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  • Publication . Article . Preprint . Conference object . 2004
    Open Access English
    Authors: 
    Sajina, Anna; Scott, Douglas; Dennefeld, Michel; Dole, Herve; Lacy, Mark; Lagache, Guilaine;
    Publisher: HAL CCSD
    Country: France
    Project: NSERC

    We present preliminary results on a study of the 2--850 micron SEDs of a sample of 30 FIRBACK galaxies selected at 170 micron. These sources are representative of the brightest ~10% of the Cosmic Infrared Background. They are a mixture of mostly local (z<~0.3) starforming galaxies, and a tail of ULIGs that extend up to z~1, and are likely to be a similar population to faint SCUBA sources. We use archival Spitzer IRAC and MIPS data to extend the spectral coverage to the mid-IR regime, resulting in an unprecended (for this redshift range) census of their infrared SEDs. This allows us to study in far greater detail this important population linking the near-IR stellar emission with PAH and thermal dust emission. We do this using a Markov Chain Monte Carlo method, which easily allows for the inclusion of ~6 free parameters, as well as an estimate of parameter uncertainties and correlations. Comment: 5 pages, 3 figures. Proceeding for the conference "Starbursts: From 30 Doradus to Lyman Break Galaxies", held in Cambridge (UK) in September, 2004

  • Open Access English
    Authors: 
    Kedong Yin; Hao Liu; Paul Harrison;
    Publisher: Copernicus Publications
    Project: NSERC

    We hypothesize that phytoplankton have the sequential nutrient uptake strategy to maintain nutrient stoichiometry and high primary productivity in the water column. According to this hypothesis, phytoplankton take up the most limiting nutrient first until depletion, continue to draw down non-limiting nutrients and then take up the most limiting nutrient rapidly when it is available. These processes would result in the variation of ambient nutrient ratios in the water column around the Redfield ratio. We used high-resolution continuous vertical profiles of nutrients, nutrient ratios and on-board ship incubation experiments to test this hypothesis in the Strait of Georgia. At the surface in summer, ambient NO3− was depleted with excess PO43− and SiO4− remaining, and as a result, both N : P and N : Si ratios were low. The two ratios increased to about 10 : 1 and 0. 45 : 1, respectively, at 20 m. Time series of vertical profiles showed that the leftover PO43− continued to be removed, resulting in additional phosphorus storage by phytoplankton. The N : P ratios at the nutricline in vertical profiles responded differently to mixing events. Field incubation of seawater samples also demonstrated the sequential uptake of NO3− (the most limiting nutrient) and then PO43− and SiO4− (the non-limiting nutrients). This sequential uptake strategy allows phytoplankton to acquire additional cellular phosphorus and silicon when they are available and wait for nitrogen to become available through frequent mixing of NO3− (or pulsed regenerated NH4). Thus, phytoplankton are able to maintain high productivity and balance nutrient stoichiometry by taking advantage of vigorous mixing regimes with the capacity of the stoichiometric plasticity. To our knowledge, this is the first study to show the in situ dynamics of continuous vertical profiles of N : P and N : Si ratios, which can provide insight into the in situ dynamics of nutrient stoichiometry in the water column and the inference of the transient status of phytoplankton nutrient stoichiometry in the coastal ocean.

  • Open Access
    Authors: 
    Shu-Qi Qiu; Yun Du; Xiaobei Duan; Xiao-Rui Geng; Jianxiong Xie; Han Gao; Ping-Chang Yang;
    Publisher: Medknow
    Project: CIHR , NSERC

    Background : The prevalence of chronic rhinitis is increasing rapidly; its pathogenesis is to be further understood; immune inflammation is one of the possible causative factors. Antigen specific CD8+ T cells play a critical role in the induction of chronic inflammation. Aims : This study aimed to investigate the role of antigen specific CD8+ T cells in the pathogenesis of chronic atypical allergic rhinitis. Material and Methods : Nasal mucosal epithelial surface scratching samples were obtained from patients with chronic obstruction atypical allergic rhinitis. Exosomes were purified from the scratching samples and examined by immune gold electron microscopy. The effect of exosomes on modulating dendritic cell's properties, the effect of exosome-pulsed dendritic cells on naive T cell differentiation and the antigen specific CD8+ T cell activation were observed by cell culture models. Results : Exosomes purified from patients with chronic atypical allergic rhinitis carried microbial products, Staphylococcal enterotoxin B (SEB), and airborne antigen, Derp1. Dendritic cells pulsed by SEB/Derp1-carrying exosomes showed high levels of CD80, CD86 and the major histocompatibility class I (MHCI). Exosome-pulsed dendritic cells could induce the naive CD3+ T cells to differentiate into CD8+ T cells. Upon the exposure to a specific antigen, the CD8+ T cells released granzyme B and perforin; more than 30% antigen specific CD8+ T cells proliferated. Conclusions : Antigen specific CD8+ T cells play an important role in the pathogenesis of chronic obstruction atypical allergic rhinitis.

  • Open Access English
    Authors: 
    Cédric Annweiler; Manuel Montero-Odasso; Susan W Muir; Olivier Beauchet;
    Publisher: HAL CCSD
    Countries: France, Canada
    Project: CIHR

    International audience; Hypovitaminosis D is associated with cognitive decline in the elderly, but the issue of causality remains unresolved. Definitive evidence would include the visualization of brain lesions resulting from hypovitaminosis D. The aim of the present article is to determine, through a literature review, the location and nature of possible brain disorders in hypovitaminosis D. We found limited brain-imaging data, which reported ischemic infarcts and white matter hyperintensities in hypovitaminosis D, though did not provide their specific location or report any focal atrophy. Based on the finding of executive dysfunctions (i.e., mental shifting and information updating impairments) in the presence of hypovitaminosis D, we suggest that hypovitaminosis D is associated with a dysfunction of the frontal-subcortical neuronal circuits, particularly the dorsolateral circuit. Further imaging studies are required to corroborate this assumption and to determine whether hypovitaminosis D results in degenerative and / or vascular lesions.

  • Publication . Preprint . Article . 2008
    Open Access English
    Authors: 
    David, Matei; Pitassi, Toniann;
    Project: NSERC

    We provide a non-explicit separation of the number-on-forehead communication complexity classes RP and NP when the number of players is up to \delta log(n) for any \delta<1. Recent lower bounds on Set-Disjointness [LS08,CA08] provide an explicit separation between these classes when the number of players is only up to o(loglog(n)).

  • Publication . Article . Other literature type . 2016
    Open Access English
    Authors: 
    Bentham, James; Cesare, Mariachiara Di; Stevens, Gretchen A.; Zhou, Bin; Bixby, Honor; Cowan, Melanie J.; Fortunato, Lea; Bennett, James E.; Danaei, Goodarz; Hajifathalian, Kaveh; +263 more
    Countries: United Kingdom, Sweden, Sweden, Spain, United Kingdom, Finland, Peru, Poland, Malta, Germany ...
    Project: WT | A Global Database on Card... (101506), WT , EC | HYPERGENES (201550)

    Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. http://purl.org/eprint/status/PeerReviewed published version Article

  • Open Access
    Authors: 
    Karoline Kuchenbaecker; Kyriaki Michailidou; Gustavo Mendoza-Fandiño; Janna Lilyquist; Curtis Olswold; Emily Hallberg; Habibul Ahsan; Kristiina Aittomäki; Irene L. Andrulis; Hoda Anton-Culver; +198 more
    Countries: Belgium, Netherlands, Spain, United States, United Kingdom, Belgium, Sweden, Spain, United Kingdom, Spain ...
    Project: CIHR , NIH | Elucidating Loci Involved... (5U19CA148537-02), EC | COGS (223175), NWO | Secure and gentle grip of... (11477), NIH | Follow-up of Ovarian Canc... (3U19CA148112-04S1), NIH | A genome-wide association... (5R01CA128978-02), WT , NIH | Discovery Expansion and R... (5U19CA148065-04)

    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, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

  • Open Access English
    Authors: 
    Mark Haas; Alexandre Loupy; Carmen Lefaucheur; Candice Roufosse; Denis Glotz; Daniel Serón; Brian J. Nankivell; Philip F. Halloran; Robert B. Colvin; Enver Akalin; +19 more
    Countries: Spain, United States, United Kingdom

    The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i‐IFTA) and its relationship to T cell–mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody‐mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i‐IFTA is associated with reduced graft survival. Furthermore, these groups presented that i‐IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i‐IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor‐specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next‐generation clinical trials. The Banff consortium presents revisions to the diagnostic criteria for T cell– and antibody‐mediated kidney transplant rejection, including specific criteria for chronic active T cell–mediated rejection, plus prospects for integrative endpoints in clinical trials. See related articles on pages 321, 364, and 377.

  • Open Access English
    Authors: 
    Mahder Seifu Manenda; Marie-Ève Picard; Li-Ping Zhang; Normand Cyr; Xiaojun Zhu; Julie Barma; John M. Pascal; Manon Couture; Changsheng Zhang; Rong Shi;
    Publisher: American Society for Biochemistry and Molecular Biology
    Project: NSERC

    Group A flavin-dependent monooxygenases catalyze the cleavage of the oxygen-oxygen bond of dioxygen, followed by the incorporation of one oxygen atom into the substrate molecule with the aid of NADPH and FAD. These flavoenzymes play an important role in many biological processes, and their most distinct structural feature is the choreographed motions of flavin, which typically adopts two distinct conformations (OUT and IN) to fulfill its function. Notably, these enzymes seem to have evolved a delicate control system to avoid the futile cycle of NADPH oxidation and FAD reduction in the absence of substrate, but the molecular basis of this system remains elusive. Using protein crystallography, size-exclusion chromatography coupled to multi-angle light scattering (SEC-MALS), and small-angle X-ray scattering (SEC-SAXS) and activity assay, we report here a structural and biochemical characterization of PieE, a member of the Group A flavin-dependent monooxygenases involved in the biosynthesis of the antibiotic piericidin A1. This analysis revealed that PieE forms a unique hexamer. Moreover, we found, to the best of our knowledge for the first time, that in addition to the classical OUT and IN conformations, FAD possesses a "sliding" conformation that exists in between the OUT and IN conformations. This observation sheds light on the underlying mechanism of how the signal of substrate binding is transmitted to the FAD-binding site to efficiently initiate NADPH binding and FAD reduction. Our findings bridge a gap currently missing in the orchestrated order of chemical events catalyzed by this important class of enzymes.

  • Publication . Article . Other literature type . 2020 . Embargo End Date: 04 Feb 2021
    Open Access
    Authors: 
    Carlevaro-Fita J.; Lanzos A.; Feuerbach L.; Hong C.; Mas-Ponte D.; Pedersen J. S.; Abascal F.; Amin S. B.; Bader G. D.; Barenboim J.; +127 more
    Publisher: Apollo - University of Cambridge Repository
    Countries: Netherlands, Switzerland, Italy, Belgium, Switzerland, Sweden, Spain, Denmark, United Kingdom

    Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis. Communications Biology, 3 (1) ISSN:2399-3642

search
Include:
The following results are related to Canada. Are you interested to view more results? Visit OpenAIRE - Explore.
92,581 Research products, page 1 of 9,259
  • Publication . Article . Preprint . Conference object . 2004
    Open Access English
    Authors: 
    Sajina, Anna; Scott, Douglas; Dennefeld, Michel; Dole, Herve; Lacy, Mark; Lagache, Guilaine;
    Publisher: HAL CCSD
    Country: France
    Project: NSERC

    We present preliminary results on a study of the 2--850 micron SEDs of a sample of 30 FIRBACK galaxies selected at 170 micron. These sources are representative of the brightest ~10% of the Cosmic Infrared Background. They are a mixture of mostly local (z<~0.3) starforming galaxies, and a tail of ULIGs that extend up to z~1, and are likely to be a similar population to faint SCUBA sources. We use archival Spitzer IRAC and MIPS data to extend the spectral coverage to the mid-IR regime, resulting in an unprecended (for this redshift range) census of their infrared SEDs. This allows us to study in far greater detail this important population linking the near-IR stellar emission with PAH and thermal dust emission. We do this using a Markov Chain Monte Carlo method, which easily allows for the inclusion of ~6 free parameters, as well as an estimate of parameter uncertainties and correlations. Comment: 5 pages, 3 figures. Proceeding for the conference "Starbursts: From 30 Doradus to Lyman Break Galaxies", held in Cambridge (UK) in September, 2004

  • Open Access English
    Authors: 
    Kedong Yin; Hao Liu; Paul Harrison;
    Publisher: Copernicus Publications
    Project: NSERC

    We hypothesize that phytoplankton have the sequential nutrient uptake strategy to maintain nutrient stoichiometry and high primary productivity in the water column. According to this hypothesis, phytoplankton take up the most limiting nutrient first until depletion, continue to draw down non-limiting nutrients and then take up the most limiting nutrient rapidly when it is available. These processes would result in the variation of ambient nutrient ratios in the water column around the Redfield ratio. We used high-resolution continuous vertical profiles of nutrients, nutrient ratios and on-board ship incubation experiments to test this hypothesis in the Strait of Georgia. At the surface in summer, ambient NO3− was depleted with excess PO43− and SiO4− remaining, and as a result, both N : P and N : Si ratios were low. The two ratios increased to about 10 : 1 and 0. 45 : 1, respectively, at 20 m. Time series of vertical profiles showed that the leftover PO43− continued to be removed, resulting in additional phosphorus storage by phytoplankton. The N : P ratios at the nutricline in vertical profiles responded differently to mixing events. Field incubation of seawater samples also demonstrated the sequential uptake of NO3− (the most limiting nutrient) and then PO43− and SiO4− (the non-limiting nutrients). This sequential uptake strategy allows phytoplankton to acquire additional cellular phosphorus and silicon when they are available and wait for nitrogen to become available through frequent mixing of NO3− (or pulsed regenerated NH4). Thus, phytoplankton are able to maintain high productivity and balance nutrient stoichiometry by taking advantage of vigorous mixing regimes with the capacity of the stoichiometric plasticity. To our knowledge, this is the first study to show the in situ dynamics of continuous vertical profiles of N : P and N : Si ratios, which can provide insight into the in situ dynamics of nutrient stoichiometry in the water column and the inference of the transient status of phytoplankton nutrient stoichiometry in the coastal ocean.

  • Open Access
    Authors: 
    Shu-Qi Qiu; Yun Du; Xiaobei Duan; Xiao-Rui Geng; Jianxiong Xie; Han Gao; Ping-Chang Yang;
    Publisher: Medknow
    Project: CIHR , NSERC

    Background : The prevalence of chronic rhinitis is increasing rapidly; its pathogenesis is to be further understood; immune inflammation is one of the possible causative factors. Antigen specific CD8+ T cells play a critical role in the induction of chronic inflammation. Aims : This study aimed to investigate the role of antigen specific CD8+ T cells in the pathogenesis of chronic atypical allergic rhinitis. Material and Methods : Nasal mucosal epithelial surface scratching samples were obtained from patients with chronic obstruction atypical allergic rhinitis. Exosomes were purified from the scratching samples and examined by immune gold electron microscopy. The effect of exosomes on modulating dendritic cell's properties, the effect of exosome-pulsed dendritic cells on naive T cell differentiation and the antigen specific CD8+ T cell activation were observed by cell culture models. Results : Exosomes purified from patients with chronic atypical allergic rhinitis carried microbial products, Staphylococcal enterotoxin B (SEB), and airborne antigen, Derp1. Dendritic cells pulsed by SEB/Derp1-carrying exosomes showed high levels of CD80, CD86 and the major histocompatibility class I (MHCI). Exosome-pulsed dendritic cells could induce the naive CD3+ T cells to differentiate into CD8+ T cells. Upon the exposure to a specific antigen, the CD8+ T cells released granzyme B and perforin; more than 30% antigen specific CD8+ T cells proliferated. Conclusions : Antigen specific CD8+ T cells play an important role in the pathogenesis of chronic obstruction atypical allergic rhinitis.

  • Open Access English
    Authors: 
    Cédric Annweiler; Manuel Montero-Odasso; Susan W Muir; Olivier Beauchet;
    Publisher: HAL CCSD
    Countries: France, Canada
    Project: CIHR

    International audience; Hypovitaminosis D is associated with cognitive decline in the elderly, but the issue of causality remains unresolved. Definitive evidence would include the visualization of brain lesions resulting from hypovitaminosis D. The aim of the present article is to determine, through a literature review, the location and nature of possible brain disorders in hypovitaminosis D. We found limited brain-imaging data, which reported ischemic infarcts and white matter hyperintensities in hypovitaminosis D, though did not provide their specific location or report any focal atrophy. Based on the finding of executive dysfunctions (i.e., mental shifting and information updating impairments) in the presence of hypovitaminosis D, we suggest that hypovitaminosis D is associated with a dysfunction of the frontal-subcortical neuronal circuits, particularly the dorsolateral circuit. Further imaging studies are required to corroborate this assumption and to determine whether hypovitaminosis D results in degenerative and / or vascular lesions.

  • Publication . Preprint . Article . 2008
    Open Access English
    Authors: 
    David, Matei; Pitassi, Toniann;
    Project: NSERC

    We provide a non-explicit separation of the number-on-forehead communication complexity classes RP and NP when the number of players is up to \delta log(n) for any \delta<1. Recent lower bounds on Set-Disjointness [LS08,CA08] provide an explicit separation between these classes when the number of players is only up to o(loglog(n)).

  • Publication . Article . Other literature type . 2016
    Open Access English
    Authors: 
    Bentham, James; Cesare, Mariachiara Di; Stevens, Gretchen A.; Zhou, Bin; Bixby, Honor; Cowan, Melanie J.; Fortunato, Lea; Bennett, James E.; Danaei, Goodarz; Hajifathalian, Kaveh; +263 more
    Countries: United Kingdom, Sweden, Sweden, Spain, United Kingdom, Finland, Peru, Poland, Malta, Germany ...
    Project: WT | A Global Database on Card... (101506), WT , EC | HYPERGENES (201550)

    Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3–19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8–144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries. http://purl.org/eprint/status/PeerReviewed published version Article

  • Open Access
    Authors: 
    Karoline Kuchenbaecker; Kyriaki Michailidou; Gustavo Mendoza-Fandiño; Janna Lilyquist; Curtis Olswold; Emily Hallberg; Habibul Ahsan; Kristiina Aittomäki; Irene L. Andrulis; Hoda Anton-Culver; +198 more
    Countries: Belgium, Netherlands, Spain, United States, United Kingdom, Belgium, Sweden, Spain, United Kingdom, Spain ...
    Project: CIHR , NIH | Elucidating Loci Involved... (5U19CA148537-02), EC | COGS (223175), NWO | Secure and gentle grip of... (11477), NIH | Follow-up of Ovarian Canc... (3U19CA148112-04S1), NIH | A genome-wide association... (5R01CA128978-02), WT , NIH | Discovery Expansion and R... (5U19CA148065-04)

    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, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5, a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations (P<0.05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction. B.C.A.C. was funded through a European Community Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175; COGS); Cancer Research UK (C1287/A10118, C1287/A10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692); the National Institutes of Health Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), R01 grants (CA128978, CA176785, CA192393), and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME-ON initiative); the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Breast Cancer Res. Foundation, and the Ovarian Cancer Research Fund. CIMBA genotyping was supported by National Institutes of Health grant (CA128978); the Department of Defence (W81XWH-10-1-0341); and the Breast Cancer Res. Foundation. CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A11174 and C1287/A10118. This study made use of data generated by the Wellcome Trust Case Control consortium. Functional studies were supported by the Florida Breast Cancer Foundation. A full description of funding and acknowledgments is provided in Supplementary Note 1.

  • Open Access English
    Authors: 
    Mark Haas; Alexandre Loupy; Carmen Lefaucheur; Candice Roufosse; Denis Glotz; Daniel Serón; Brian J. Nankivell; Philip F. Halloran; Robert B. Colvin; Enver Akalin; +19 more
    Countries: Spain, United States, United Kingdom

    The kidney sessions of the 2017 Banff Conference focused on 2 areas: clinical implications of inflammation in areas of interstitial fibrosis and tubular atrophy (i‐IFTA) and its relationship to T cell–mediated rejection (TCMR), and the continued evolution of molecular diagnostics, particularly in the diagnosis of antibody‐mediated rejection (ABMR). In confirmation of previous studies, it was independently demonstrated by 2 groups that i‐IFTA is associated with reduced graft survival. Furthermore, these groups presented that i‐IFTA, particularly when involving >25% of sclerotic cortex in association with tubulitis, is often a sequela of acute TCMR in association with underimmunosuppression. The classification was thus revised to include moderate i‐IFTA plus moderate or severe tubulitis as diagnostic of chronic active TCMR. Other studies demonstrated that certain molecular classifiers improve diagnosis of ABMR beyond what is possible with histology, C4d, and detection of donor‐specific antibodies (DSAs) and that both C4d and validated molecular assays can serve as potential alternatives and/or complements to DSAs in the diagnosis of ABMR. The Banff ABMR criteria are thus updated to include these alternatives. Finally, the present report paves the way for the Banff scheme to be part of an integrative approach for defining surrogate endpoints in next‐generation clinical trials. The Banff consortium presents revisions to the diagnostic criteria for T cell– and antibody‐mediated kidney transplant rejection, including specific criteria for chronic active T cell–mediated rejection, plus prospects for integrative endpoints in clinical trials. See related articles on pages 321, 364, and 377.

  • Open Access English
    Authors: 
    Mahder Seifu Manenda; Marie-Ève Picard; Li-Ping Zhang; Normand Cyr; Xiaojun Zhu; Julie Barma; John M. Pascal; Manon Couture; Changsheng Zhang; Rong Shi;
    Publisher: American Society for Biochemistry and Molecular Biology
    Project: NSERC

    Group A flavin-dependent monooxygenases catalyze the cleavage of the oxygen-oxygen bond of dioxygen, followed by the incorporation of one oxygen atom into the substrate molecule with the aid of NADPH and FAD. These flavoenzymes play an important role in many biological processes, and their most distinct structural feature is the choreographed motions of flavin, which typically adopts two distinct conformations (OUT and IN) to fulfill its function. Notably, these enzymes seem to have evolved a delicate control system to avoid the futile cycle of NADPH oxidation and FAD reduction in the absence of substrate, but the molecular basis of this system remains elusive. Using protein crystallography, size-exclusion chromatography coupled to multi-angle light scattering (SEC-MALS), and small-angle X-ray scattering (SEC-SAXS) and activity assay, we report here a structural and biochemical characterization of PieE, a member of the Group A flavin-dependent monooxygenases involved in the biosynthesis of the antibiotic piericidin A1. This analysis revealed that PieE forms a unique hexamer. Moreover, we found, to the best of our knowledge for the first time, that in addition to the classical OUT and IN conformations, FAD possesses a "sliding" conformation that exists in between the OUT and IN conformations. This observation sheds light on the underlying mechanism of how the signal of substrate binding is transmitted to the FAD-binding site to efficiently initiate NADPH binding and FAD reduction. Our findings bridge a gap currently missing in the orchestrated order of chemical events catalyzed by this important class of enzymes.

  • Publication . Article . Other literature type . 2020 . Embargo End Date: 04 Feb 2021
    Open Access
    Authors: 
    Carlevaro-Fita J.; Lanzos A.; Feuerbach L.; Hong C.; Mas-Ponte D.; Pedersen J. S.; Abascal F.; Amin S. B.; Bader G. D.; Barenboim J.; +127 more
    Publisher: Apollo - University of Cambridge Repository
    Countries: Netherlands, Switzerland, Italy, Belgium, Switzerland, Sweden, Spain, Denmark, United Kingdom

    Long non-coding RNAs (lncRNAs) are a growing focus of cancer genomics studies, creating the need for a resource of lncRNAs with validated cancer roles. Furthermore, it remains debated whether mutated lncRNAs can drive tumorigenesis, and whether such functions could be conserved during evolution. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we introduce the Cancer LncRNA Census (CLC), a compilation of 122 GENCODE lncRNAs with causal roles in cancer phenotypes. In contrast to existing databases, CLC requires strong functional or genetic evidence. CLC genes are enriched amongst driver genes predicted from somatic mutations, and display characteristic genomic features. Strikingly, CLC genes are enriched for driver mutations from unbiased, genome-wide transposon-mutagenesis screens in mice. We identified 10 tumour-causing mutations in orthologues of 8 lncRNAs, including LINC-PINT and NEAT1, but not MALAT1. Thus CLC represents a dataset of high-confidence cancer lncRNAs. Mutagenesis maps are a novel means for identifying deeply-conserved roles of lncRNAs in tumorigenesis. Communications Biology, 3 (1) ISSN:2399-3642