPs at 12 loci in active enhancers or promoters. We investigated 4 risk loci in depth that were most significantly enriched (−logeP > 14) and contained 8 putative enhancers in the different cell types. These enriched loci, along with eQTL associations, were unexpectedly present in non-neuronal cell types. These included lymphocytes, mesendoderm, liver- and fat-cells, indicating that cell types outside the brain are involved in the genetic predisposition to PD. Annotating regulatory risk regions within specific cell types may unravel new putative risk mechanisms and molecular pathways that contribute to PD development. PMID:27461410

Association analysis identifies 65 new breast cancer risk loci.

Science.gov (United States)

Michailidou, Kyriaki; Lindström, Sara; Dennis, Joe; Beesley, Jonathan; Hui, Shirley; Kar, Siddhartha; Lemaçon, Audrey; Soucy, Penny; Glubb, Dylan; Rostamianfar, Asha; Bolla, Manjeet K; Wang, Qin; Tyrer, Jonathan; Dicks, Ed; Lee, Andrew; Wang, Zhaoming; Allen, Jamie; Keeman, Renske; Eilber, Ursula; French, Juliet D; Qing Chen, Xiao; Fachal, Laura; McCue, Karen; McCart Reed, Amy E; Ghoussaini, Maya; Carroll, Jason S; Jiang, Xia; Finucane, Hilary; Adams, Marcia; Adank, Muriel A; Ahsan, Habibul; Aittomäki, Kristiina; Anton-Culver, Hoda; Antonenkova, Natalia N; Arndt, Volker; Aronson, Kristan J; Arun, Banu; Auer, Paul L; Bacot, François; Barrdahl, Myrto; Baynes, Caroline; Beckmann, Matthias W; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Bernstein, Leslie; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brand, Judith S; Brauch, Hiltrud; Brennan, Paul; Brenner, Hermann; Brinton, Louise; Broberg, Per; Brock, Ian W; Broeks, Annegien; Brooks-Wilson, Angela; Brucker, Sara Y; Brüning, Thomas; Burwinkel, Barbara; Butterbach, Katja; Cai, Qiuyin; Cai, Hui; Caldés, Trinidad; Canzian, Federico; Carracedo, Angel; Carter, Brian D; Castelao, Jose E; Chan, Tsun L; David Cheng, Ting-Yuan; Seng Chia, Kee; Choi, Ji-Yeob; Christiansen, Hans; Clarke, Christine L; Collée, Margriet; Conroy, Don M; Cordina-Duverger, Emilie; Cornelissen, Sten; Cox, David G; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Doheny, Kimberly F; Dörk, Thilo; Dos-Santos-Silva, Isabel; Dumont, Martine; Durcan, Lorraine; Dwek, Miriam; Eccles, Diana M; Ekici, Arif B; Eliassen, A Heather; Ellberg, Carolina; Elvira, Mingajeva; Engel, Christoph; Eriksson, Mikael; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Fletcher, Olivia; Flyger, Henrik; Fritschi, Lin; Gaborieau, Valerie; Gabrielson, Marike; Gago-Dominguez, Manuela; Gao, Yu-Tang; Gapstur, Susan M; García-Sáenz, José A; Gaudet, Mia M; Georgoulias, Vassilios; Giles, Graham G; Glendon, Gord; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Grenaker Alnæs, Grethe I; Grip, Mervi; Gronwald, Jacek; Grundy, Anne; Guénel, Pascal; Haeberle, Lothar; Hahnen, Eric; Haiman, Christopher A; Håkansson, Niclas; Hamann, Ute; Hamel, Nathalie; Hankinson, Susan; Harrington, Patricia; Hart, Steven N; Hartikainen, Jaana M; Hartman, Mikael; Hein, Alexander; Heyworth, Jane; Hicks, Belynda; Hillemanns, Peter; Ho, Dona N; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Hou, Ming-Feng; Hsiung, Chia-Ni; Huang, Guanmengqian; Humphreys, Keith; Ishiguro, Junko; Ito, Hidemi; Iwasaki, Motoki; Iwata, Hiroji; Jakubowska, Anna; Janni, Wolfgang; John, Esther M; Johnson, Nichola; Jones, Kristine; Jones, Michael; Jukkola-Vuorinen, Arja; Kaaks, Rudolf; Kabisch, Maria; Kaczmarek, Katarzyna; Kang, Daehee; Kasuga, Yoshio; Kerin, Michael J; Khan, Sofia; Khusnutdinova, Elza; Kiiski, Johanna I; Kim, Sung-Won; Knight, Julia A; Kosma, Veli-Matti; Kristensen, Vessela N; Krüger, Ute; Kwong, Ava; Lambrechts, Diether; Le Marchand, Loic; Lee, Eunjung; Lee, Min Hyuk; Lee, Jong Won; Neng Lee, Chuen; Lejbkowicz, Flavio; Li, Jingmei; Lilyquist, Jenna; Lindblom, Annika; Lissowska, Jolanta; Lo, Wing-Yee; Loibl, Sibylle; Long, Jirong; Lophatananon, Artitaya; Lubinski, Jan; Luccarini, Craig; Lux, Michael P; Ma, Edmond S K; MacInnis, Robert J; Maishman, Tom; Makalic, Enes; Malone, Kathleen E; Kostovska, Ivana Maleva; Mannermaa, Arto; Manoukian, Siranoush; Manson, JoAnn E; Margolin, Sara; Mariapun, Shivaani; Martinez, Maria Elena; Matsuo, Keitaro; Mavroudis, Dimitrios; McKay, James; McLean, Catriona; Meijers-Heijboer, Hanne; Meindl, Alfons; Menéndez, Primitiva; Menon, Usha; Meyer, Jeffery; Miao, Hui; Miller, Nicola; Taib, Nur Aishah Mohd; Muir, Kenneth; Mulligan, Anna Marie; Mulot, Claire; Neuhausen, Susan L; Nevanlinna, Heli; Neven, Patrick; Nielsen, Sune F; Noh, Dong-Young; Nordestgaard, Børge G; Norman, Aaron; Olopade, Olufunmilayo I; Olson, Janet E; Olsson, Håkan; Olswold, Curtis; Orr, Nick; Pankratz, V Shane; Park, Sue K; Park-Simon, Tjoung-Won; Lloyd, Rachel; Perez, Jose I A; Peterlongo, Paolo; Peto, Julian; Phillips, Kelly-Anne; Pinchev, Mila; Plaseska-Karanfilska, Dijana; Prentice, Ross; Presneau, Nadege; Prokofyeva, Darya; Pugh, Elizabeth; Pylkäs, Katri; Rack, Brigitte; Radice, Paolo; Rahman, Nazneen; Rennert, Gadi; Rennert, Hedy S; Rhenius, Valerie; Romero, Atocha; Romm, Jane; Ruddy, Kathryn J; Rüdiger, Thomas; Rudolph, Anja; Ruebner, Matthias; Rutgers, Emiel J T; Saloustros, Emmanouil; Sandler, Dale P; Sangrajrang, Suleeporn; Sawyer, Elinor J; Schmidt, Daniel F; Schmutzler, Rita K; Schneeweiss, Andreas; Schoemaker, Minouk J; Schumacher, Fredrick; Schürmann, Peter; Scott, Rodney J; Scott, Christopher; Seal, Sheila; Seynaeve, Caroline; Shah, Mitul; Sharma, Priyanka; Shen, Chen-Yang; Sheng, Grace; Sherman, Mark E; Shrubsole, Martha J; Shu, Xiao-Ou; Smeets, Ann; Sohn, Christof; Southey, Melissa C; Spinelli, John J; Stegmaier, Christa; Stewart-Brown, Sarah; Stone, Jennifer; Stram, Daniel O; Surowy, Harald; Swerdlow, Anthony; Tamimi, Rulla; Taylor, Jack A; Tengström, Maria; Teo, Soo H; Beth Terry, Mary; Tessier, Daniel C; Thanasitthichai, Somchai; Thöne, Kathrin; Tollenaar, Rob A E M; Tomlinson, Ian; Tong, Ling; Torres, Diana; Truong, Thérèse; Tseng, Chiu-Chen; Tsugane, Shoichiro; Ulmer, Hans-Ulrich; Ursin, Giske; Untch, Michael; Vachon, Celine; van Asperen, Christi J; Van Den Berg, David; van den Ouweland, Ans M W; van der Kolk, Lizet; van der Luijt, Rob B; Vincent, Daniel; Vollenweider, Jason; Waisfisz, Quinten; Wang-Gohrke, Shan; Weinberg, Clarice R; Wendt, Camilla; Whittemore, Alice S; Wildiers, Hans; Willett, Walter; Winqvist, Robert; Wolk, Alicja; Wu, Anna H; Xia, Lucy; Yamaji, Taiki; Yang, Xiaohong R; Har Yip, Cheng; Yoo, Keun-Young; Yu, Jyh-Cherng; Zheng, Wei; Zheng, Ying; Zhu, Bin; Ziogas, Argyrios; Ziv, Elad; Lakhani, Sunil R; Antoniou, Antonis C; Droit, Arnaud; Andrulis, Irene L; Amos, Christopher I; Couch, Fergus J; Pharoah, Paul D P; Chang-Claude, Jenny; Hall, Per; Hunter, David J; Milne, Roger L; García-Closas, Montserrat; Schmidt, Marjanka K; Chanock, Stephen J; Dunning, Alison M; Edwards, Stacey L; Bader, Gary D; Chenevix-Trench, Georgia; Simard, Jacques; Kraft, Peter; Easton, Douglas F

2017-11-02

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10 -8 . The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention.

Type II NKT cells: a distinct CD1d-restricted immune regulatory NKT cell subset.

Science.gov (United States)

Dasgupta, Suryasarathi; Kumar, Vipin

2016-08-01

Type II natural killer T cells (NKT) are a subset of the innate-like CD1d-restricted lymphocytes that are reactive to lipid antigens. Unlike the type I NKT cells, which express a semi-invariant TCR, type II NKT cells express a broader TCR repertoire. Additionally, other features, such as their predominance over type I cells in humans versus mice, the nature of their ligands, CD1d/lipid/TCR binding, and modulation of immune responses, distinguish type II NKT cells from type I NKT cells. Interestingly, it is the self-lipid-reactivity of type II NKT cells that has helped define their physiological role in health and in disease. The discovery of sulfatide as one of the major antigens for CD1d-restricted type II NKT cells in mice has been instrumental in the characterization of these cells, including the TCR repertoire, the crystal structure of the CD1d/lipid/TCR complex, and their function. Subsequently, several other glycolipids and phospholipids from both endogenous and microbial sources have been shown to activate type II NKT cells. The activation of a specific subset of type II NKT cells following administration with sulfatide or lysophosphatidylcholine (LPC) leads to engagement of a dominant immunoregulatory pathway associated with the inactivation of type I NKT cells, conventional dendritic cells, and inhibition of the proinflammatory Th1/Th17 cells. Thus, type II NKT cells have been shown to be immunosuppressive in autoimmune diseases, inflammatory liver diseases, and in cancer. Knowing their relatively higher prevalence in human than type I NKT cells, understanding their biology is imperative for health and disease.

Comparison of first quadrant yield loci for Ti--6Al--4V with those predicted by Knoop hardness measurements

International Nuclear Information System (INIS)

Amateau, M.F.; Hanna, W.D.

1975-01-01

Knoop hardness impressions were used to construct biaxial yield loci in Ti--6A l--4V for a variety of textures. These results were compared with partial yield loci in the first quadrant, determined from flow stress measurements at three stress ratios. In each case, the Knoop hardness technique was not sufficiently sensitive to predict the shape of the yield locus, the largest discrepancy occurring for the most anisotropic sample. (U.S.)

PHYLUCE is a software package for the analysis of conserved genomic loci.

Science.gov (United States)

Faircloth, Brant C

2016-03-01

Targeted enrichment of conserved and ultraconserved genomic elements allows universal collection of phylogenomic data from hundreds of species at multiple time scales ( 300 Ma). Prior to downstream inference, data from these types of targeted enrichment studies must undergo preprocessing to assemble contigs from sequence data; identify targeted, enriched loci from the off-target background data; align enriched contigs representing conserved loci to one another; and prepare and manipulate these alignments for subsequent phylogenomic inference. PHYLUCE is an efficient and easy-to-install software package that accomplishes these tasks across hundreds of taxa and thousands of enriched loci. PHYLUCE is written for Python 2.7. PHYLUCE is supported on OSX and Linux (RedHat/CentOS) operating systems. PHYLUCE source code is distributed under a BSD-style license from https://www.github.com/faircloth-lab/phyluce/ PHYLUCE is also available as a package (https://binstar.org/faircloth-lab/phyluce) for the Anaconda Python distribution that installs all dependencies, and users can request a PHYLUCE instance on iPlant Atmosphere (tag: phyluce). The software manual and a tutorial are available from http://phyluce.readthedocs.org/en/latest/ and test data are available from doi: 10.6084/m9.figshare.1284521. brant@faircloth-lab.org Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Novel Associations of Nonstructural Loci with Paraoxonase Activity

Directory of Open Access Journals (Sweden)

Ellen E. Quillen

2012-01-01

Full Text Available The high-density-lipoprotein-(HDL- associated esterase paraoxonase 1 (PON1 is a likely contributor to the antioxidant and antiatherosclerotic capabilities of HDL. Two nonsynonymous mutations in the structural gene, PON1, have been associated with variation in activity levels, but substantial interindividual differences remain unexplained and are greatest for substrates other than the eponymous paraoxon. PON1 activity levels were measured for three substrates—organophosphate paraoxon, arylester phenyl acetate, and lactone dihydrocoumarin—in 767 Mexican American individuals from San Antonio, Texas. Genetic influences on activity levels for each substrate were evaluated by association with approximately one million single nucleotide polymorphism (SNPs while conditioning on PON1 genotypes. Significant associations were detected at five loci including regions on chromosomes 4 and 17 known to be associated with atherosclerosis and lipoprotein regulation and loci on chromosome 3 that regulate ubiquitous transcription factors. These loci explain 7.8% of variation in PON1 activity with lactone as a substrate, 5.6% with the arylester, and 3.0% with paraoxon. In light of the potential importance of PON1 in preventing cardiovascular disease/events, these novel loci merit further investigation.

Gender determination in populus

Energy Technology Data Exchange (ETDEWEB)

McLetchie, D.N. [Univ. of Kentucky, Lexington, KY (United States). Dept. of Biological Sciences; Tuskan, G.A. [Oak Ridge National Lab., TN (United States)

1994-12-31

Gender, the expression of maleness or femaleness, in dioecious plants has been associated with changes in morphology, physiology, ecological position, and commercial importance of several species, including members of the Salicaceae family. Various mechanisms have been proposed to explain the expression of gender in Salicaceae, including sex chromosomes, simple Mendelian genes, quantitative genes, environment, and genotype-by-environment interactions. Published reports would favor a genetic basis for gender. The objective of this study was to identify molecular markers associated with gender in a segregating family of hybrid poplars. Bulked segregant analysis and chi-squared analysis were used to test for the occurrence of sex chromosomes, individual loci, and chromosome ratios (i.e., ploidy levels) as the mechanisms for gender determination. Examination of 2488 PCR based RAPD markers from 1219 primers revealed nine polymorphic bands between male and female bulked samples. However, linkage analysis indicated that none of these markers were significantly associated with gender. Chisquared results for difference in male-to-female ratios between diploid and triploid genotypes also revealed no significant differences. These findings suggest gender is not controlled via sex chromosomes, simple Mendelian loci or ratios of autosome to gender-determining loci. It is possible that gender is determined genetically by regions of the genome not sampled by the tested markers or by a complex of loci operating in an additive threshold manner or in an epistatic manner. It is also possible that gender is determined environmentally at an early zygote stage, canalizing gender expression.

Genes and quality trait loci (QTLs) associated with firmness in Malus x domestica

KAUST Repository

Marondedze, Claudius

2013-03-31

Fruit firmness, a quality quantitative trait, has long been established as a key textural property and one of the essential parameters for estimating ripening and shelf life of apples. Loss of firmness, also referred to as fruit softening, is undesirable in apples and represents a serious problem for growers in many countries. This results in the reduction of apple shelf life and in turn influences its commercialization. Low firmness impacts negatively on the sensory values of juiciness, crunchiness and crispness. Fruit firmness is affected by the inheritance of alleles at multiple loci and their possible interactions with the environment. Identification of these loci is key for the determination of genetic candidate markers that can be implemented in marker assisted selection and breeding for trees and/or cultivars that can yield firmer fruits with economic value. In turn, this technique can help reduce the time needed to evaluate plants and new cultivars could become available faster. This review provides an overview of quantitative trait loci (QTL), including additional putative QTLs that we have identified, and genes associated with firmness and their importance to biotechnology, the breeding industry and eventually the consumers.

Cell type-specific response to high intracellular loading of polyacrylic acid-coated magnetic nanoparticles

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Lojk, Jasna; Bregar, Vladimir B; Rajh, Maruša; Miš, Katarina; Kreft, Mateja Erdani; Pirkmajer, Sergej; Veranič, Peter; Pavlin, Mojca

2015-01-01

Magnetic nanoparticles (NPs) are a special type of NP with a ferromagnetic, electron-dense core that enables several applications such as cell tracking, hyperthermia, and magnetic separation, as well as multimodality. So far, superparamagnetic iron oxide NPs (SPIONs) are the only clinically approved type of metal oxide NPs, but cobalt ferrite NPs have properties suitable for biomedical applications as well. In this study, we analyzed the cellular responses to magnetic cobalt ferrite NPs coated with polyacrylic acid (PAA) in three cell types: Chinese Hamster Ovary (CHO), mouse melanoma (B16) cell line, and primary human myoblasts (MYO). We compared the internalization pathway, intracellular trafficking, and intracellular fate of our NPs using fluorescence and transmission electron microscopy (TEM) as well as quantified NP uptake and analyzed uptake dynamics. We determined cell viability after 24 or 96 hours’ exposure to increasing concentrations of NPs, and quantified the generation of reactive oxygen species (ROS) upon 24 and 48 hours’ exposure. Our NPs have been shown to readily enter and accumulate in cells in high quantities using the same two endocytic pathways; mostly by macropinocytosis and partially by clathrin-mediated endocytosis. The cell types differed in their uptake rate, the dynamics of intracellular trafficking, and the uptake capacity, as well as in their response to higher concentrations of internalized NPs. The observed differences in cell responses stress the importance of evaluation of NP–cell interactions on several different cell types for better prediction of possible toxic effects on different cell and tissue types in vivo. PMID:25733835

Monogenic Diabetes: What It Teaches Us on the Common Forms of Type 1 and Type 2 Diabetes

Science.gov (United States)

2016-01-01

To date, more than 30 genes have been linked to monogenic diabetes. Candidate gene and genome-wide association studies have identified > 50 susceptibility loci for common type 1 diabetes (T1D) and approximately 100 susceptibility loci for type 2 diabetes (T2D). About 1–5% of all cases of diabetes result from single-gene mutations and are called monogenic diabetes. Here, we review the pathophysiological basis of the role of monogenic diabetes genes that have also been found to be associated with common T1D and/or T2D. Variants of approximately one-third of monogenic diabetes genes are associated with T2D, but not T1D. Two of the T2D-associated monogenic diabetes genes—potassium inward-rectifying channel, subfamily J, member 11 (KCNJ11), which controls glucose-stimulated insulin secretion in the β-cell; and peroxisome proliferator-activated receptor γ (PPARG), which impacts multiple tissue targets in relation to inflammation and insulin sensitivity—have been developed as major antidiabetic drug targets. Another monogenic diabetes gene, the preproinsulin gene (INS), is unique in that INS mutations can cause hyperinsulinemia, hyperproinsulinemia, neonatal diabetes mellitus, one type of maturity-onset diabetes of the young (MODY10), and autoantibody-negative T1D. Dominant heterozygous INS mutations are the second most common cause of permanent neonatal diabetes. Moreover, INS gene variants are strongly associated with common T1D (type 1a), but inconsistently with T2D. Variants of the monogenic diabetes gene Gli-similar 3 (GLIS3) are associated with both T1D and T2D. GLIS3 is a key transcription factor in insulin production and β-cell differentiation during embryonic development, which perturbation forms the basis of monogenic diabetes as well as its association with T1D. GLIS3 is also required for compensatory β-cell proliferation in adults; impairment of this function predisposes to T2D. Thus, monogenic forms of diabetes are invaluable “human models” that

Intercellular Uptake of Technetium-99m Pertechnetate by Different Types of Cell Lines

International Nuclear Information System (INIS)

Safri Zainal Abidin; Raizulnasuha Abdul Rashid; Muhammad Afiq Khairil Anuar; Wan Nordiana A Abd Rahman

2015-01-01

The purpose of this study is to determine the technetium-99m pertechnetate ( 99m TcO 4 ) intercellular uptake by different types of cell lines. HeLa, human fetal osteoblast (hFOB), glial and glioma cell lines grown in 6-wells culture plates were incubated with 99m TcO 4 of activity of 200, 400, 600, 800 and 1000 μCi for 30 minutes at 37 degree Celsius and 5 % CO 2 humidified atmosphere. After incubation, the cells were washed 3 times with phosphate buffer saline to remove the extracellular traces of 99m TcO 4 . Measurement of the intercellular 99m TcO 4 into the cells was calculated. The intercellular uptake of 99m TcO 4 was found to be inversely correlate to the radioactivity. HHeLa cell shows the highest uptake followed by hFOB, glial and glioma cell lines. Comparison of uptake between normal and cancer cells present indistinguishable results. The findings of this study suggest that the intercellular uptake of 99m TcO 4 is highly dependent on the type of cells despite no significant different of uptake was found between normal and cancer cell lines. The level of radioactivity is also an important determinant factor that influence the uptake of 99m TcO 4 into the cell. The study will be the first precedent toward understanding the cellular characteristics and pharmacokinetic of non-invasive imaging tracer for future molecular imaging and therapy. (author)

Development of ten microsatellite loci in the invasive giant African land snail, Achatina (=Lissachatina) fulica Bowdich, 1822

Science.gov (United States)

Morrison, Cheryl L.; Springmann, Marcus J.; Iwanowicz, Deborah D.; Wade, Christopher M.

2015-01-01

A suite of tetra-nucleotide microsatellite loci were developed for the invasive giant African land snail, Achatina (=Lissachatina) fulica Bowdich, 1822, from Ion Torrent next-generation sequencing data. Ten of the 96 primer sets tested amplified consistently in 30 snails from Miami, Florida, plus 12 individuals representative of their native East Africa, Indian and Pacific Ocean regions. The loci displayed moderate levels of allelic diversity (average 5.6 alleles/locus) and heterozygosity (average 42 %). Levels of genetic diversity were sufficient to produce unique multi-locus genotypes and detect phylogeographic structuring among regional samples. The invasive A. fulica can cause extensive damage to important food crops and natural resources, including native flora and fauna. The loci characterized here will be useful for determining the origins and tracking the spread of invasions, detecting fine-scale spatial structuring and estimating demographic parameters.

Regulated gene expression in cultured type II cells of adult human lung.

Science.gov (United States)

Ballard, Philip L; Lee, Jae W; Fang, Xiaohui; Chapin, Cheryl; Allen, Lennell; Segal, Mark R; Fischer, Horst; Illek, Beate; Gonzales, Linda W; Kolla, Venkatadri; Matthay, Michael A

2010-07-01

Alveolar type II cells have multiple functions, including surfactant production and fluid clearance, which are critical for lung function. Differentiation of type II cells occurs in cultured fetal lung epithelial cells treated with dexamethasone plus cAMP and isobutylmethylxanthine (DCI) and involves increased expression of 388 genes. In this study, type II cells of human adult lung were isolated at approximately 95% purity, and gene expression was determined (Affymetrix) before and after culturing 5 days on collagen-coated dishes with or without DCI for the final 3 days. In freshly isolated cells, highly expressed genes included SFTPA/B/C, SCGB1A, IL8, CXCL2, and SFN in addition to ubiquitously expressed genes. Transcript abundance was correlated between fetal and adult cells (r = 0.88), with a subset of 187 genes primarily related to inflammation and immunity that were expressed >10-fold higher in adult cells. During control culture, expression increased for 8.1% of expressed genes and decreased for approximately 4% including 118 immune response and 10 surfactant-related genes. DCI treatment promoted lamellar body production and increased expression of approximately 3% of probed genes by > or =1.5-fold; 40% of these were also induced in fetal cells. Highly induced genes (> or =10-fold) included PGC, ZBTB16, DUOX1, PLUNC, CIT, and CRTAC1. Twenty-five induced genes, including six genes related to surfactant (SFTPA/B/C, PGC, CEBPD, and ADFP), also had decreased expression during control culture and thus are candidates for hormonal regulation in vivo. Our results further define the adult human type II cell molecular phenotype and demonstrate that a subset of genes remains hormone responsive in cultured adult cells.

Structure of the type IV secretion system in different strains of Anaplasma phagocytophilum

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Al-Khedery Basima

2012-11-01

Full Text Available Abstract Background Anaplasma phagocytophilum is an intracellular organism in the Order Rickettsiales that infects diverse animal species and is causing an emerging disease in humans, dogs and horses. Different strains have very different cell tropisms and virulence. For example, in the U.S., strains have been described that infect ruminants but not dogs or rodents. An intriguing question is how the strains of A. phagocytophilum differ and what different genome loci are involved in cell tropisms and/or virulence. Type IV secretion systems (T4SS are responsible for translocation of substrates across the cell membrane by mechanisms that require contact with the recipient cell. They are especially important in organisms such as the Rickettsiales which require T4SS to aid colonization and survival within both mammalian and tick vector cells. We determined the structure of the T4SS in 7 strains from the U.S. and Europe and revised the sequence of the repetitive virB6 locus of the human HZ strain. Results Although in all strains the T4SS conforms to the previously described split loci for vir genes, there is great diversity within these loci among strains. This is particularly evident in the virB2 and virB6 which are postulated to encode the secretion channel and proteins exposed on the bacterial surface. VirB6-4 has an unusual highly repetitive structure and can have a molecular weight greater than 500,000. For many of the virs, phylogenetic trees position A. phagocytophilum strains infecting ruminants in the U.S. and Europe distant from strains infecting humans and dogs in the U.S. Conclusions Our study reveals evidence of gene duplication and considerable diversity of T4SS components in strains infecting different animals. The diversity in virB2 is in both the total number of copies, which varied from 8 to 15 in the herein characterized strains, and in the sequence of each copy. The diversity in virB6 is in the sequence of each of the 4 copies in

Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

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Zhidong Tu

Full Text Available Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6 and diabetes-susceptible (BTBR mouse strains made genetically obese by the Leptin(ob/ob mutation (Lep(ob. High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

Sensitive cell-based assay for determination of human immunodeficiency virus type 1 coreceptor tropism.

Science.gov (United States)

Weber, Jan; Vazquez, Ana C; Winner, Dane; Gibson, Richard M; Rhea, Ariel M; Rose, Justine D; Wylie, Doug; Henry, Kenneth; Wright, Alison; King, Kevin; Archer, John; Poveda, Eva; Soriano, Vicente; Robertson, David L; Olivo, Paul D; Arts, Eric J; Quiñones-Mateu, Miguel E

2013-05-01

CCR5 antagonists are a powerful new class of antiretroviral drugs that require a companion assay to evaluate the presence of CXCR4-tropic (non-R5) viruses prior to use in human immunodeficiency virus (HIV)-infected individuals. In this study, we have developed, characterized, verified, and prevalidated a novel phenotypic test to determine HIV-1 coreceptor tropism (VERITROP) based on a sensitive cell-to-cell fusion assay. A proprietary vector was constructed containing a near-full-length HIV-1 genome with the yeast uracil biosynthesis (URA3) gene replacing the HIV-1 env coding sequence. Patient-derived HIV-1 PCR products were introduced by homologous recombination using an innovative yeast-based cloning strategy. The env-expressing vectors were then used in a cell-to-cell fusion assay to determine the presence of R5 and/or non-R5 HIV-1 variants within the viral population. Results were compared with (i) the original version of Trofile (Monogram Biosciences, San Francisco, CA), (ii) population sequencing, and (iii) 454 pyrosequencing, with the genotypic data analyzed using several bioinformatics tools, i.e., the 11/24/25 rule, Geno2Pheno (2% to 5.75%, 3.5%, or 10% false-positive rate [FPR]), and webPSSM. VERITROP consistently detected minority non-R5 variants from clinical specimens, with an analytical sensitivity of 0.3%, with viral loads of ≥1,000 copies/ml, and from B and non-B subtypes. In a pilot study, a 73.7% (56/76) concordance was observed with the original Trofile assay, with 19 of the 20 discordant results corresponding to non-R5 variants detected using VERITROP and not by the original Trofile assay. The degree of concordance of VERITROP and Trofile with population and deep sequencing results depended on the algorithm used to determine HIV-1 coreceptor tropism. Overall, VERITROP showed better concordance with deep sequencing/Geno2Pheno at a 0.3% detection threshold (67%), whereas Trofile matched better with population sequencing (79%). However, 454

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

DEFF Research Database (Denmark)

Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki

2016-01-01

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci...

Identification of four novel susceptibility loci for oestrogen receptor negative breast cancer

NARCIS (Netherlands)

Couch, Fergus J; Kuchenbaecker, Karoline B; Michailidou, Kyriaki; Mendoza-Fandino, Gustavo A; Nord, Silje; Lilyquist, Janna; Olswold, Curtis; Hallberg, Emily; Agata, Simona; Ahsan, Habibul; Aittomäki, Kristiina; Ambrosone, Christine; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arun, Banu K; Arver, Brita; Barile, Monica; Barkardottir, Rosa B; Barrowdale, Daniel; Beckmann, Lars; Beckmann, Matthias W; Benitez, Javier; Blank, Stephanie V; Blomqvist, Carl; Bogdanova, Natalia V; Bojesen, Stig E; Bolla, Manjeet K; Bonanni, Bernardo; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Canzian, Federico; Carpenter, Jane; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen B M; Cox, Angela; Cross, Simon S; Cunningham, Julie M; Czene, Kamila; Daly, Mary B; Damiola, Francesca; Darabi, Hatef; de la Hoya, Miguel; Devilee, Peter; Diez, Orland; Ding, Yuan C; Dolcetti, Riccardo; Domchek, Susan M; Dorfling, Cecilia M; Dos-Santos-Silva, Isabel; Dumont, Martine; Dunning, Alison M; Eccles, Diana M; Ehrencrona, Hans; Ekici, Arif B; Eliassen, Heather; Ellis, Steve; Fasching, Peter A; Figueroa, Jonine; Flesch-Janys, Dieter; Försti, Asta; Fostira, Florentia; Foulkes, William D; Friebel, Tara; Friedman, Eitan; Frost, Debra; Gabrielson, Marike; Gammon, Marilie D; Ganz, Patricia A; Gapstur, Susan M; Garber, Judy; Gaudet, Mia M; Gayther, Simon A; Gerdes, Anne-Marie; Ghoussaini, Maya; Giles, Graham G; Glendon, Gord; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E; González-Neira, Anna; Greene, Mark H; Gronwald, Jacek; Guénel, Pascal; Gunter, Marc; Haeberle, Lothar; Haiman, Christopher A; Hamann, Ute; Hansen, Thomas V O; Hart, Steven; Healey, Sue; Heikkinen, Tuomas; Henderson, Brian E; Herzog, Josef; Hogervorst, Frans B L; Hollestelle, Antoinette; Hooning, Maartje J; Hoover, Robert N; Hopper, John L; Humphreys, Keith; Hunter, David J; Huzarski, Tomasz; Imyanitov, Evgeny N; Isaacs, Claudine; Jakubowska, Anna; James, Paul; Janavicius, Ramunas; Jensen, Uffe Birk; John, Esther M; Jones, Michael; Kabisch, Maria; Kar, Siddhartha; Karlan, Beth Y; Khan, Sofia; Khaw, Kay-Tee; Kibriya, Muhammad G; Knight, Julia A; Ko, Yon-Dschun; Konstantopoulou, Irene; Kosma, Veli-Matti; Kristensen, Vessela; Kwong, Ava; Laitman, Yael; Lambrechts, Diether; Lazaro, Conxi; Lee, Eunjung; Le Marchand, Loic; Lester, Jenny; Lindblom, Annika; Lindor, Noralane; Lindstrom, Sara; Liu, Jianjun; Long, Jirong; Lubinski, Jan; Mai, Phuong L; Makalic, Enes; Malone, Kathleen E; Mannermaa, Arto; Manoukian, Siranoush; Margolin, Sara; Marme, Frederik; Martens, John W M; McGuffog, Lesley; Meindl, Alfons; Miller, Austin; Milne, Roger L; Miron, Penelope; Montagna, Marco; Mazoyer, Sylvie; Mulligan, Anna M; Muranen, Taru A; Nathanson, Katherine L; Neuhausen, Susan L; Nevanlinna, Heli; Nordestgaard, Børge G; Nussbaum, Robert L; Offit, Kenneth; Olah, Edith; Olopade, Olufunmilayo I; Olson, Janet E; Osorio, Ana; Park, Sue K; Peeters, Petra H; Peissel, Bernard; Peterlongo, Paolo; Peto, Julian; Phelan, Catherine M; Pilarski, Robert; Poppe, Bruce; Pylkäs, Katri; Radice, Paolo; Rahman, Nazneen; Rantala, Johanna; Rappaport, Christine; Rennert, Gad; Richardson, Andrea; Robson, Mark; Romieu, Isabelle; Rudolph, Anja; Rutgers, Emiel J; Sanchez, Maria-Jose; Santella, Regina M; Sawyer, Elinor J; Schmidt, Daniel F; Schmidt, Marjanka K; Schmutzler, Rita K; Schumacher, Fredrick; Scott, Rodney; Senter, Leigha; Sharma, Priyanka; Simard, Jacques; Singer, Christian F; Sinilnikova, Olga M; Soucy, Penny; Southey, Melissa; Steinemann, Doris; Stenmark-Askmalm, Marie; Stoppa-Lyonnet, Dominique; Swerdlow, Anthony; Szabo, Csilla I; Tamimi, Rulla; Tapper, William; Teixeira, Manuel R; Teo, Soo-Hwang; Terry, Mary B; Thomassen, Mads; Thompson, Deborah; Tihomirova, Laima; Toland, Amanda E; Tollenaar, Robert A E M; Tomlinson, Ian; Truong, Thérèse; Tsimiklis, Helen; Teulé, Alex; Tumino, Rosario; Tung, Nadine; Turnbull, Clare; Ursin, Giski; van Deurzen, Carolien H M; van Rensburg, Elizabeth J; Varon-Mateeva, Raymonda; Wang, Zhaoming; Wang-Gohrke, Shan; Weiderpass, Elisabete; Weitzel, Jeffrey N; Whittemore, Alice; Wildiers, Hans; Winqvist, Robert; Yang, Xiaohong R; Yannoukakos, Drakoulis; Yao, Song; Zamora, M Pilar; Zheng, Wei; Hall, Per; Kraft, Peter; Vachon, Celine; Slager, Susan; Chenevix-Trench, Georgia; Pharoah, Paul D P; Monteiro, Alvaro A N; García-Closas, Montserrat; Easton, Douglas F; Antoniou, Antonis C

2016-01-01

Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations (P<5 × 10(-8)) with oestrogen receptor (ER)-negative breast cancer and BRCA1-associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci,

Genius loci jako estetický problém

OpenAIRE

Křížová, Lucie

2016-01-01

(in English): Diploma thesis Genius loci as an aesthetic problem is addressed by defining the concept of genius loci and exploring its aesthetic implications and parallels. After clarification of the ontological nature of this phenomenon its commonalities will be monitored with selected concepts of environmental philosophy and aesthetics, especially the aesthetic dimension of the environmental experience. Publications of Christian Norberg-Schulz and David E. Cooper are used as a starting mate...

Functional cell types in taste buds have distinct longevities.

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Isabel Perea-Martinez

Full Text Available Taste buds are clusters of polarized sensory cells embedded in stratified oral epithelium. In adult mammals, taste buds turn over continuously and are replenished through the birth of new cells in the basal layer of the surrounding non-sensory epithelium. The half-life of cells in mammalian taste buds has been estimated as 8-12 days on average. Yet, earlier studies did not address whether the now well-defined functional taste bud cell types all exhibit the same lifetime. We employed a recently developed thymidine analog, 5-ethynil-2'-deoxyuridine (EdU to re-evaluate the incorporation of newly born cells into circumvallate taste buds of adult mice. By combining EdU-labeling with immunostaining for selected markers, we tracked the differentiation and lifespan of the constituent cell types of taste buds. EdU was primarily incorporated into basal extragemmal cells, the principal source for replenishing taste bud cells. Undifferentiated EdU-labeled cells began migrating into circumvallate taste buds within 1 day of their birth. Type II (Receptor taste cells began to differentiate from EdU-labeled precursors beginning 2 days after birth and then were eliminated with a half-life of 8 days. Type III (Presynaptic taste cells began differentiating after a delay of 3 days after EdU-labeling, and they survived much longer, with a half-life of 22 days. We also scored taste bud cells that belong to neither Type II nor Type III, a heterogeneous group that includes mostly Type I cells, and also undifferentiated or immature cells. A non-linear decay fit described these cells as two sub-populations with half-lives of 8 and 24 days respectively. Our data suggest that many post-mitotic cells may remain quiescent within taste buds before differentiating into mature taste cells. A small number of slow-cycling cells may also exist within the perimeter of the taste bud. Based on their incidence, we hypothesize that these may be progenitors for Type III cells.

Functional cell types in taste buds have distinct longevities.

Science.gov (United States)

Perea-Martinez, Isabel; Nagai, Takatoshi; Chaudhari, Nirupa

2013-01-01

Taste buds are clusters of polarized sensory cells embedded in stratified oral epithelium. In adult mammals, taste buds turn over continuously and are replenished through the birth of new cells in the basal layer of the surrounding non-sensory epithelium. The half-life of cells in mammalian taste buds has been estimated as 8-12 days on average. Yet, earlier studies did not address whether the now well-defined functional taste bud cell types all exhibit the same lifetime. We employed a recently developed thymidine analog, 5-ethynil-2'-deoxyuridine (EdU) to re-evaluate the incorporation of newly born cells into circumvallate taste buds of adult mice. By combining EdU-labeling with immunostaining for selected markers, we tracked the differentiation and lifespan of the constituent cell types of taste buds. EdU was primarily incorporated into basal extragemmal cells, the principal source for replenishing taste bud cells. Undifferentiated EdU-labeled cells began migrating into circumvallate taste buds within 1 day of their birth. Type II (Receptor) taste cells began to differentiate from EdU-labeled precursors beginning 2 days after birth and then were eliminated with a half-life of 8 days. Type III (Presynaptic) taste cells began differentiating after a delay of 3 days after EdU-labeling, and they survived much longer, with a half-life of 22 days. We also scored taste bud cells that belong to neither Type II nor Type III, a heterogeneous group that includes mostly Type I cells, and also undifferentiated or immature cells. A non-linear decay fit described these cells as two sub-populations with half-lives of 8 and 24 days respectively. Our data suggest that many post-mitotic cells may remain quiescent within taste buds before differentiating into mature taste cells. A small number of slow-cycling cells may also exist within the perimeter of the taste bud. Based on their incidence, we hypothesize that these may be progenitors for Type III cells.

Toxin-antitoxin loci as stress-response-elements: ChpAK/MazF and ChpBK cleave translated RNAs and are counteracted by tmRNA

DEFF Research Database (Denmark)

Christensen, S.K.; Pedersen, K.; Hansen, Flemming G.

2003-01-01

Prokaryotic chromosomes encode toxin-antitoxin loci, often in multiple copies. In most cases, the function of these genes is not known. The chpA (mazEF) locus of Escherichia coli has been described as a cell killing module that induces bacterial apoptosis during nutritional stress. However, we...... found recently that ChpAK (MazF) does not confer cell killing but rather, induces a bacteriostatic condition from which the cells could be resuscitated. Results presented here yield a mechanistic explanation for the detrimental effect on cell growth exerted by ChpAK and the homologous ChpBK protein of E......AK cleaved tmRNA in its coding region. Thus, ChpAK and ChpBK inhibit translation by a mechanism very similar to that of E. coli RelE. On the basis of these results, we propose a model that integrates TA loci into general prokaryotic stress physiology....

Polarized and persistent Ca²⁺ plumes define loci for formation of wall ingrowth papillae in transfer cells.

Science.gov (United States)

Zhang, Hui-Ming; Imtiaz, Mohammad S; Laver, Derek R; McCurdy, David W; Offler, Christina E; van Helden, Dirk F; Patrick, John W

2015-03-01

Transfer cell morphology is characterized by a polarized ingrowth wall comprising a uniform wall upon which wall ingrowth papillae develop at right angles into the cytoplasm. The hypothesis that positional information directing construction of wall ingrowth papillae is mediated by Ca(2+) signals generated by spatiotemporal alterations in cytosolic Ca(2+) ([Ca(2+)]cyt) of cells trans-differentiating to a transfer cell morphology was tested. This hypothesis was examined using Vicia faba cotyledons. On transferring cotyledons to culture, their adaxial epidermal cells synchronously trans-differentiate to epidermal transfer cells. A polarized and persistent Ca(2+) signal, generated during epidermal cell trans-differentiation, was found to co-localize with the site of ingrowth wall formation. Dampening Ca(2+) signal intensity, by withdrawing extracellular Ca(2+) or blocking Ca(2+) channel activity, inhibited formation of wall ingrowth papillae. Maintenance of Ca(2+) signal polarity and persistence depended upon a rapid turnover (minutes) of cytosolic Ca(2+) by co-operative functioning of plasma membrane Ca(2+)-permeable channels and Ca(2+)-ATPases. Viewed paradermally, and proximal to the cytosol-plasma membrane interface, the Ca(2+) signal was organized into discrete patches that aligned spatially with clusters of Ca(2+)-permeable channels. Mathematical modelling demonstrated that these patches of cytosolic Ca(2+) were consistent with inward-directed plumes of elevated [Ca(2+)]cyt. Plume formation depended upon an alternating distribution of Ca(2+)-permeable channels and Ca(2+)-ATPase clusters. On further inward diffusion, the Ca(2+) plumes coalesced into a uniform Ca(2+) signal. Blocking or dispersing the Ca(2+) plumes inhibited deposition of wall ingrowth papillae, while uniform wall formation remained unaltered. A working model envisages that cytosolic Ca(2+) plumes define the loci at which wall ingrowth papillae are deposited. © The Author 2014. Published by Oxford

The loci controlling plasticity in flax

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Bickel CL

2012-02-01

Full Text Available Cory L Bickel, Marshall Lukacs, Christopher A CullisCase Western Reserve University, Cleveland OH, USAAbstract: Flax undergoes heritable genomic changes in response to nutrient stress, including changes in total DNA content, rDNA copy number variation, and the appearance of Linum Insertion Sequence 1 (LIS-1. The nature of the genomic changes suggests a very different mechanism, which is not yet understood, from that of other DNA changes in response to stress, such as the activation of transposable elements. To identify the genes that control genomic changes in response to stress in flax, reciprocal crosses were made between a responsive flax line, Stormont cirrus, and an unresponsive line, Bethune. The ability of the F2 generation (from selfed F1 plants to respond to nutrient stress was assayed using the insertion of LIS-1 as the criteria for responsiveness. Twenty-nine out of 89 F2s responded at 5 weeks, suggesting that 3-4 dominant loci were all necessary for early LIS-1 insertion. Seventy out of 76 responded at 10 weeks, indicating two dominant loci independently capable of initiating LIS-1 insertion under prolonged nutrient stress. F1 plants and their progeny with either P1 or Bethune as the maternal parent were capable of responding with LIS-1 insertion, indicating that LIS-1 insertion is under nuclear genetic control and does not involve maternal factors. Thus, a small number of loci within the genome of Stormont cirrus appear to control the ability to respond to nutrient stress with LIS-1 insertion. A genetic map of the flax genome is currently under construction, and will be used to identify these loci within the genome.Keywords: nutrient stress, genomic plasticity, flax, Linum usitatissimum, LIS-1 

Express determination of the volume 222Rn activity using the Lucas Type scintillation cells

International Nuclear Information System (INIS)

Muellerova, M.; Holy, K.; Polaskova, A.

2006-01-01

This report deals with the possibility of the accurate determination of the volume radon activity using the Lucas type scintillation chamber before the radioactive equilibrium between the radon and its decay products is achieved. This method allows to obtain data about the volume activity of the sample promptly and also it offers a possibility to apply the detector for measurements more times a day. We developed a method for the determination of the detection efficiency of the scintillation chamber for varied time periods after the chamber was filled up with a sample. The volume radon activity calculated from the count rates in saturated conditions is in a good agreement with the volume radon activity calculated from our derived relation. It was shown that the scintillation chamber can be used for the express determination of the volume radon activity. The time between the individual applications of the scintillation chamber can be compressed maintaining of sufficient accuracy of the determination of the volume radon activity. (authors)

Isolation and characterization of microsatellite loci from the Arctic cisco (Coregonus autumnalis)

Science.gov (United States)

Ramey, A.; Graziano, S.L.; Nielsen, J.L.

2008-01-01

Eight polymorphic microsatellite loci were isolated and characterized for the Arctic cisco, Coregonus autumnalis. Loci were evaluated in 21 samples from the Colville River subsistence fishery. The number of alleles per locus ranged from two to 18. Observed heterozygosity of loci varied from 0.10 to 1.00, and expected heterozygosity ranged from 0.09 to 0.92. All eight microsatellite markers were in Hardy-Weinberg equilibrium. The loci presented here will be useful in describing population structure and exploring populations of origin for Arctic cisco. ?? 2007 Blackwell Publishing Ltd.

Role of wild-type p53 in apoptotic and non-apoptotic cell death induced by X-irradiation and heat treatment in p53-mutated mouse M10 cells

International Nuclear Information System (INIS)

Ito, Atsushi; Nakano, Hisako; Shinohara, Kunio

2010-01-01

The sensitizing effects of wild-type p53 on X-ray-induced cell death and on heat-induced apoptosis in M10, a radiosensitive and Trp53 (mouse p53 gene)-mutated lymphoma cell line which dies through necrosis by X-irradiation, were investigated using three M10 derived transfectants with wild-type TP53 (human p53 gene). Cell death was determined by colony formation and/or dye exclusion test, and apoptosis was detected as the changes in nuclear morphology by Giemsa staining. Expression of wild-type p53 protein increased radiosensitivity of cell death as determined by both clonogenic and dye exclusion assays. This increase in radiosensitivity was attributable largely to apoptosis induction in addition to a small enhancement of necrosis. Interestingly neither pathway to cell death was accompanied by caspase-3 activation. On the other hand, heat-induced caspase-3 dependent apoptotic cell death without transfection was further increased by the transfection of wild-type p53. In conclusion, the introduction of wild-type p53 enhanced apoptotic cell death by X-rays or heat via different mechanisms that do or do not activate caspase-3, respectively. In addition, p53 also enhanced the X-ray-induced necrosis in M10 cells. (author)

Characterization of EST-based SSR loci in the spruce budworm, Choristoneura fumiferana (Lepidoptera: Tortricidae)

Science.gov (United States)

B.M.T. Brunet; D. Doucet; B.R. Sturtevant; F.A.H. Sperling

2013-01-01

After identifying 114 microsatellite loci from Choristoneura fumiferana expressed sequence tags, 87 loci were assayed in a panel of 11 wild-caught individuals, giving 29 polymorphic loci. Further analysis of 20 of these loci on 31 individuals collected from a single population in northern Minnesota identified 14 in Hardy-Weinberg equilibrium.

Arachidonate metabolism increases as rat alveolar type II cells differentiate in vitro

International Nuclear Information System (INIS)

Lipchik, R.J.; Chauncey, J.B.; Paine, R.; Simon, R.H.; Peters-Golden, M.

1990-01-01

Rat type II alveolar epithelial cells are known to undergo morphological and functional changes when maintained in culture for several days. Having previously demonstrated that these cells can deacylate free arachidonic acid (AA) and metabolize it to products of the cyclooxygenase pathway, the present study was undertaken to determine whether in vitro differentiation was accompanied by alterations in the availability and metabolism of AA. We assessed the constitutive and ionophore A23187-induced deacylation and metabolism of endogenous AA, as well as the metabolism of exogenously supplied AA, in primary cultures of rat type II cells at days 2, 4, and 7 after isolation. Levels of free endogenous AA were increased at day 4, whereas eicosanoid synthesis, predominantly prostaglandin E2 and prostacyclin, increased markedly only at day 7. A similar time course of augmentation of prostanoid release was seen in response to exogenous AA. Type II cells cultured on fibronectin, intended to hasten cell flattening and spreading, demonstrated accelerated increases in available free AA in response to A23187; cells cultured on basement membrane derived from Engelbreth-Holm-Swarm mouse sarcoma, known to maintain the type II phenotype, exhibited diminished levels of available free AA. From these findings, we conclude that alterations in arachidonate metabolism are linked to alterations in cellular phenotype. The potentiation of eicosanoid synthesis accompanying in vitro differentiation suggests a possible role for the alveolar epithelium in the modulation of inflammation and fibrosis in the distal lung

The Method of Loci as a Mnemonic Device to Facilitate Learning in Endocrinology Leads to Improvement in Student Performance as Measured by Assessments

Science.gov (United States)

Qureshi, Ayisha; Rizvi, Farwa; Syed, Anjum; Shahid, Aqueel; Manzoor, Hana

2014-01-01

Cognitive psychology has demonstrated that the way knowledge is structured in memory determines the ability to retain, recall, and use it to solve problems. The method of loci (MOL) is a mnemonic device that relies on spatial relationships between "loci" (e.g., locations on a familiar route or rooms in a familiar building) to arrange and…

Typing of Mycobacterium avium subspecies paratuberculosis isolates from Newfoundland using fragment analysis.

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Milka P Podder

Full Text Available Short Sequence Repeat (SSR typing of Mycobacterium avium subspecies paratuberculosis (Map isolates is one of the most commonly used method for genotyping this pathogen. Currently used techniques have challenges in analyzing mononucleotide repeats >15 bp, which include some of the Map SSRs. Fragment analysis is a relatively simple technique, which can accurately measure the size of DNA fragments and can be used to calculate the repeat length of the target SSR loci. In the present study, fragment analysis was used to analyze 4 Map SSR loci known to provide sufficient discriminatory power to determine the relationship between Map isolates. Eighty-five Map isolates from 18 animals from the island of Newfoundland were successfully genotyped using fragment analysis. To the best of our knowledge, this is the first report on Map SSR diversity from Newfoundland dairy farms. Previously unreported Map SSR-types or combinations were also identified during the course of the described work. In addition, multiple Map SSR-types were isolated from a single animal in many cases, which is not a common finding.

Development of a Hierarchical Variable-Number Tandem Repeat Typing Scheme for Mycobacterium tuberculosis in China

Science.gov (United States)

Luo, Tao; Yang, Chongguang; Pang, Yu; Zhao, Yanlin; Mei, Jian; Gao, Qian

2014-01-01

Molecular typing based on variable-number tandem repeats (VNTR) analysis is a promising tool for identifying transmission of Mycobacterium tuberculosis. However, the currently proposed 15- and 24-locus VNTR sets (VNTR-15/24) only have limited resolution and contain too many loci for large-scale typing in high burden countries. To develop an optimal typing scheme in China, we evaluated the resolution and robustness of 25 VNTR loci, using population-based collections of 1362 clinical isolates from six provinces across the country. The resolution of most loci showed considerable variations among regions. By calculating the average resolution of all possible combinations of 20 robust loci, we identified an optimal locus set with a minimum of 9 loci (VNTR-9) that could achieve comparable resolution of the standard VNTR-15. The VNTR-9 had consistently high resolutions in all six regions, and it was highly concordant with VNTR-15 for defining both clustered and unique genotypes. Furthermore, VNTR-9 was phylogenetically informative for classifying lineages/sublineages of M. tuberculosis. Three hypervariable loci (HV-3), VNTR 3232, VNTR 3820 and VNTR 4120, were proved important for further differentiating unrelated clustered strains based on VNTR-9. We propose the optimized VNTR-9 as first-line method and the HV-3 as second-line method for molecular typing of M. tuberculosis in China and surrounding countries. The development of hierarchical VNTR typing methods that can achieve high resolution with a small number of loci could be suitable for molecular epidemiology study in other high burden countries. PMID:24586989

Killer Immunoglobulin-Like Receptor Allele Determination Using Next-Generation Sequencing Technology

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Bercelin Maniangou

2017-05-01

Full Text Available The impact of natural killer (NK cell alloreactivity on hematopoietic stem cell transplantation (HSCT outcome is still debated due to the complexity of graft parameters, HLA class I environment, the nature of killer cell immunoglobulin-like receptor (KIR/KIR ligand genetic combinations studied, and KIR+ NK cell repertoire size. KIR genes are known to be polymorphic in terms of gene content, copy number variation, and number of alleles. These allelic polymorphisms may impact both the phenotype and function of KIR+ NK cells. We, therefore, speculate that polymorphisms may alter donor KIR+ NK cell phenotype/function thus modulating post-HSCT KIR+ NK cell alloreactivity. To investigate KIR allele polymorphisms of all KIR genes, we developed a next-generation sequencing (NGS technology on a MiSeq platform. To ensure the reliability and specificity of our method, genomic DNA from well-characterized cell lines were used; high-resolution KIR typing results obtained were then compared to those previously reported. Two different bioinformatic pipelines were used allowing the attribution of sequencing reads to specific KIR genes and the assignment of KIR alleles for each KIR gene. Our results demonstrated successful long-range KIR gene amplifications of all reference samples using intergenic KIR primers. The alignment of reads to the human genome reference (hg19 using BiRD pipeline or visualization of data using Profiler software demonstrated that all KIR genes were completely sequenced with a sufficient read depth (mean 317× for all loci and a high percentage of mapping (mean 93% for all loci. Comparison of high-resolution KIR typing obtained to those published data using exome capture resulted in a reported concordance rate of 95% for centromeric and telomeric KIR genes. Overall, our results suggest that NGS can be used to investigate the broad KIR allelic polymorphism. Hence, these data improve our knowledge, not only on KIR+ NK cell alloreactivity in

Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers.

Science.gov (United States)

Andrew, Angeline S; Baron, John A; Butterly, Lynn F; Suriawinata, Arief A; Tsongalis, Gregory J; Robinson, Christina M; Amos, Christopher I

2017-03-02

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%-35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our rightsided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 x 10-10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals.

Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD.

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Carsten A Böger

2011-09-01

Full Text Available Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD and end stage renal disease (ESRD. Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m(2 at follow-up and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls. SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1. SNPs in UMOD (OR = 0.92, p = 0.04 and GCKR (OR = 0.93, p = 0.03 were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.

The influence of Glu-1 and Glu-3 loci on dough rheology and bread-making properties in wheat (Triticum aestivum L.) doubled haploid lines.

Science.gov (United States)

Langner, Monika; Krystkowiak, Karolina; Salmanowicz, Bolesław P; Adamski, Tadeusz; Krajewski, Paweł; Kaczmarek, Zygmunt; Surma, Maria

2017-12-01

The major determinants of wheat quality are Glu-1 and Glu-3 glutenin loci and environmental factors. Additive effects of alleles at the Glu-1 and Glu-3 loci, as well as their interactions, were evaluated for dough rheology and baking properties in four groups of wheat doubled haploid lines differing in high- and low-molecular-weight glutenin composition. Flour quality, Reomixer (Reologica Instruments, Lund, Sweden), dough extension, Farinograph (Brabender GmbH, Duisburg, Germany) and baking parameters were determined. Groups of lines with the alleles Glu-A3b and Glu-B3d were characterized by higher values of dough and baking parameters compared to those with the Glu-A3e and Glu-B3a alleles. Effects of interactions between allelic variants at the Glu-1 and Glu-3 loci on Reomixer parameters, dough extension tests and baking parameters were significant, although additive effects of individual alleles were not always significant. The allelic variants at Glu-B3 had a much greater effect on dough rheological parameters than the variants at Glu-A3 or Glu-D3 loci. The effect of allelic variations at the Glu-D3 loci on rheological parameters and bread-making quality was non-significant, whereas their interactions with a majority of alleles at the other Glu-1 × Glu-3 loci were significant. © 2017 Society of Chemical Industry. © 2017 Society of Chemical Industry.

Genome-wide meta-analysis identifies new susceptibility loci for migraine.

Science.gov (United States)

Anttila, Verneri; Winsvold, Bendik S; Gormley, Padhraig; Kurth, Tobias; Bettella, Francesco; McMahon, George; Kallela, Mikko; Malik, Rainer; de Vries, Boukje; Terwindt, Gisela; Medland, Sarah E; Todt, Unda; McArdle, Wendy L; Quaye, Lydia; Koiranen, Markku; Ikram, M Arfan; Lehtimäki, Terho; Stam, Anine H; Ligthart, Lannie; Wedenoja, Juho; Dunham, Ian; Neale, Benjamin M; Palta, Priit; Hamalainen, Eija; Schürks, Markus; Rose, Lynda M; Buring, Julie E; Ridker, Paul M; Steinberg, Stacy; Stefansson, Hreinn; Jakobsson, Finnbogi; Lawlor, Debbie A; Evans, David M; Ring, Susan M; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari A; Freilinger, Tobias; Schoenen, Jean; Frants, Rune R; Pelzer, Nadine; Weller, Claudia M; Zielman, Ronald; Heath, Andrew C; Madden, Pamela A F; Montgomery, Grant W; Martin, Nicholas G; Borck, Guntram; Göbel, Hartmut; Heinze, Axel; Heinze-Kuhn, Katja; Williams, Frances M K; Hartikainen, Anna-Liisa; Pouta, Anneli; van den Ende, Joyce; Uitterlinden, Andre G; Hofman, Albert; Amin, Najaf; Hottenga, Jouke-Jan; Vink, Jacqueline M; Heikkilä, Kauko; Alexander, Michael; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Wichmann, Heinz Erich; Aromaa, Arpo; Eriksson, Johan G; Traynor, Bryan; Trabzuni, Daniah; Rossin, Elizabeth; Lage, Kasper; Jacobs, Suzanne B R; Gibbs, J Raphael; Birney, Ewan; Kaprio, Jaakko; Penninx, Brenda W; Boomsma, Dorret I; van Duijn, Cornelia; Raitakari, Olli; Jarvelin, Marjo-Riitta; Zwart, John-Anker; Cherkas, Lynn; Strachan, David P; Kubisch, Christian; Ferrari, Michel D; van den Maagdenberg, Arn M J M; Dichgans, Martin; Wessman, Maija; Smith, George Davey; Stefansson, Kari; Daly, Mark J; Nyholt, Dale R; Chasman, Daniel; Palotie, Aarno

2013-08-01

Migraine is the most common brain disorder, affecting approximately 14% of the adult population, but its molecular mechanisms are poorly understood. We report the results of a meta-analysis across 29 genome-wide association studies, including a total of 23,285 individuals with migraine (cases) and 95,425 population-matched controls. We identified 12 loci associated with migraine susceptibility (P<5×10(-8)). Five loci are new: near AJAP1 at 1p36, near TSPAN2 at 1p13, within FHL5 at 6q16, within C7orf10 at 7p14 and near MMP16 at 8q21. Three of these loci were identified in disease subgroup analyses. Brain tissue expression quantitative trait locus analysis suggests potential functional candidate genes at four loci: APOA1BP, TBC1D7, FUT9, STAT6 and ATP5B.

Genome-wide analysis identifies 12 loci influencing human reproductive behavior

Science.gov (United States)

Barban, Nicola; Jansen, Rick; de Vlaming, Ronald; Vaez, Ahmad; Mandemakers, Jornt J.; Tropf, Felix C.; Shen, Xia; Wilson, James F.; Chasman, Daniel I.; Nolte, Ilja M.; Tragante, Vinicius; van der Laan, Sander W.; Perry, John R. B.; Kong, Augustine; Ahluwalia, Tarunveer; Albrecht, Eva; Yerges-Armstrong, Laura; Atzmon, Gil; Auro, Kirsi; Ayers, Kristin; Bakshi, Andrew; Ben-Avraham, Danny; Berger, Klaus; Bergman, Aviv; Bertram, Lars; Bielak, Lawrence F.; Bjornsdottir, Gyda; Bonder, Marc Jan; Broer, Linda; Bui, Minh; Barbieri, Caterina; Cavadino, Alana; Chavarro, Jorge E; Turman, Constance; Concas, Maria Pina; Cordell, Heather J.; Davies, Gail; Eibich, Peter; Eriksson, Nicholas; Esko, Tõnu; Eriksson, Joel; Falahi, Fahimeh; Felix, Janine F.; Fontana, Mark Alan; Franke, Lude; Gandin, Ilaria; Gaskins, Audrey J.; Gieger, Christian; Gunderson, Erica P.; Guo, Xiuqing; Hayward, Caroline; He, Chunyan; Hofer, Edith; Huang, Hongyan; Joshi, Peter K.; Kanoni, Stavroula; Karlsson, Robert; Kiechl, Stefan; Kifley, Annette; Kluttig, Alexander; Kraft, Peter; Lagou, Vasiliki; Lecoeur, Cecile; Lahti, Jari; Li-Gao, Ruifang; Lind, Penelope A.; Liu, Tian; Makalic, Enes; Mamasoula, Crysovalanto; Matteson, Lindsay; Mbarek, Hamdi; McArdle, Patrick F.; McMahon, George; Meddens, S. Fleur W.; Mihailov, Evelin; Miller, Mike; Missmer, Stacey A.; Monnereau, Claire; van der Most, Peter J.; Myhre, Ronny; Nalls, Mike A.; Nutile, Teresa; Panagiota, Kalafati Ioanna; Porcu, Eleonora; Prokopenko, Inga; Rajan, Kumar B.; Rich-Edwards, Janet; Rietveld, Cornelius A.; Robino, Antonietta; Rose, Lynda M.; Rueedi, Rico; Ryan, Kathy; Saba, Yasaman; Schmidt, Daniel; Smith, Jennifer A.; Stolk, Lisette; Streeten, Elizabeth; Tonjes, Anke; Thorleifsson, Gudmar; Ulivi, Sheila; Wedenoja, Juho; Wellmann, Juergen; Willeit, Peter; Yao, Jie; Yengo, Loic; Zhao, Jing Hua; Zhao, Wei; Zhernakova, Daria V.; Amin, Najaf; Andrews, Howard; Balkau, Beverley; Barzilai, Nir; Bergmann, Sven; Biino, Ginevra; Bisgaard, Hans; Bønnelykke, Klaus; Boomsma, Dorret I.; Buring, Julie E.; Campbell, Harry; Cappellani, Stefania; Ciullo, Marina; Cox, Simon R.; Cucca, Francesco; Daniela, Toniolo; Davey-Smith, George; Deary, Ian J.; Dedoussis, George; Deloukas, Panos; van Duijn, Cornelia M.; de Geus, Eco JC.; Eriksson, Johan G.; Evans, Denis A.; Faul, Jessica D.; Felicita, Sala Cinzia; Froguel, Philippe; Gasparini, Paolo; Girotto, Giorgia; Grabe, Hans-Jörgen; Greiser, Karin Halina; Groenen, Patrick J.F.; de Haan, Hugoline G.; Haerting, Johannes; Harris, Tamara B.; Heath, Andrew C.; Heikkilä, Kauko; Hofman, Albert; Homuth, Georg; Holliday, Elizabeth G; Hopper, John; Hypponen, Elina; Jacobsson, Bo; Jaddoe, Vincent W. V.; Johannesson, Magnus; Jugessur, Astanand; Kähönen, Mika; Kajantie, Eero; Kardia, Sharon L.R.; Keavney, Bernard; Kolcic, Ivana; Koponen, Päivikki; Kovacs, Peter; Kronenberg, Florian; Kutalik, Zoltan; La Bianca, Martina; Lachance, Genevieve; Iacono, William; Lai, Sandra; Lehtimäki, Terho; Liewald, David C; Lindgren, Cecilia; Liu, Yongmei; Luben, Robert; Lucht, Michael; Luoto, Riitta; Magnus, Per; Magnusson, Patrik K.E.; Martin, Nicholas G.; McGue, Matt; McQuillan, Ruth; Medland, Sarah E.; Meisinger, Christa; Mellström, Dan; Metspalu, Andres; Michela, Traglia; Milani, Lili; Mitchell, Paul; Montgomery, Grant W.; Mook-Kanamori, Dennis; de Mutsert, Renée; Nohr, Ellen A; Ohlsson, Claes; Olsen, Jørn; Ong, Ken K.; Paternoster, Lavinia; Pattie, Alison; Penninx, Brenda WJH; Perola, Markus; Peyser, Patricia A.; Pirastu, Mario; Polasek, Ozren; Power, Chris; Kaprio, Jaakko; Raffel, Leslie J.; Räikkönen, Katri; Raitakari, Olli; Ridker, Paul M.; Ring, Susan M.; Roll, Kathryn; Rudan, Igor; Ruggiero, Daniela; Rujescu, Dan; Salomaa, Veikko; Schlessinger, David; Schmidt, Helena; Schmidt, Reinhold; Schupf, Nicole; Smit, Johannes; Sorice, Rossella; Spector, Tim D.; Starr, John M.; Stöckl, Doris; Strauch, Konstantin; Stumvoll, Michael; Swertz, Morris A.; Thorsteinsdottir, Unnur; Thurik, A. Roy; Timpson, Nicholas J.; Tönjes, Anke; Tung, Joyce Y.; Uitterlinden, André G.; Vaccargiu, Simona; Viikari, Jorma; Vitart, Veronique; Völzke, Henry; Vollenweider, Peter; Vuckovic, Dragana; Waage, Johannes; Wagner, Gert G.; Wang, Jie Jin; Wareham, Nicholas J.; Weir, David R.; Willemsen, Gonneke; Willeit, Johann; Wright, Alan F.; Zondervan, Krina T.; Stefansson, Kari; Krueger, Robert F.; Lee, James J.; Benjamin, Daniel J.; Cesarini, David; Koellinger, Philipp D.; den Hoed, Marcel; Snieder, Harold; Mills, Melinda C.

2017-01-01

The genetic architecture of human reproductive behavior – age at first birth (AFB) and number of children ever born (NEB) – has a strong relationship with fitness, human development, infertility and risk of neuropsychiatric disorders. However, very few genetic loci have been identified and the underlying mechanisms of AFB and NEB are poorly understood. We report the largest genome-wide association study to date of both sexes including 251,151 individuals for AFB and 343,072 for NEB. We identified 12 independent loci that are significantly associated with AFB and/or NEB in a SNP-based genome-wide association study, and four additional loci in a gene-based effort. These loci harbor genes that are likely to play a role – either directly or by affecting non-local gene expression – in human reproduction and infertility, thereby increasing our understanding of these complex traits. PMID:27798627

Genomic Analysis of Pathogenicity Determinants in Mycobacterium kansasii Type I

KAUST Repository

Guan, Qingtian

2016-05-01

Mycobacteria, a genus within Actinobacteria Phylum, are well known for two pathogens that cause human diseases: leprosy and tuberculosis. Other than the obligate human mycobacteria, there is a group of bacteria that are present in the environment and occasionally cause diseases in immunocompromised persons: the non-tuberculosis mycobacteria (NTM). Mycobacterium kansasii, which was first discovered in the Kansas state, is the main etiologic agent responsible for lung infections caused by NTM and raises attention because of its co-infection with human immunodeficiency virus (HIV). Five subspecies of M. kansasii (Type I-V) were described and only M. kansasii Type I is pathogenic to humans. M. kansasii is a Gram-positive bacteria that has a unique cell wall and secretion system, which is essential for its pathogenicity. We undertook a comparative genomics and transcriptomic approach to identify components of M. kansasii Type I pathogenicity. Our previous study showed that espA (ESX-1 essential protein) operon, a major component of the secretion system, is exclusively present in M. kansasii Type I. The purpose of this study was to test the functional role of the espA operon in pathogenicity and identify other components that may also be involved in pathogenicity. This study provides a new molecular diagnostic method for M. kansasii Type I infection using PCR (Polymerase Chain Reaction) technique to target the espAoperon. With detailed manual curation of the comparative genomics datasets, we found several genes exclusively present in M. kansasii Type I including ppsA/ppsC and whiB6, that we believe are involved, or have an effect on ESX-mediated secretion system. We have also highlighted, in our study, the differences in genetic components coding for the cell membrane composition between the five subspecies of M. kansasii. These results shed light on genetic components that are responsible for pathogenicity determinants in Type I M. kansasii and may help to design better

Molecular Determinants of Human T-lymphotropic Virus Type 1 Transmission and Spread

Directory of Open Access Journals (Sweden)

Patrick L. Green

2011-07-01

Full Text Available Human T-lymphotrophic virus type-1 (HTLV-1 infects approximately 15 to 20 million people worldwide, with endemic areas in Japan, the Caribbean, and Africa. The virus is spread through contact with bodily fluids containing infected cells, most often from mother to child through breast milk or via blood transfusion. After prolonged latency periods, approximately 3 to 5% of HTLV-1 infected individuals will develop either adult T-cell leukemia/lymphoma (ATL, or other lymphocyte-mediated disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. The genome of this complex retrovirus contains typical gag, pol, and env genes, but also unique nonstructural proteins encoded from the pX region. These nonstructural genes encode the Tax and Rex regulatory proteins, as well as novel proteins essential for viral spread in vivo such as, p30, p12, p13 and the antisense encoded HBZ. While progress has been made in the understanding of viral determinants of cell transformation and host immune responses, host and viral determinants of HTLV-1 transmission and spread during the early phases of infection are unclear. Improvements in the molecular tools to test these viral determinants in cellular and animal models have provided new insights into the early events of HTLV-1 infection. This review will focus on studies that test HTLV-1 determinants in context to full length infectious clones of the virus providing insights into the mechanisms of transmission and spread of HTLV-1.

Multi-virulence-locus sequence typing of Staphylococcus lugdunensis generates results consistent with a clonal population structure and is reliable for epidemiological typing.

Science.gov (United States)

Didi, Jennifer; Lemée, Ludovic; Gibert, Laure; Pons, Jean-Louis; Pestel-Caron, Martine

2014-10-01

Staphylococcus lugdunensis is an emergent virulent coagulase-negative staphylococcus responsible for severe infections similar to those caused by Staphylococcus aureus. To understand its potentially pathogenic capacity and have further detailed knowledge of the molecular traits of this organism, 93 isolates from various geographic origins were analyzed by multi-virulence-locus sequence typing (MVLST), targeting seven known or putative virulence-associated loci (atlLR2, atlLR3, hlb, isdJ, SLUG_09050, SLUG_16930, and vwbl). The polymorphisms of the putative virulence-associated loci were moderate and comparable to those of the housekeeping genes analyzed by multilocus sequence typing (MLST). However, the MVLST scheme generated 43 virulence types (VTs) compared to 20 sequence types (STs) based on MLST, indicating that MVLST was significantly more discriminating (Simpson's index [D], 0.943). No hypervirulent lineage or cluster specific to carriage strains was defined. The results of multilocus sequence analysis of known and putative virulence-associated loci are consistent with a clonal population structure for S. lugdunensis, suggesting a coevolution of these genes with housekeeping genes. Indeed, the nonsynonymous to synonymous evolutionary substitutions (dN/dS) ratio, the Tajima's D test, and Single-likelihood ancestor counting (SLAC) analysis suggest that all virulence-associated loci were under negative selection, even atlLR2 (AtlL protein) and SLUG_16930 (FbpA homologue), for which the dN/dS ratios were higher. In addition, this analysis of virulence-associated loci allowed us to propose a trilocus sequence typing scheme based on the intragenic regions of atlLR3, isdJ, and SLUG_16930, which is more discriminant than MLST for studying short-term epidemiology and further characterizing the lineages of the rare but highly pathogenic S. lugdunensis. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

Intra HLA-D/DR region recombinant detected by primed lymphocyte typing (PLT)

DEFF Research Database (Denmark)

Jakobsen, B K; Kristensen, T; Lamm, L U

1983-01-01

lymphocyte typing (PLT) for HLA-D/DR region associated DP antigens. None of these studies gave evidence that the recombinations had occurred within the HLA region. Mixed leucocyte culture (MLC) tests within the families showed no detectable stimulation between the HLA identical siblings in two......The chromosome 6 markers, HLA-ABC, D, DR, MT, properdin factor Bf, and complement factors 2 (C2) and 5 (C4), were studied in three families, each of which included two HLA identical siblings, one or both of whom were known to be HLA-B: GLO recombinants. The families were also typed with primed...... to reactive reagents. One of these (GHx), reacted with a determinant which segregated within the GG family as if child G was a paternal recombinant between the HLA-D, DR, DP, and C4 loci, on the one hand, and on the other hand one or more loci governing other HLA-D/DR region controlled lymphocyte activating...

Extent of Mycobacterium bovis transmission among animals of dairy and beef cattle and deer farms in South Korea determined by variable-number tandem repeats typing.

Science.gov (United States)

Je, Sungmo; Ku, Bok Kyung; Jeon, Bo-Young; Kim, Jae-Myoung; Jung, Suk-Chan; Cho, Sang-Nae

2015-04-17

Identifying sources of Mycobacterium bovis transmission would be essential for establishing effective control programs of bovine tuberculosis (TB), a major zoonosis threatening human health worldwide. As an effort to determine the extent of M. bovis transmission among dairy and beef cattle and deer populations, a mycobacterial interspersed repetitive units (MIRU)-variable-number tandem repeats (VNTR) typing method was employed for analysis of 131 M. bovis isolates from 59 Holstein dairy cattle, 39 Korean beef cattle, and 33 deer. Of 31 MIRU-VNTR markers, 15 showed allelic diversity. The most discriminatory locus for M. bovis isolates was VNTR 3336 (h=0.59) followed by QUB 26, MIRU 31, VNTR 2401, and VNTR 3171 which showed high discriminatory power (h=0.43). The combined VNTR loci had an allelic diversity of 0.83. On the basis of the VNTR profiles of 30 VNTR loci, 24 genotypes were identified, and two genotypes were highly prevalent among all M. bovis isolates (33.6% and 19.1%, respectively), thus indicating that more than 50% of the isolates shared common molecular characteristics. Six additional genotypes were common in 2 of the 3 animal species, suggesting a wide interspecies transmission of M. bovis. This study thus demonstrates that MIRU-VNTR typing is useful in differentiation of M. bovis isolates and that M. bovis transmission occurs frequently among farmed animal species, highlighting the importance of bovine TB control programs in different animal species which are often raised in the same villages. Copyright © 2015 Elsevier B.V. All rights reserved.

Imperforate Anus: Determination of Type Using Transperineal Ultrasonography

International Nuclear Information System (INIS)

Choi, Young Hun; Kim, In One; Cheon, Jung Eun; Kim, Woo Sun; Yeon, Kyung Mo

2009-01-01

This study was designed to assess the usefulness of transperineal ultrasonography (US) for the determination of imperforate anus (IA) type. From January 2000 to December 2004, 46 of 193 patients with an IA underwent transperineal US prior to corrective surgery. Sonographic findings were reviewed to identify the presence of internal fistulas and to determine 'distal rectal pouch to perineum (P-P)' distances. IA types were determined based on the sonographic findings, and the diagnostic accuracy of transperineal US was evaluated based on surgical findings. Of the 46 patients, 17 patients were surgically confirmed as having a high-type IA, three patients were confirmed as having an intermediate-type IA and 26 patients were confirmed as having a low-type IA. The IA type was correctly diagnosed by the use of transperineal US in 39 of the 46 patients (85%). In 14 of the 17 patients with a high-type IA, internal fistulas were correctly identified. All cases with a P-P distance > 16 mm were high-type IAs and all cases with a P-P distance < 5 mm were low-type IAs. Transperineal US is a good diagnostic modality for the identification of internal fistulas in cases of high-type IA and for defining the IA level

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

Science.gov (United States)

Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O.; Sovio, Ulla; Taal, H. Rob; Hennig, Branwen J.; Bradfield, Jonathan P.; St. Pourcain, Beate; Evans, David M.; Charoen, Pimphen; Kaakinen, Marika; Cousminer, Diana L.; Lehtimäki, Terho; Kreiner-Møller, Eskil; Warrington, Nicole M.; Bustamante, Mariona; Feenstra, Bjarke; Berry, Diane J.; Thiering, Elisabeth; Pfab, Thiemo; Barton, Sheila J.; Shields, Beverley M.; Kerkhof, Marjan; van Leeuwen, Elisabeth M.; Fulford, Anthony J.; Kutalik, Zoltán; Zhao, Jing Hua; den Hoed, Marcel; Mahajan, Anubha; Lindi, Virpi; Goh, Liang-Kee; Hottenga, Jouke-Jan; Wu, Ying; Raitakari, Olli T.; Harder, Marie N.; Meirhaeghe, Aline; Ntalla, Ioanna; Salem, Rany M.; Jameson, Karen A.; Zhou, Kaixin; Monies, Dorota M.; Lagou, Vasiliki; Kirin, Mirna; Heikkinen, Jani; Adair, Linda S.; Alkuraya, Fowzan S.; Al-Odaib, Ali; Amouyel, Philippe; Andersson, Ehm Astrid; Bennett, Amanda J.; Blakemore, Alexandra I.F.; Buxton, Jessica L.; Dallongeville, Jean; Das, Shikta; de Geus, Eco J. C.; Estivill, Xavier; Flexeder, Claudia; Froguel, Philippe; Geller, Frank; Godfrey, Keith M.; Gottrand, Frédéric; Groves, Christopher J.; Hansen, Torben; Hirschhorn, Joel N.; Hofman, Albert; Hollegaard, Mads V.; Hougaard, David M.; Hyppönen, Elina; Inskip, Hazel M.; Isaacs, Aaron; Jørgensen, Torben; Kanaka-Gantenbein, Christina; Kemp, John P.; Kiess, Wieland; Kilpeläinen, Tuomas O.; Klopp, Norman; Knight, Bridget A.; Kuzawa, Christopher W.; McMahon, George; Newnham, John P.; Niinikoski, Harri; Oostra, Ben A.; Pedersen, Louise; Postma, Dirkje S.; Ring, Susan M.; Rivadeneira, Fernando; Robertson, Neil R.; Sebert, Sylvain; Simell, Olli; Slowinski, Torsten; Tiesler, Carla M.T.; Tönjes, Anke; Vaag, Allan; Viikari, Jorma S.; Vink, Jacqueline M.; Vissing, Nadja Hawwa; Wareham, Nicholas J.; Willemsen, Gonneke; Witte, Daniel R.; Zhang, Haitao; Zhao, Jianhua; Wilson, James F.; Stumvoll, Michael; Prentice, Andrew M.; Meyer, Brian F.; Pearson, Ewan R.; Boreham, Colin A.G.; Cooper, Cyrus; Gillman, Matthew W.; Dedoussis, George V.; Moreno, Luis A; Pedersen, Oluf; Saarinen, Maiju; Mohlke, Karen L.; Boomsma, Dorret I.; Saw, Seang-Mei; Lakka, Timo A.; Körner, Antje; Loos, Ruth J.F.; Ong, Ken K.; Vollenweider, Peter; van Duijn, Cornelia M.; Koppelman, Gerard H.; Hattersley, Andrew T.; Holloway, John W.; Hocher, Berthold; Heinrich, Joachim; Power, Chris; Melbye, Mads; Guxens, Mònica; Pennell, Craig E.; Bønnelykke, Klaus; Bisgaard, Hans; Eriksson, Johan G.; Widén, Elisabeth; Hakonarson, Hakon; Uitterlinden, André G.; Pouta, Anneli; Lawlor, Debbie A.; Smith, George Davey; Frayling, Timothy M.; McCarthy, Mark I.; Grant, Struan F.A.; Jaddoe, Vincent W.V.; Jarvelin, Marjo-Riitta; Timpson, Nicholas J.; Prokopenko, Inga; Freathy, Rachel M.

2012-01-01

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood1. Previous genome-wide association studies identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes, and a second variant, near CCNL1, with no obvious link to adult traits2. In an expanded genome-wide association meta-analysis and follow-up study (up to 69,308 individuals of European descent from 43 studies), we have now extended the number of genome-wide significant loci to seven, accounting for a similar proportion of variance to maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes; ADRB1 with adult blood pressure; and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism. PMID:23202124

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism

DEFF Research Database (Denmark)

Horikoshi, Momoko; Yaghootkar, Hanieh; Mook-Kanamori, Dennis O

2013-01-01

-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between...... diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome......Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2...

Single-cell multiple gene expression analysis based on single-molecule-detection microarray assay for multi-DNA determination

Energy Technology Data Exchange (ETDEWEB)

Li, Lu [School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); Wang, Xianwei [School of Life Sciences, Shandong University, Jinan 250100 (China); Zhang, Xiaoli [School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China); Wang, Jinxing [School of Life Sciences, Shandong University, Jinan 250100 (China); Jin, Wenrui, E-mail: jwr@sdu.edu.cn [School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100 (China)

2015-01-07

Highlights: • A single-molecule-detection (SMD) microarray for 10 samples is fabricated. • The based-SMD microarray assay (SMA) can determine 8 DNAs for each sample. • The limit of detection of SMA is as low as 1.3 × 10{sup −16} mol L{sup −1}. • The SMA can be applied in single-cell multiple gene expression analysis. - Abstract: We report a novel ultra-sensitive and high-selective single-molecule-detection microarray assay (SMA) for multiple DNA determination. In the SMA, a capture DNA (DNAc) microarray consisting of 10 subarrays with 9 spots for each subarray is fabricated on a silanized glass coverslip as the substrate. On the subarrays, the spot-to-spot spacing is 500 μm and each spot has a diameter of ∼300 μm. The sequence of the DNAcs on the 9 spots of a subarray is different, to determine 8 types of target DNAs (DNAts). Thus, 8 types of DNAts are captured to their complementary DNAcs at 8 spots of a subarray, respectively, and then labeled with quantum dots (QDs) attached to 8 types of detection DNAs (DNAds) with different sequences. The ninth spot is used to detect the blank value. In order to determine the same 8 types of DNAts in 10 samples, the 10 DNAc-modified subarrays on the microarray are identical. Fluorescence single-molecule images of the QD-labeled DNAts on each spot of the subarray are acquired using a home-made single-molecule microarray reader. The amounts of the DNAts are quantified by counting the bright dots from the QDs. For a microarray, 8 types of DNAts in 10 samples can be quantified in parallel. The limit of detection of the SMA for DNA determination is as low as 1.3 × 10{sup −16} mol L{sup −1}. The SMA for multi-DNA determination can also be applied in single-cell multiple gene expression analysis through quantification of complementary DNAs (cDNAs) corresponding to multiple messenger RNAs (mRNAs) in single cells. To do so, total RNA in single cells is extracted and reversely transcribed into their cDNAs. Three

Isolation and characterization of 21 polymorphic microsatellite loci in the Japanese dace (Tribolodon hakonensis)

Science.gov (United States)

Koizumi, Noriyuki; Quinn, Thomas W.; Park, Myeongsoo; Fike, Jennifer A.; Nishida, Kazuya; Takemura, Takeshi; Watabe, Keiji; Mori, Atsushi

2011-01-01

Twenty one polymorphic microsatellite loci for the Japanese dace (Tribolodon hakonensis) were isolated and characterized. The number of observed alleles per locus in 32 individuals ranged from 3 to 30. The observed and expected heterozygosities ranged from 0.125 to 0.969 and from 0.175 to 0.973, respectively. All loci conformed to Hardy–Weinberg equilibrium, no linkage disequilibrium was observed between pairs of loci and no loci showed evidence of null alleles. These microsatellite loci will be useful for investigating the intraspecific genetic variation and population structure of this species.

Cross-amplification and characterization of microsatellite loci for the Neotropical orchid genus Epidendrum

Directory of Open Access Journals (Sweden)

Fábio Pinheiro

2009-01-01

Full Text Available In this study we tested the cross-amplification of 33 microsatellite loci previously developed for two closely related Neotropical orchid genera (Epidendrum and Laelia. A set of ten loci were polymorphic across five examined species (20 individuals each with 2 to 15 alleles per locus. The mean expected and observed heterozygosity (average across species ranged from 0.34 to 0.82 and from 0.27 to 0.85, respectively. In addition we tested all loci in 35 species representative of the genus Epidendrum. Of these, 26 loci showed successful amplification. Cross-application of these loci represent a potential source of co-dominant markers for evolutionary, ecological and conservation studies in this important orchid genus.

Establishment of a vascular endothelial cell-reactive type II NKT cell clone from a rat model of autoimmune vasculitis.

Science.gov (United States)

Iinuma, Chihiro; Waki, Masashi; Kawakami, Ai; Yamaguchi, Madoka; Tomaru, Utano; Sasaki, Naomi; Masuda, Sakiko; Matsui, Yuki; Iwasaki, Sari; Baba, Tomohisa; Kasahara, Masanori; Yoshiki, Takashi; Paletta, Daniel; Herrmann, Thomas; Ishizu, Akihiro

2015-02-01

We previously generated a rat model that spontaneously developed small vessel vasculitis (SVV). In this study, a T cell clone reactive with rat vascular endothelial cells (REC) was established and named VASC-1. Intravenous injection of VASC-1 induced SVV in normal recipients. VASC-1 was a TCRαβ/CD3-positive CD4/CD8 double-negative T cell clone with expression of NKG2D. The cytokine mRNA profile under unstimulated condition was positive for IL-4 and IFN-γ but negative for IL-2 and IL-10. After interaction with REC, the mRNA expression of IL-2, IL-5 and IL-6 was induced in VASC-1, which was inhibited by blocking of CD1d on the REC surface. Although the protein levels of these cytokines seemed to be lower than the detection limit in the culture medium, IFN-γ was detectable. The production of IFN-γ from the VASC-1 stimulated with LPS-pre-treated REC was inhibited by the CD1d blockade on the REC. These findings indicated VASC-1 as an NKT cell clone. The NKT cell pool includes two major subsets, namely types I and II. Type I NKT cells are characterized by expression of semi-invariant TCRs and the potential to bind to marine sponge-derived α-galactosylceramide (α-GalCer) loaded on CD1d; whereas, type II NKT cells do not manifest these characteristics. VASC-1 exhibited a usage of TCR other than the type I invariant TCR α chain and did not bind to α-GalCer-loaded CD1d; therefore, it was determined as a type II NKT cell clone. The collective evidence suggested that REC-reactive type II NKT cells could be involved in the pathogenesis of SVV in rats. © The Japanese Society for Immunology. 2014. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Identification of novel type 1 diabetes candidate genes by integrating genome-wide association data, protein-protein interactions, and human pancreatic islet gene expression

DEFF Research Database (Denmark)

Bergholdt, Regine; Brorsson, Caroline; Palleja, Albert

2012-01-01

Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases. For type 1 diabetes, >40 susceptibility loci have been discovered. However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated with dis......-cells. Our results provide novel insight to the mechanisms behind type 1 diabetes pathogenesis and, thus, may provide the basis for the design of novel treatment strategies.......Genome-wide association studies (GWAS) have heralded a new era in susceptibility locus discovery in complex diseases. For type 1 diabetes, >40 susceptibility loci have been discovered. However, GWAS do not inevitably lead to identification of the gene or genes in a given locus associated...... with disease, and they do not typically inform the broader context in which the disease genes operate. Here, we integrated type 1 diabetes GWAS data with protein-protein interactions to construct biological networks of relevance for disease. A total of 17 networks were identified. To prioritize...

Isolation and characterization of microsatellite loci from the Australasian sea snake, Aipysurus laevis

DEFF Research Database (Denmark)

Lukoschek, Vimoksalehi; Waycott, Michelle; Dunshea, Glenn

2005-01-01

We developed 13 microsatellite loci for the olive sea snake, Aipysurus laevis, using both enriched and unenriched genomic DNA libraries. Eleven codominant loci, that reliably amplified, were used to screen 32 individuals across the geographic range of A. laevis. Four loci had four or more alleles...... (maximum 12), whereas the other seven had either two or three. All but one locus was in Hardy-Weinberg equilibrium. These loci will provide useful markers to investigate population genetic structure for the olive sea snake....

Isolation and characterization of eight novel microsatellite loci in the double-crested cormorant (Phalacrocorax auritus)

Science.gov (United States)

Mercer, Dacey; Haig, Susan; Mullins, Thomas

2010-01-01

We describe the isolation and characterization of eight microsatellite loci from the double-crested cormorant (Phalacrocorax auritus). Genetic variability was assessed using 60 individuals from three populations. All loci were variable with the number of alleles ranging from two to 17 per locus, and observed heterozygosity varying from 0.05 to 0.89. No loci showed signs of linkage disequilibrium and all loci conformed to Hardy–Weinberg equilibrium frequencies. Further, all loci amplified and were polymorphic in two related Phalacrocorax species. These loci should prove useful for population genetic studies of the double-crested cormorant and other pelecaniform species.

Characterization of ten microsatellite loci in the Broad-tailed hummingbird (Selasphorus platycercus)

Science.gov (United States)

Oyler-McCance, Sara J.; Fike, Jennifer A.; Talley-Farnham, Tiffany; Engelman, Tena; Engelman, Fred

2011-01-01

The Broad-tailed Hummingbird (Selaphorus platycercus) breeds at higher elevations in the central and southern Rockies, eastern California, and Mexico and has been studied for 8 years in Rocky Mountain National Park, Colorado. Questions regarding the relatedness of Broad-tailed Hummingbirds banded together and then recaptured in close time proximity in later years led us to isolate and develop primers for 10 polymorphic microsatellite loci. In a screen of 25 individuals from a population in Rocky Mountain National Park, the 10 loci were found to have levels of variability ranging from two to 16 alleles. No loci were found to depart from linkage disequilibrium, although two loci revealed significant departures from Hardy–Weinberg equilibrium. These 10 microsatellite loci will be applicable for population genetic analyses, investigation of mating systems and relatedness, and may help gain insight into the migration timing and routes for this species.

Characterization of ten microsatellite loci in midget faded rattlesnake (Crotalus oreganus concolor)

Science.gov (United States)

Oyler-McCance, Sara J.; Parker, Joshua M.

2010-01-01

Primers for 10 microsatellite loci were developed for midget faded rattlesnake (Crotalus oreganus concolor), a small bodied subspecies of the Western Rattlesnake, which is found in the Colorado Plateau of eastern Utah, western Colorado and southwestern Wyoming. In a screen of 23 individuals from the most northern portion of the subspecies range in southwestern Wyoming, the 10 loci were found to have levels of variability ranging from 4 to 11 alleles. No loci were found to be linked, although one locus revealed significant departures from Hardy–Weinberg equilibrium. These microsatellite loci will be applicable for population genetic analyses, which will ultimately aid in management efforts for this rare subspecies of rattlesnake.

Amiloride-sensitive channels in type I fungiform taste cells in mouse

Directory of Open Access Journals (Sweden)

Clapp Tod R

2008-01-01

Full Text Available Abstract Background Taste buds are the sensory organs of taste perception. Three types of taste cells have been described. Type I cells have voltage-gated outward currents, but lack voltage-gated inward currents. These cells have been presumed to play only a support role in the taste bud. Type II cells have voltage-gated Na+ and K+ current, and the receptors and transduction machinery for bitter, sweet, and umami taste stimuli. Type III cells have voltage-gated Na+, K+, and Ca2+ currents, and make prominent synapses with afferent nerve fibers. Na+ salt transduction in part involves amiloride-sensitive epithelial sodium channels (ENaCs. In rodents, these channels are located in taste cells of fungiform papillae on the anterior part of the tongue innervated by the chorda tympani nerve. However, the taste cell type that expresses ENaCs is not known. This study used whole cell recordings of single fungiform taste cells of transgenic mice expressing GFP in Type II taste cells to identify the taste cells responding to amiloride. We also used immunocytochemistry to further define and compare cell types in fungiform and circumvallate taste buds of these mice. Results Taste cell types were identified by their response to depolarizing voltage steps and their presence or absence of GFP fluorescence. TRPM5-GFP taste cells expressed large voltage-gated Na+ and K+ currents, but lacked voltage-gated Ca2+ currents, as expected from previous studies. Approximately half of the unlabeled cells had similar membrane properties, suggesting they comprise a separate population of Type II cells. The other half expressed voltage-gated outward currents only, typical of Type I cells. A single taste cell had voltage-gated Ca2+ current characteristic of Type III cells. Responses to amiloride occurred only in cells that lacked voltage-gated inward currents. Immunocytochemistry showed that fungiform taste buds have significantly fewer Type II cells expressing PLC signalling

Direct determination of phosphatase activity from physiological substrates in cells.

Directory of Open Access Journals (Sweden)

Zhongyuan Ren

Full Text Available A direct and continuous approach to determine simultaneously protein and phosphate concentrations in cells and kinetics of phosphate release from physiological substrates by cells without any labeling has been developed. Among the enzymes having a phosphatase activity, tissue non-specific alkaline phosphatase (TNAP performs indispensable, multiple functions in humans. It is expressed in numerous tissues with high levels detected in bones, liver and neurons. It is absolutely required for bone mineralization and also necessary for neurotransmitter synthesis. We provided the proof of concept that infrared spectroscopy is a reliable assay to determine a phosphatase activity in the osteoblasts. For the first time, an overall specific phosphatase activity in cells was determined in a single step by measuring simultaneously protein and substrate concentrations. We found specific activities in osteoblast like cells amounting to 116 ± 13 nmol min(-1 mg(-1 for PPi, to 56 ± 11 nmol min(-1 mg(-1 for AMP, to 79 ± 23 nmol min(-1 mg(-1 for beta-glycerophosphate and to 73 ± 15 nmol min(-1 mg(-1 for 1-alpha-D glucose phosphate. The assay was also effective to monitor phosphatase activity in primary osteoblasts and in matrix vesicles. The use of levamisole--a TNAP inhibitor--served to demonstrate that a part of the phosphatase activity originated from this enzyme. An IC50 value of 1.16 ± 0.03 mM was obtained for the inhibition of phosphatase activity of levamisole in osteoblast like cells. The infrared assay could be extended to determine any type of phosphatase activity in other cells. It may serve as a metabolomic tool to monitor an overall phosphatase activity including acid phosphatases or other related enzymes.

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

NARCIS (Netherlands)

Scott, Robert A.; Lagou, Vasiliki; Welch, Ryan P.; Wheeler, Eleanor; Montasser, May E.; Luan, Jian'an; Mägi, Reedik; Strawbridge, Rona J.; Rehnberg, Emil; Gustafsson, Stefan; Kanoni, Stavroula; Rasmussen-Torvik, Laura J.; Yengo, Loïc; Lecoeur, Cecile; Shungin, Dmitry; Sanna, Serena; Sidore, Carlo; Johnson, Paul C. D.; Jukema, J. Wouter; Johnson, Toby; Mahajan, Anubha; Verweij, Niek; Thorleifsson, Gudmar; Hottenga, Jouke-Jan; Shah, Sonia; Smith, Albert V.; Sennblad, Bengt; Gieger, Christian; Salo, Perttu; Perola, Markus; Timpson, Nicholas J.; Evans, David M.; Pourcain, Beate St; Wu, Ying; Andrews, Jeanette S.; Hui, Jennie; Bielak, Lawrence F.; Zhao, Wei; Horikoshi, Momoko; Navarro, Pau; Isaacs, Aaron; O'Connell, Jeffrey R.; Stirrups, Kathleen; Vitart, Veronique; Hayward, Caroline; Esko, Tõnu; Mihailov, Evelin; Fraser, Ross M.; Fall, Tove; Voight, Benjamin F.; Raychaudhuri, Soumya; Chen, Han; Lindgren, Cecilia M.; Morris, Andrew P.; Rayner, Nigel W.; Robertson, Neil; Rybin, Denis; Liu, Ching-Ti; Beckmann, Jacques S.; Willems, Sara M.; Chines, Peter S.; Jackson, Anne U.; Kang, Hyun Min; Stringham, Heather M.; Song, Kijoung; Tanaka, Toshiko; Peden, John F.; Goel, Anuj; Hicks, Andrew A.; An, Ping; Müller-Nurasyid, Martina; Franco-Cereceda, Anders; Folkersen, Lasse; Marullo, Letizia; Jansen, Hanneke; Oldehinkel, Albertine J.; Bruinenberg, Marcel; Pankow, James S.; North, Kari E.; Forouhi, Nita G.; Loos, Ruth J. F.; Edkins, Sarah; Varga, Tibor V.; Hallmans, Göran; Oksa, Heikki; Antonella, Mulas; Nagaraja, Ramaiah; Trompet, Stella; Ford, Ian; Bakker, Stephan J. L.; Kong, Augustine; Kumari, Meena; Gigante, Bruna; Herder, Christian; Munroe, Patricia B.; Caulfield, Mark; Antti, Jula; Mangino, Massimo; Small, Kerrin; Miljkovic, Iva; Liu, Yongmei; Atalay, Mustafa; Kiess, Wieland; James, Alan L.; Rivadeneira, Fernando; Uitterlinden, Andre G.; Palmer, Colin N. A.; Doney, Alex S. F.; Willemsen, Gonneke; Smit, Johannes H.; Campbell, Susan; Polasek, Ozren; Bonnycastle, Lori L.; Hercberg, Serge; Dimitriou, Maria; Bolton, Jennifer L.; Fowkes, Gerard R.; Kovacs, Peter; Lindström, Jaana; Zemunik, Tatijana; Bandinelli, Stefania; Wild, Sarah H.; Basart, Hanneke V.; Rathmann, Wolfgang; Grallert, Harald; Maerz, Winfried; Kleber, Marcus E.; Boehm, Bernhard O.; Peters, Annette; Pramstaller, Peter P.; Province, Michael A.; Borecki, Ingrid B.; Hastie, Nicholas D.; Rudan, Igor; Campbell, Harry; Watkins, Hugh; Farrall, Martin; Stumvoll, Michael; Ferrucci, Luigi; Waterworth, Dawn M.; Bergman, Richard N.; Collins, Francis S.; Tuomilehto, Jaakko; Watanabe, Richard M.; de Geus, Eco J. C.; Penninx, Brenda W.; Hofman, Albert; Oostra, Ben A.; Psaty, Bruce M.; Vollenweider, Peter; Wilson, James F.; Wright, Alan F.; Hovingh, G. Kees; Metspalu, Andres; Uusitupa, Matti; Magnusson, Patrik K. E.; Kyvik, Kirsten O.; Kaprio, Jaakko; Price, Jackie F.; Dedoussis, George V.; Deloukas, Panos; Meneton, Pierre; Lind, Lars; Boehnke, Michael; Shuldiner, Alan R.; van Duijn, Cornelia M.; Morris, Andrew D.; Toenjes, Anke; Peyser, Patricia A.; Beilby, John P.; Körner, Antje; Kuusisto, Johanna; Laakso, Markku; Bornstein, Stefan R.; Schwarz, Peter E. H.; Lakka, Timo A.; Rauramaa, Rainer; Adair, Linda S.; Smith, George Davey; Spector, Tim D.; Illig, Thomas; de Faire, Ulf; Hamsten, Anders; Gudnason, Vilmundur; Kivimaki, Mika; Hingorani, Aroon; Keinanen-Kiukaanniemi, Sirkka M.; Saaristo, Timo E.; Boomsma, Dorret I.; Stefansson, Kari; van der Harst, Pim; Dupuis, Josée; Pedersen, Nancy L.; Sattar, Naveed; Harris, Tamara B.; Cucca, Francesco; Ripatti, Samuli; Salomaa, Veikko; Mohlke, Karen L.; Balkau, Beverley; Froguel, Philippe; Pouta, Anneli; Jarvelin, Marjo-Riitta; Wareham, Nicholas J.; Bouatia-Naji, Nabila; McCarthy, Mark I.; Franks, Paul W.; Meigs, James B.; Teslovich, Tanya M.; Florez, Jose C.; Langenberg, Claudia; Ingelsson, Erik; Prokopenko, Inga; Barroso, Inês

2012-01-01

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes

Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways

DEFF Research Database (Denmark)

Scott, Robert A; Lagou, Vasiliki; Welch, Ryan P

2012-01-01

Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes...

Genome-Wide Association Study of the Genetic Determinants of Emphysema Distribution.

Science.gov (United States)

Boueiz, Adel; Lutz, Sharon M; Cho, Michael H; Hersh, Craig P; Bowler, Russell P; Washko, George R; Halper-Stromberg, Eitan; Bakke, Per; Gulsvik, Amund; Laird, Nan M; Beaty, Terri H; Coxson, Harvey O; Crapo, James D; Silverman, Edwin K; Castaldi, Peter J; DeMeo, Dawn L

2017-03-15

Emphysema has considerable variability in the severity and distribution of parenchymal destruction throughout the lungs. Upper lobe-predominant emphysema has emerged as an important predictor of response to lung volume reduction surgery. Yet, aside from alpha-1 antitrypsin deficiency, the genetic determinants of emphysema distribution remain largely unknown. To identify the genetic influences of emphysema distribution in non-alpha-1 antitrypsin-deficient smokers. A total of 11,532 subjects with complete genotype and computed tomography densitometry data in the COPDGene (Genetic Epidemiology of Chronic Obstructive Pulmonary Disease [COPD]; non-Hispanic white and African American), ECLIPSE (Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints), and GenKOLS (Genetics of Chronic Obstructive Lung Disease) studies were analyzed. Two computed tomography scan emphysema distribution measures (difference between upper-third and lower-third emphysema; ratio of upper-third to lower-third emphysema) were tested for genetic associations in all study subjects. Separate analyses in each study population were followed by a fixed effect metaanalysis. Single-nucleotide polymorphism-, gene-, and pathway-based approaches were used. In silico functional evaluation was also performed. We identified five loci associated with emphysema distribution at genome-wide significance. These loci included two previously reported associations with COPD susceptibility (4q31 near HHIP and 15q25 near CHRNA5) and three new associations near SOWAHB, TRAPPC9, and KIAA1462. Gene set analysis and in silico functional evaluation revealed pathways and cell types that may potentially contribute to the pathogenesis of emphysema distribution. This multicohort genome-wide association study identified new genomic loci associated with differential emphysematous destruction throughout the lungs. These findings may point to new biologic pathways on which to expand diagnostic and therapeutic

Clinical significance of determination of changes of serum contents of TGF-β1, IL-8 and T cell subsets distribution type in patients with nasopharangeal carcinoma

International Nuclear Information System (INIS)

Ren Liang; Gu Tao

2006-01-01

Objective: To explore the significance of changes of serum transform growth factor β 1 (TGF-β 1 ) and IL-8 as well as T cell subsets distribution type in patients with nasopharangeal carcinoma. Methods: Serum TGF-β 1 (with ELISA), IL-8 ( with RIA) levels and T cell subsets distribution type (with monoclonal antibody technique) were determined in 31 patients with nasopharan-geal carcinoma as well as in 35 controls. Results: The serum levels of TGF-β 1 , IL-8 and CD8 percentage were significantly higher in the patients than those in controls (P 1 levels were positively correlated with CD8 percentage and negatively correlated with CD4 percentage and CD4/CD8 ratio, Conclusion: The altered levels of TGF-β 1 and IL-8 as well as the decrease of CD4/CD8 were correlated with the clinical development and prognosis in patients with nasopharangeal carcinoma. (authors)

Six quantitative trait loci influence task thresholds for hygienic behaviour in honeybees (Apis mellifera).

Science.gov (United States)

Oxley, Peter R; Spivak, Marla; Oldroyd, Benjamin P

2010-04-01

Honeybee hygienic behaviour provides colonies with protection from many pathogens and is an important model system of the genetics of a complex behaviour. It is a textbook example of complex behaviour under simple genetic control: hygienic behaviour consists of two components--uncapping a diseased brood cell, followed by removal of the contents--each of which are thought to be modulated independently by a few loci of medium to large effect. A worker's genetic propensity to engage in hygienic tasks affects the intensity of the stimulus required before she initiates the behaviour. Genetic diversity within colonies leads to task specialization among workers, with a minority of workers performing the majority of nest-cleaning tasks. We identify three quantitative trait loci that influence the likelihood that workers will engage in hygienic behaviour and account for up to 30% of the phenotypic variability in hygienic behaviour in our population. Furthermore, we identify two loci that influence the likelihood that a worker will perform uncapping behaviour only, and one locus that influences removal behaviour. We report the first candidate genes associated with engaging in hygienic behaviour, including four genes involved in olfaction, learning and social behaviour, and one gene involved in circadian locomotion. These candidates will allow molecular characterization of this distinctive behavioural mode of disease resistance, as well as providing the opportunity for marker-assisted selection for this commercially significant trait.

CD4+ T-Cell Reactivity to Orexin/Hypocretin in Patients With Narcolepsy Type 1.

Science.gov (United States)

Ramberger, Melanie; Högl, Birgit; Stefani, Ambra; Mitterling, Thomas; Reindl, Markus; Lutterotti, Andreas

2017-03-01

Narcolepsy type 1 is accompanied by a selective loss of orexin/hypocretin (hcrt) neurons in the lateral hypothalamus caused by yet unknown mechanisms. Epidemiologic and genetic associations strongly suggest an immune-mediated pathogenesis of the disease. We compared specific T-cell reactivity to orexin/hcrt peptides in peripheral blood mononuclear cells of narcolepsy type 1 patients to healthy controls by a carboxyfluorescein succinimidyl ester proliferation assay. Orexin/hcrt-specific T-cell reactivity was also determined by cytokine (interferon gamma and granulocyte-macrophage colony-stimulating factor) analysis. Individuals were considered as responders if the cell division index of CD3+CD4+ T cells and both stimulation indices of cytokine secretion exceeded the cutoff 3. Additionally, T-cell reactivity to orexin/hcrt had to be confirmed by showing reactivity to single peptides present in different peptide pools. Using these criteria, 3/15 patients (20%) and 0/13 controls (0%) showed orexin/hcrt-specific CD4+ T-cell proliferation (p = .2262). The heterogeneous reactivity pattern did not allow the identification of a preferential target epitope. A significant role of orexin/hcrt-specific T cells in narcolepsy type 1 patients could not be confirmed in this study. Further studies are needed to assess the exact role of CD4+ T cells and possible target antigens in narcolepsy type 1 patients. © Sleep Research Society 2016. Published by Oxford University Press [on behalf of the Sleep Research Society].

Somatic hypermutation of T cell receptor α chain contributes to selection in nurse shark thymus.

Science.gov (United States)

Ott, Jeannine A; Castro, Caitlin D; Deiss, Thaddeus C; Ohta, Yuko; Flajnik, Martin F; Criscitiello, Michael F

2018-04-17

Since the discovery of the T cell receptor (TcR), immunologists have assigned somatic hypermutation (SHM) as a mechanism employed solely by B cells to diversify their antigen receptors. Remarkably, we found SHM acting in the thymus on α chain locus of shark TcR. SHM in developing shark T cells likely is catalyzed by activation-induced cytidine deaminase (AID) and results in both point and tandem mutations that accumulate non-conservative amino acid replacements within complementarity-determining regions (CDRs). Mutation frequency at TcRα was as high as that seen at B cell receptor loci (BcR) in sharks and mammals, and the mechanism of SHM shares unique characteristics first detected at shark BcR loci. Additionally, fluorescence in situ hybridization showed the strongest AID expression in thymic corticomedullary junction and medulla. We suggest that TcRα utilizes SHM to broaden diversification of the primary αβ T cell repertoire in sharks, the first reported use in vertebrates. © 2018, Ott et al.

Crosstalk between type II NKT cells and T cells leads to spontaneous chronic inflammatory liver disease.

Science.gov (United States)

Weng, Xiufang; He, Ying; Visvabharathy, Lavanya; Liao, Chia-Min; Tan, Xiaosheng; Balakumar, Arjun; Wang, Chyung-Ru

2017-10-01

Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jα18 wild-type (Lck-CD1dTgJα18 + ; type I NKT cell sufficient) and Jα18-deficient (Lck-CD1dTgJα18 o , type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. Lck-CD1dTgJα18 o and Lck-CD1dTgJα18 + mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in T h 1-skewing and impaired T h 2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a T h 1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the

Genome-wide association analysis of more than 120,000 individuals identifies 15 new susceptibility loci for breast cancer.

Science.gov (United States)

Michailidou, Kyriaki; Beesley, Jonathan; Lindstrom, Sara; Canisius, Sander; Dennis, Joe; Lush, Michael J; Maranian, Mel J; Bolla, Manjeet K; Wang, Qin; Shah, Mitul; Perkins, Barbara J; Czene, Kamila; Eriksson, Mikael; Darabi, Hatef; Brand, Judith S; Bojesen, Stig E; Nordestgaard, Børge G; Flyger, Henrik; Nielsen, Sune F; Rahman, Nazneen; Turnbull, Clare; Fletcher, Olivia; Peto, Julian; Gibson, Lorna; dos-Santos-Silva, Isabel; Chang-Claude, Jenny; Flesch-Janys, Dieter; Rudolph, Anja; Eilber, Ursula; Behrens, Sabine; Nevanlinna, Heli; Muranen, Taru A; Aittomäki, Kristiina; Blomqvist, Carl; Khan, Sofia; Aaltonen, Kirsimari; Ahsan, Habibul; Kibriya, Muhammad G; Whittemore, Alice S; John, Esther M; Malone, Kathleen E; Gammon, Marilie D; Santella, Regina M; Ursin, Giske; Makalic, Enes; Schmidt, Daniel F; Casey, Graham; Hunter, David J; Gapstur, Susan M; Gaudet, Mia M; Diver, W Ryan; Haiman, Christopher A; Schumacher, Fredrick; Henderson, Brian E; Le Marchand, Loic; Berg, Christine D; Chanock, Stephen J; Figueroa, Jonine; Hoover, Robert N; Lambrechts, Diether; Neven, Patrick; Wildiers, Hans; van Limbergen, Erik; Schmidt, Marjanka K; Broeks, Annegien; Verhoef, Senno; Cornelissen, Sten; Couch, Fergus J; Olson, Janet E; Hallberg, Emily; Vachon, Celine; Waisfisz, Quinten; Meijers-Heijboer, Hanne; Adank, Muriel A; van der Luijt, Rob B; Li, Jingmei; Liu, Jianjun; Humphreys, Keith; Kang, Daehee; Choi, Ji-Yeob; Park, Sue K; Yoo, Keun-Young; Matsuo, Keitaro; Ito, Hidemi; Iwata, Hiroji; Tajima, Kazuo; Guénel, Pascal; Truong, Thérèse; Mulot, Claire; Sanchez, Marie; Burwinkel, Barbara; Marme, Frederik; Surowy, Harald; Sohn, Christof; Wu, Anna H; Tseng, Chiu-chen; Van Den Berg, David; Stram, Daniel O; González-Neira, Anna; Benitez, Javier; Zamora, M Pilar; Perez, Jose Ignacio Arias; Shu, Xiao-Ou; Lu, Wei; Gao, Yu-Tang; Cai, Hui; Cox, Angela; Cross, Simon S; Reed, Malcolm W R; Andrulis, Irene L; Knight, Julia A; Glendon, Gord; Mulligan, Anna Marie; Sawyer, Elinor J; Tomlinson, Ian; Kerin, Michael J; Miller, Nicola; Lindblom, Annika; Margolin, Sara; Teo, Soo Hwang; Yip, Cheng Har; Taib, Nur Aishah Mohd; Tan, Gie-Hooi; Hooning, Maartje J; Hollestelle, Antoinette; Martens, John W M; Collée, J Margriet; Blot, William; Signorello, Lisa B; Cai, Qiuyin; Hopper, John L; Southey, Melissa C; Tsimiklis, Helen; Apicella, Carmel; Shen, Chen-Yang; Hsiung, Chia-Ni; Wu, Pei-Ei; Hou, Ming-Feng; Kristensen, Vessela N; Nord, Silje; Alnaes, Grethe I Grenaker; Giles, Graham G; Milne, Roger L; McLean, Catriona; Canzian, Federico; Trichopoulos, Dimitrios; Peeters, Petra; Lund, Eiliv; Sund, Malin; Khaw, Kay-Tee; Gunter, Marc J; Palli, Domenico; Mortensen, Lotte Maxild; Dossus, Laure; Huerta, Jose-Maria; Meindl, Alfons; Schmutzler, Rita K; Sutter, Christian; Yang, Rongxi; Muir, Kenneth; Lophatananon, Artitaya; Stewart-Brown, Sarah; Siriwanarangsan, Pornthep; Hartman, Mikael; Miao, Hui; Chia, Kee Seng; Chan, Ching Wan; Fasching, Peter A; Hein, Alexander; Beckmann, Matthias W; Haeberle, Lothar; Brenner, Hermann; Dieffenbach, Aida Karina; Arndt, Volker; Stegmaier, Christa; Ashworth, Alan; Orr, Nick; Schoemaker, Minouk J; Swerdlow, Anthony J; Brinton, Louise; Garcia-Closas, Montserrat; Zheng, Wei; Halverson, Sandra L; Shrubsole, Martha; Long, Jirong; Goldberg, Mark S; Labrèche, France; Dumont, Martine; Winqvist, Robert; Pylkäs, Katri; Jukkola-Vuorinen, Arja; Grip, Mervi; Brauch, Hiltrud; Hamann, Ute; Brüning, Thomas; Radice, Paolo; Peterlongo, Paolo; Manoukian, Siranoush; Bernard, Loris; Bogdanova, Natalia V; Dörk, Thilo; Mannermaa, Arto; Kataja, Vesa; Kosma, Veli-Matti; Hartikainen, Jaana M; Devilee, Peter; Tollenaar, Robert A E M; Seynaeve, Caroline; Van Asperen, Christi J; Jakubowska, Anna; Lubinski, Jan; Jaworska, Katarzyna; Huzarski, Tomasz; Sangrajrang, Suleeporn; Gaborieau, Valerie; Brennan, Paul; McKay, James; Slager, Susan; Toland, Amanda E; Ambrosone, Christine B; Yannoukakos, Drakoulis; Kabisch, Maria; Torres, Diana; Neuhausen, Susan L; Anton-Culver, Hoda; Luccarini, Craig; Baynes, Caroline; Ahmed, Shahana; Healey, Catherine S; Tessier, Daniel C; Vincent, Daniel; Bacot, Francois; Pita, Guillermo; Alonso, M Rosario; Álvarez, Nuria; Herrero, Daniel; Simard, Jacques; Pharoah, Paul P D P; Kraft, Peter; Dunning, Alison M; Chenevix-Trench, Georgia; Hall, Per; Easton, Douglas F

2015-04-01

Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P association analysis with ChIP-seq chromatin binding data in mammary cell lines and ChIA-PET chromatin interaction data from ENCODE, we identified likely target genes in two regions: SETBP1 at 18q12.3 and RNF115 and PDZK1 at 1q21.1. One association appears to be driven by an amino acid substitution encoded in EXO1.

Reassessment of MLST schemes for Leptospira spp. typing worldwide.

Science.gov (United States)

Varni, Vanina; Ruybal, Paula; Lauthier, Juan José; Tomasini, Nicolás; Brihuega, Bibiana; Koval, Ariel; Caimi, Karina

2014-03-01

Leptospirosis is a neglected zoonosis of global importance. Several multilocus sequence typing (MLST) methods have been developed for Leptospira spp., the causative agent of leptospirosis. In this study we reassessed the most commonly used MLST schemes in a set of worldwide isolates, in order to select the loci that achieve the maximum power of discrimination for typing Leptospira spp. Global eBURST algorithm was used to detect clonal complexes among STs and phylogenetic relationships among concatenated and individual sequences were inferred through maximum likelihood (ML) analysis. The evaluation of 12 loci combined to type a subset of strains rendered 57 different STs. Seven of these loci were selected into a final scheme upon studying the number of alleles and polymorphisms, the typing efficiency, the discriminatory power and the ratio dN/dS per nucleotide site for each locus. This new 7-locus scheme was applied to a wider collection of worldwide strains. The ML tree constructed from concatenated sequences of the 7 loci identified 6 major clusters corresponding to 6 Leptospira species. Global eBURST established 8 CCs, which showed that genotypes were clearly related by geographic origin and host. ST52 and ST47, represented mostly by Argentinian isolates, grouped the higher number of isolates. These isolates were serotyped as serogroups Pomona and Icterohaemorrhagiae, showing a unidirectional correlation in which the isolates with the same ST belong to the same serogroup. In summary, this scheme combines the best loci from the most widely used MLST schemes for Leptospira spp. and supports worldwide strains classification. The Argentinian isolates exhibited congruence between allelic profile and serogroup, providing an alternative to serological methods. Published by Elsevier B.V.

Beta cell 5'-shifted isomiRs are candidate regulatory hubs in type 2 diabetes.

Directory of Open Access Journals (Sweden)

Jeanette Baran-Gale

Full Text Available Next-generation deep sequencing of small RNAs has unveiled the complexity of the microRNA (miRNA transcriptome, which is in large part due to the diversity of miRNA sequence variants ("isomiRs". Changes to a miRNA's seed sequence (nucleotides 2-8, including shifted start positions, can redirect targeting to a dramatically different set of RNAs and alter biological function. We performed deep sequencing of small RNA from mouse insulinoma (MIN6 cells (widely used as a surrogate for the study of pancreatic beta cells and developed a bioinformatic analysis pipeline to profile isomiR diversity. Additionally, we applied the pipeline to recently published small RNA-seq data from primary human beta cells and whole islets and compared the miRNA profiles with that of MIN6. We found that: (1 the miRNA expression profile in MIN6 cells is highly correlated with those of primary human beta cells and whole islets; (2 miRNA loci can generate multiple highly expressed isomiRs with different 5'-start positions (5'-isomiRs; (3 isomiRs with shifted start positions (5'-shifted isomiRs are highly expressed, and can be as abundant as their unshifted counterparts (5'-reference miRNAs. Finally, we identified 10 beta cell miRNA families as candidate regulatory hubs in a type 2 diabetes (T2D gene network. The most significant candidate hub was miR-29, which we demonstrated regulates the mRNA levels of several genes critical to beta cell function and implicated in T2D. Three of the candidate miRNA hubs were novel 5'-shifted isomiRs: miR-375+1, miR-375-1 and miR-183-5p+1. We showed by in silico target prediction and in vitro transfection studies that both miR-375+1 and miR-375-1 are likely to target an overlapping, but distinct suite of beta cell genes compared to canonical miR-375. In summary, this study characterizes the isomiR profile in beta cells for the first time, and also highlights the potential functional relevance of 5'-shifted isomiRs to T2D.

Chromosomal mapping of quantitative trait loci controlling elastin content in rat aorta.

Science.gov (United States)

Gauguier, Dominique; Behmoaras, Jacques; Argoud, Karène; Wilder, Steven P; Pradines, Christelle; Bihoreau, Marie Thérèse; Osborne-Pellegrin, Mary; Jacob, Marie Paule

2005-03-01

Extracellular matrix molecules such as elastin and collagens provide mechanical support to the vessel wall. In addition to its structural role, elastin is a regulator that maintains homeostasis through biologic signaling. Genetically determined minor modifications in elastin and collagen in the aorta could influence the onset and evolution of arterial pathology, such as hypertension and its complications. We previously demonstrated that the inbred Brown Norway (BN) rat shows an aortic elastin deficit in both abdominal and thoracic segments, partly because of a decrease in tropoelastin synthesis when compared with the LOU rat, that elastin gene polymorphisms in these strains do not significantly account for. After a genome-wide search for quantitative trait loci (QTL) influencing the aortic elastin, collagen, and cell protein contents in an F2 population derived from BN and LOU rats, we identified on chromosomes 2 and 14, 3 QTL specifically controlling elastin levels, and a further highly significant QTL on chromosome 17 linked to the level of cell proteins. We also mapped 3 highly significant QTL linked to body weight (on chromosomes 1 and 3) and heart weight (on chromosome 1) in the cross. This study demonstrates the polygenic control of the content of key components of the arterial wall. Such information represents a first step in understanding possible mechanisms involved in dysregulation of these parameters in arterial pathology.

Types and distribution of mucous cells of the abalone Haliotis ...

African Journals Online (AJOL)

user

2012-05-08

May 8, 2012 ... Key words: Haliotis diversicolor; mucous cells, types, distribution. .... Figure 2. The shape of the mucous cells. O (oval or circle-like); c (cup- like); s ... (J) mucous cells at base of gill filaments, small cells, type II and type III; (K) a ...

Meta-analysis of 375,000 individuals identifies 38 susceptibility loci for migraine.

Science.gov (United States)

Gormley, Padhraig; Anttila, Verneri; Winsvold, Bendik S; Palta, Priit; Esko, Tonu; Pers, Tune H; Farh, Kai-How; Cuenca-Leon, Ester; Muona, Mikko; Furlotte, Nicholas A; Kurth, Tobias; Ingason, Andres; McMahon, George; Ligthart, Lannie; Terwindt, Gisela M; Kallela, Mikko; Freilinger, Tobias M; Ran, Caroline; Gordon, Scott G; Stam, Anine H; Steinberg, Stacy; Borck, Guntram; Koiranen, Markku; Quaye, Lydia; Adams, Hieab H H; Lehtimäki, Terho; Sarin, Antti-Pekka; Wedenoja, Juho; Hinds, David A; Buring, Julie E; Schürks, Markus; Ridker, Paul M; Hrafnsdottir, Maria Gudlaug; Stefansson, Hreinn; Ring, Susan M; Hottenga, Jouke-Jan; Penninx, Brenda W J H; Färkkilä, Markus; Artto, Ville; Kaunisto, Mari; Vepsäläinen, Salli; Malik, Rainer; Heath, Andrew C; Madden, Pamela A F; Martin, Nicholas G; Montgomery, Grant W; Kurki, Mitja I; Kals, Mart; Mägi, Reedik; Pärn, Kalle; Hämäläinen, Eija; Huang, Hailiang; Byrnes, Andrea E; Franke, Lude; Huang, Jie; Stergiakouli, Evie; Lee, Phil H; Sandor, Cynthia; Webber, Caleb; Cader, Zameel; Muller-Myhsok, Bertram; Schreiber, Stefan; Meitinger, Thomas; Eriksson, Johan G; Salomaa, Veikko; Heikkilä, Kauko; Loehrer, Elizabeth; Uitterlinden, Andre G; Hofman, Albert; van Duijn, Cornelia M; Cherkas, Lynn; Pedersen, Linda M; Stubhaug, Audun; Nielsen, Christopher S; Männikkö, Minna; Mihailov, Evelin; Milani, Lili; Göbel, Hartmut; Esserlind, Ann-Louise; Christensen, Anne Francke; Hansen, Thomas Folkmann; Werge, Thomas; Kaprio, Jaakko; Aromaa, Arpo J; Raitakari, Olli; Ikram, M Arfan; Spector, Tim; Järvelin, Marjo-Riitta; Metspalu, Andres; Kubisch, Christian; Strachan, David P; Ferrari, Michel D; Belin, Andrea C; Dichgans, Martin; Wessman, Maija; van den Maagdenberg, Arn M J M; Zwart, John-Anker; Boomsma, Dorret I; Smith, George Davey; Stefansson, Kari; Eriksson, Nicholas; Daly, Mark J; Neale, Benjamin M; Olesen, Jes; Chasman, Daniel I; Nyholt, Dale R; Palotie, Aarno

2016-08-01

Migraine is a debilitating neurological disorder affecting around one in seven people worldwide, but its molecular mechanisms remain poorly understood. There is some debate about whether migraine is a disease of vascular dysfunction or a result of neuronal dysfunction with secondary vascular changes. Genome-wide association (GWA) studies have thus far identified 13 independent loci associated with migraine. To identify new susceptibility loci, we carried out a genetic study of migraine on 59,674 affected subjects and 316,078 controls from 22 GWA studies. We identified 44 independent single-nucleotide polymorphisms (SNPs) significantly associated with migraine risk (P < 5 × 10(-8)) that mapped to 38 distinct genomic loci, including 28 loci not previously reported and a locus that to our knowledge is the first to be identified on chromosome X. In subsequent computational analyses, the identified loci showed enrichment for genes expressed in vascular and smooth muscle tissues, consistent with a predominant theory of migraine that highlights vascular etiologies.

The role of dendritic cell subsets and innate immunity in the pathogenesis of type 1 diabetes and other autoimmune diseases

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Jeffrey D. Price

2015-06-01

Full Text Available Dendritic cells (DCs are key antigen presenting cells that have an important role in autoimmune pathogenesis. DCs control both steady-state T cell tolerance and activation of pathogenic responses. The balance between these two outcomes depends on several factors, including genetic susceptibility, environmental signals that stimulate varied innate responses, and which DC subset is presenting antigen. Although the specific DC phenotype can diverge depending on the tissue location and context, there are 4 main subsets identified in both mouse and human: conventional cDC1 and cDC2, plasmacytoid DCs, and monocyte-derived DCs. In this review, we will discuss the role of these subsets in autoimmune pathogenesis and regulation, as well as the genetic and environmental signals that influence their function. Specific topics to be addressed include: impact of susceptibility loci on DC subsets, alterations in DC subset development, the role of infection- and host-derived innate inflammatory signals, and the role of the intestinal microbiota on DC phenotype. The effects of these various signals on disease progression and the relative effects of DC subset composition and maturation level of DCs will be examined. These areas will be explored using examples from several autoimmune diseases but will focus mainly on type 1 diabetes.

Genetic sub-structure in western Mediterranean populations revealed by 12 Y-chromosome STR loci

DEFF Research Database (Denmark)

Rodríguez, V; Tomas Mas, Carmen; Sánchez, J J

2008-01-01

Haplotype and allele frequencies of 12 Y-chromosome short tandem repeat (Y-STR) loci (DYS19, DYS389I, DYS389II, DYS390, DYS391, DYS392, DYS393, DYS385 a/b, DYS437, DYS438 and DYS439) included in the Powerplex(R) Y System were determined in seven western Mediterranean populations from Valencia, Ma...

Type two innate lymphoid cells; the Janus cells in health and disease

Science.gov (United States)

Maazi, Hadi; Akbari, Omid

2017-01-01

Summary Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2 and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by costimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. PMID:28658553

Type two innate lymphoid cells: the Janus cells in health and disease.

Science.gov (United States)

Maazi, Hadi; Akbari, Omid

2017-07-01

Innate lymphoid cells are functionally diverse subsets of immune cells including the conventional natural killer cells, lymphoid tissue inducers, type 1, 2, and 3 with significant roles in immunity and pathogenesis of inflammatory diseases. Type 2 innate lymphoid cells (ILC2s) resemble type 2 helper (Th2) cells in cytokine production and contribute to anti-helminth immunity, maintaining mucosal tissue integrity, and adipose tissue browning. ILC2s play important roles in the pathogenesis of allergic diseases and asthma. Studying the pathways of activation and regulation of ILC2s are currently a priority for giving a better understanding of pathogenesis of diseases with immunological roots. Recently, our laboratory and others have shown several pathways of regulation of ILC2s by co-stimulatory molecules such as ICOS, regulatory T cells and by compounds such as nicotine. In this review, we summarize the current understanding of the mechanisms of activation and regulation of ILC2s and the role of these cells in health and disease. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Retrospective genetic study of germinative mutations in Str loci of individuals potentially exposed to ionizing radiation

International Nuclear Information System (INIS)

Costa, Emilia Oliveira Alves

2010-01-01

The Brazilian radiological accident that occurred in 1987, in Goiania, it was a terrible radiation episode. As a consequence, hundreds of people were contaminated due to the Cesium-137 radiation. Recently, many studies had shown that genome instabilities, such as, mutations, chromosomal aberrations, micronuclei formation and micro satellite instability and a delay on cellular death are usually reported on mammal cells exposed to ionizing radiation, being considered as a manly risk to humans. Mutations can be spontaneous, and the occurrence is dependent on the organism, or, induced, being associated to mutagenic exposition. Ionizing radiations are an example of physical and mutagenic agents that could harm the cell repair and could cause the development of many types of cancer. The evaluation of the biological effects of the ionizing radiation, in somatic and germ line cells, with a consequent determination of the radio-induced mutations, it is extremely important to estimate the genetic risks, manly in population exposed to radiation. The analyses of repetitive DNA sequences have been demonstrated that such sequences are prone to high rates of spontaneous mutations. The minisatellites and microsatellites have been used to demonstrate the induction of germ line mutation rates on mouse, humans, among others organisms. The aim of the present study was to analyze the frequency of microsatellite alterations to determine the mutation rates occurred in germ cells of the parents exposed to the ionizing radiation of the Cesium-137. The studied group was constitute of 10 families of individuals accidentally exposed to Cesium-137 and by the control group constituted by 645 healthy individuals who carried out paternity tests on 2009. We found only one mutation of paternal origin in the D8S1179 locus on the exposed group, being the mutation rate of 0.002. In the control group, we found 01 mutation on D16S539 loei and on D3S1358; 02 mutations on Penta E loeus; 04 mutations on D

Meta-analysis of loci associated with age at natural menopause in African-American women

Science.gov (United States)

Chen, Christina T.L.; Liu, Ching-Ti; Chen, Gary K.; Andrews, Jeanette S.; Arnold, Alice M.; Dreyfus, Jill; Franceschini, Nora; Garcia, Melissa E.; Kerr, Kathleen F.; Li, Guo; Lohman, Kurt K.; Musani, Solomon K.; Nalls, Michael A.; Raffel, Leslie J.; Smith, Jennifer; Ambrosone, Christine B.; Bandera, Elisa V.; Bernstein, Leslie; Britton, Angela; Brzyski, Robert G.; Cappola, Anne; Carlson, Christopher S.; Couper, David; Deming, Sandra L.; Goodarzi, Mark O.; Heiss, Gerardo; John, Esther M.; Lu, Xiaoning; Le Marchand, Loic; Marciante, Kristin; Mcknight, Barbara; Millikan, Robert; Nock, Nora L.; Olshan, Andrew F.; Press, Michael F.; Vaiyda, Dhananjay; Woods, Nancy F.; Taylor, Herman A.; Zhao, Wei; Zheng, Wei; Evans, Michele K.; Harris, Tamara B.; Henderson, Brian E.; Kardia, Sharon L.R.; Kooperberg, Charles; Liu, Yongmei; Mosley, Thomas H.; Psaty, Bruce; Wellons, Melissa; Windham, Beverly G.; Zonderman, Alan B.; Cupples, L. Adrienne; Demerath, Ellen W.; Haiman, Christopher; Murabito, Joanne M.; Rajkovic, Aleksandar

2014-01-01

Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA. PMID:24493794

Loci Affecting Gamma-Glutamyl Transferase in Adults and Adolescents Show Age X SNP interaction and Cardiometabolic Disease Associations

NARCIS (Netherlands)

Middelberg, R.P.S.; Benyamin, B.; de Moor, M.H.M.; Warrington, N.M.; Gordon, S.; Henders, A.K.; Medland, S.E.; Nyholt, DR; de Geus, E.J.C.; Hottenga, J.J.; Willemsen, G.; Beilin, L.J.; Mori, T.A.; Wright, M.J.; Heath, A.C.; Madden, P.A.F.; Boomsma, D.I.; Pennell, C.E.; Montgomery, G.W.; Martin, N.G.; Whitfield, J.B.

2012-01-01

Serum gamma-glutamyl transferase (GGT) activity is a marker of liver disease which is also prospectively associated with the risk of all-cause mortality, cardiovascular disease, type 2 diabetes and cancers. We have discovered novel loci affecting GGT in a genome-wide association study (rs1497406 in

Advantages of using Ti-mesh type electrodes for flexible dye-sensitized solar cells

International Nuclear Information System (INIS)

He Weizhen; Kim, Hyung-Kook; Hwang, Yoon-Hwae; Qiu Jijun; Zhuge Fuwei; Li Xiaomin; Lee, Jae-Ho; Kim, Yang-Do

2012-01-01

We used Ti meshes for both the photoanodes and counter electrodes of dye-sensitized solar cells (DSSCs) to improve the flexibility and conductivity of the electrodes. These mesh type electrodes showed good transparency and high bendability when subjected to an external force. We demonstrated the advantages of cells using such electrodes compared to traditional transparent conducting oxide based electrodes and back side illuminated DSSCs, such as low sheet resistance, elevated photo-induced current and enhanced sunlight utilization. Nanotube layers of different thicknesses were investigated to determine their effect on the photovoltaic parameters of the cell. The overall efficiency of the best cells was approximately 5.3% under standard air mass 1.5 global (AM 1.5 G) solar conditions. Furthermore, the DSSCs showed an efficiency of approximately 3.15% due to the all Ti-mesh type electrodes even after illumination from the back side. (paper)

Alzheimer's Disease Risk Polymorphisms Regulate Gene Expression in the ZCWPW1 and the CELF1 Loci.

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Celeste M Karch

Full Text Available Late onset Alzheimer's disease (LOAD is a genetically complex and clinically heterogeneous disease. Recent large-scale genome wide association studies (GWAS have identified more than twenty loci that modify risk for AD. Despite the identification of these loci, little progress has been made in identifying the functional variants that explain the association with AD risk. Thus, we sought to determine whether the novel LOAD GWAS single nucleotide polymorphisms (SNPs alter expression of LOAD GWAS genes and whether expression of these genes is altered in AD brains. The majority of LOAD GWAS SNPs occur in gene dense regions under large linkage disequilibrium (LD blocks, making it unclear which gene(s are modified by the SNP. Thus, we tested for brain expression quantitative trait loci (eQTLs between LOAD GWAS SNPs and SNPs in high LD with the LOAD GWAS SNPs in all of the genes within the GWAS loci. We found a significant eQTL between rs1476679 and PILRB and GATS, which occurs within the ZCWPW1 locus. PILRB and GATS expression levels, within the ZCWPW1 locus, were also associated with AD status. Rs7120548 was associated with MTCH2 expression, which occurs within the CELF1 locus. Additionally, expression of several genes within the CELF1 locus, including MTCH2, were highly correlated with one another and were associated with AD status. We further demonstrate that PILRB, as well as other genes within the GWAS loci, are most highly expressed in microglia. These findings together with the function of PILRB as a DAP12 receptor supports the critical role of microglia and neuroinflammation in AD risk.

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production.

Science.gov (United States)

Zhu, Jinfang

2015-09-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these "type 2 immune response-related" cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. Published by Elsevier Ltd.

T helper 2 (Th2) cell differentiation, type 2 innate lymphoid cell (ILC2) development and regulation of interleukin-4 (IL-4) and IL-13 production

Science.gov (United States)

Zhu, Jinfang

2015-01-01

Interleukin-4 (IL-4), IL-5 and IL-13, the signature cytokines that are produced during type 2 immune responses, are critical for protective immunity against infections of extracellular parasites and are responsible for asthma and many other allergic inflammatory diseases. Although many immune cell types within the myeloid lineage compartment including basophils, eosinophils and mast cells are capable of producing at least one of these cytokines, the production of these “type 2 immune response-related” cytokines by lymphoid lineages, CD4 T helper 2 (Th2) cells and type 2 innate lymphoid cells (ILC2s) in particular, are the central events during type 2 immune responses. In this review, I will focus on the signaling pathways and key molecules that determine the differentiation of naïve CD4 T cells into Th2 cells, and how the expression of Th2 cytokines, especially IL-4 and IL-13, is regulated in Th2 cells. The similarities and differences in the differentiation of Th2 cells, IL-4-producing T follicular helper (Tfh) cells and ILC2s as well as their relationships will also be discussed. PMID:26044597

Genetic Sharing with Cardiovascular Disease Risk Factors and Diabetes Reveals Novel Bone Mineral Density Loci.

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Sjur Reppe

Full Text Available Bone Mineral Density (BMD is a highly heritable trait, but genome-wide association studies have identified few genetic risk factors. Epidemiological studies suggest associations between BMD and several traits and diseases, but the nature of the suggestive comorbidity is still unknown. We used a novel genetic pleiotropy-informed conditional False Discovery Rate (FDR method to identify single nucleotide polymorphisms (SNPs associated with BMD by leveraging cardiovascular disease (CVD associated disorders and metabolic traits. By conditioning on SNPs associated with the CVD-related phenotypes, type 1 diabetes, type 2 diabetes, systolic blood pressure, diastolic blood pressure, high density lipoprotein, low density lipoprotein, triglycerides and waist hip ratio, we identified 65 novel independent BMD loci (26 with femoral neck BMD and 47 with lumbar spine BMD at conditional FDR < 0.01. Many of the loci were confirmed in genetic expression studies. Genes validated at the mRNA levels were characteristic for the osteoblast/osteocyte lineage, Wnt signaling pathway and bone metabolism. The results provide new insight into genetic mechanisms of variability in BMD, and a better understanding of the genetic underpinnings of clinical comorbidity.

Prospective associations of coronary heart disease loci in African Americans using the MetaboChip: the PAGE study.

Directory of Open Access Journals (Sweden)

Nora Franceschini

Full Text Available Coronary heart disease (CHD is a leading cause of morbidity and mortality in African Americans. However, there is a paucity of studies assessing genetic determinants of CHD in African Americans. We examined the association of published variants in CHD loci with incident CHD, attempted to fine map these loci, and characterize novel variants influencing CHD risk in African Americans.Up to 8,201 African Americans (including 546 first CHD events were genotyped using the MetaboChip array in the Atherosclerosis Risk in Communities (ARIC study and Women's Health Initiative (WHI. We tested associations using Cox proportional hazard models in sex- and study-stratified analyses and combined results using meta-analysis. Among 44 validated CHD loci available in the array, we replicated and fine-mapped the SORT1 locus, and showed same direction of effects as reported in studies of individuals of European ancestry for SNPs in 22 additional published loci. We also identified a SNP achieving array wide significance (MYC: rs2070583, allele frequency 0.02, P = 8.1 × 10(-8, but the association did not replicate in an additional 8,059 African Americans (577 events from the WHI, HealthABC and GeneSTAR studies, and in a meta-analysis of 5 cohort studies of European ancestry (24,024 individuals including 1,570 cases of MI and 2,406 cases of CHD from the CHARGE Consortium.Our findings suggest that some CHD loci previously identified in individuals of European ancestry may be relevant to incident CHD in African Americans.

The Functions of Type I and Type II Natural Killer T (NKT) Cells in Inflammatory Bowel Diseases

Science.gov (United States)

Liao, Chia-Min; Zimmer, Michael I.; Wang, Chyung-Ru

2013-01-01

CD1d-restricted natural killer T (NKT) cells are a distinct subset of T cells that rapidly produce an array of cytokines upon activation and play a critical role in regulating various immune responses. NKT cells are classified into two groups based on differences in T cell receptor (TCR) usage. Type I NKT cells have an invariant TCRα-chain and are readily detectable by α-galactosylceramide (α-GalCer)-loaded CD1d tetramers. Type II NKT cells have a more diverse TCR repertoire and cannot be directly identified. Both types of NKT cells as well as multiple CD1d-expressing cell types are present in the intestine and their interactions are likely to be modulated by pathogenic and commensal microbes, which in turn contribute to the intestinal immune responses in health and disease. Indeed, in several animal models of inflammatory bowel disease (IBD), Type I NKT cells have been shown to make both protective and pathogenic contributions to disease. In contrast, in human patients suffering from ulcerative colitis (UC), and a mouse model in which both CD1d expression and the frequency of Type II NKT cells are increased, Type II NKT cells appear to promote intestinal inflammation. In this review, we summarize present knowledge on the antigen recognition, activation and function of NKT cells with a particular focus on their role in IBD, and discuss factors that may influence the functional outcome of NKT cell responses in intestinal inflammation. PMID:23518808

Type II NKT-TFH cells against Gaucher lipids regulate B-cell immunity and inflammation.

Science.gov (United States)

Nair, Shiny; Boddupalli, Chandra Sekhar; Verma, Rakesh; Liu, Jun; Yang, Ruhua; Pastores, Gregory M; Mistry, Pramod K; Dhodapkar, Madhav V

2015-02-19

Chronic inflammation including B-cell activation is commonly observed in both inherited (Gaucher disease [GD]) and acquired disorders of lipid metabolism. However, the cellular mechanisms underlying B-cell activation in these settings remain to be elucidated. Here, we report that β-glucosylceramide 22:0 (βGL1-22) and glucosylsphingosine (LGL1), 2 major sphingolipids accumulated in GD, can be recognized by a distinct subset of CD1d-restricted human and murine type II natural killer T (NKT) cells. Human βGL1-22- and LGL1-reactive CD1d tetramer-positive T cells have a distinct T-cell receptor usage and genomic and cytokine profiles compared with the classical type I NKT cells. In contrast to type I NKT cells, βGL1-22- and LGL1-specific NKT cells constitutively express T-follicular helper (TFH) phenotype. Injection of these lipids leads to an increase in respective lipid-specific type II NKT cells in vivo and downstream induction of germinal center B cells, hypergammaglobulinemia, and production of antilipid antibodies. Human βGL1-22- and LGL1-specific NKT cells can provide efficient cognate help to B cells in vitro. Frequency of LGL1-specific T cells in GD mouse models and patients correlates with disease activity and therapeutic response. Our studies identify a novel type II NKT-mediated pathway for glucosphingolipid-mediated dysregulation of humoral immunity and increased risk of B-cell malignancy observed in metabolic lipid disorders. © 2015 by The American Society of Hematology.

Intrafamilial, Preferentially Mother-to-Child and Intraspousal, Helicobacter pylori Infection in Japan Determined by Mutilocus Sequence Typing and Random Amplified Polymorphic DNA Fingerprinting.

Science.gov (United States)

Yokota, Shin-ichi; Konno, Mutsuko; Fujiwara, Shin-ichi; Toita, Nariaki; Takahashi, Michiko; Yamamoto, Soh; Ogasawara, Noriko; Shiraishi, Tsukasa

2015-10-01

The infection route of Helicobacter pylori has been recognized to be mainly intrafamilial, preferentially mother-to-child, especially in developed countries. To determine the transmission route, we examined whether multilocus sequence typing (MLST) was useful for analysis of intrafamilial infection. The possibility of intraspousal infection was also evaluated. Clonal relationships between strains derived from 35 index Japanese pediatric patients, and their family members were analyzed by two genetic typing procedures, MLST and random amplified polymorphic DNA (RAPD) fingerprinting. Mostly coincident results were obtained by MLST and RAPD. By MLST, the allele of loci in the isolates mostly matched between the index child and both the father and mother for 9 (25.7%) of the 35 patients, between the index child and the mother for 25 (60.0%) of the 35 patients. MLST is useful for analyzing the infection route of H. pylori as a highly reproducible method. Intrafamilial, especially mother-to-children and sibling, infection is the dominant transmission route. Intraspousal infection is also thought to occur in about a quarter in the Japanese families. © 2015 John Wiley & Sons Ltd.