203 research outputs found
Genome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas.
No full textOBJECTIVE: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA1c reduction. RESEARCH DESIGN AND METHODS: As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA1c reduction after 12 months of therapy followed by meta-analysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions. RESULTS: After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction at a genome-wide scale (P < 5 × 10-8). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10-8), lower reduction in HbA1c. Similarly, the C allele was associated with higher glucose trough levels (β = 1.61, P = 0.005) in healthy volunteers in the SUGAR-MGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (β = 0.21, P = 2.04 × 10-58). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA1c (P = 4.80 × 10-8). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10-7), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor. CONCLUSIONS: We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs
Genomic editing of metformin efficacy-associated genetic variants in<i> SLC47A1</i> does not alter <i>SLC47A1</i> expression
Get PDFSeveral pharmacogenetics studies have identified an association between a greater metformindependent reduction in HbA1c levels and the minor A allele at rs2289669 in intron 10 of SLC47A1, encoding multidrug and toxin extrusion 1 (MATE1), a presumed metformin transporter. It is currently unknown if the rs2289669 locus is a cis-eQTL, which would validate its role as predictor of metformin efficacy. We looked at association between common genetic variants in the SLC47A1 gene region and HbA1c reduction after metformin treatment using locus-wise meta-analysis from the MetGen consortium. CRISPR-Cas9 was applied to perform allele editing of, or genomic deletion around, rs2289669 and of the closely linked rs8065082 in HepG2 cells. The genome-edited cells were evaluated for SLC47A1 expression and splicing. None of the common variants including rs2289669 showed significant association with metformin response. Genomic editing of either rs2289669 or rs8065082 did not alter SLC47A1 expression or splicing. Experimental and in silico analyses show that the rs2289669-containing haploblock does not appear to carry genetic variants that could explain its previously reported association with metformin efficacy
Vers une existence théologique de plus en plus fragile…
No full textThéologien, l’auteur s’intéresse aux conditions de la pratique théologique en contexte séculier contemporain. Face aux soutiens institutionnels de plus en plus défaillants, une pratique théologique renouvelée doit reconnaître sa fragilité et, de là, apprendre à s’inventer dans une herméneutique critique de la différence théologale.As a theologian, the author is interested in the conditions of practicing theology in a contemporary secular context. In the face of increasingly weak institutional support, a renewed theological practice must recognize its fragility and thus learn to invent itself in a critical hermeneutic of theological difference
Clean hydrogen production with the Cu–Cl cycle – Progress of international consortium, I: Experimental unit operations
No full textAdvancement of the thermochemical copper–chlorine (Cu–Cl) cycle for hydrogen production is reviewed and discussed in this paper. Individual unit operations and their linkage into an integrated cycle are being developed by a Canadian consortium, as part of the Generation IV International Forum (GIF) for hydrogen production with the next generation of nuclear reactors. This paper focuses on the consortium’s latest advances on the Cu–Cl cycle, particularly with respect to hydrogen production with Canada’s Generation IV reactor, called SCWR (Super-Critical Water Reactor). Other heat sources may also be utilized for the Cu–Cl cycle, such as solar energy or industrial waste heat. In this first of two companion papers, recent developments in Canada’s nuclear hydrogen program are reported, specifically unit operation experiments of the Cu–Cl cycle and system integration. The following second companion paper will present system modeling with Aspen Plus, corrosion resistant materials, thermochemistry, safety, and reliability aspects of the Cu–Cl cycle.Atomic Energy of Canada LimitedOntario Research Excellence FundNatural Sciences and Engineering Research Council of CanadaUniversity Network of Excellence in Nuclear Engineering (UNENE)Canada Research Chairs progra
Extended early childhood intervention and school achievement: Age 13 findings from the Chicago longitudinal study
Get PDFWe evaluated the effects of participation in an extended program of compensatory education for a large sample of inner-city black children up to the seventh grade. The intervention is the Chicago Child-Parent Center and Expansion Program. Groups included 426 children who participated in the program from preschool to grades 2 or 3 and 133 school-stable children whose participation ceased in kindergarten. After taking into account initial differences in both the level and the growth rate of achievement, frequency of school mobility after the program, and sample selection bias, program participation for two or three years after preschool and kindergarten is positively associated with reading and math achievement in grade 7 and negatively associated with cumulative grade retention four years after the end of the program. Study findings provide rare longitudinal evidence from an established program concerning the effects of extending compensatory education into the primary grades.
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Genome-wide meta-analysis identifies genetic variants associated with glycemic response to sulfonylureas
Get PDFObjective: Sulfonylureas, the first available drugs for the management of type 2 diabetes, remain widely prescribed today. However, there exists significant variability in glycemic response to treatment. We aimed to establish heritability of sulfonylurea response and identify genetic variants and interacting treatments associated with HbA 1c reduction.Research Design and Methods: As an initiative of the Metformin Genetics Plus Consortium (MetGen Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortium, 5,485 White Europeans with type 2 diabetes treated with sulfonylureas were recruited from six referral centers in Europe and North America. We first estimated heritability using the generalized restricted maximum likelihood approach and then undertook genome-wide association studies of glycemic response to sulfonylureas measured as HbA 1c reduction after 12 months of therapy followed by metaanalysis. These results were supported by acute glipizide challenge in humans who were naïve to type 2 diabetes medications, cis expression quantitative trait loci (eQTL), and functional validation in cellular models. Finally, we examined for possible drug-drug-gene interactions.Results: After establishing that sulfonylurea response is heritable (mean ± SEM 37 ± 11%), we identified two independent loci near the GXYLT1 and SLCO1B1 genes associated with HbA 1c reduction at a genome-wide scale (P < 5×10 28). The C allele at rs1234032, near GXYLT1, was associated with 0.14% (1.5 mmol/mol), P = 2.39 × 10 28), lower reduction in HbA 1c. Similarly, the C allele was associated with higher glucose trough levels (b = 1.61, P = 0.005) in healthy volunteers in the SUGARMGH given glipizide (N = 857). In 3,029 human whole blood samples, the C allele is a cis eQTL for increased expression of GXYLT1 (b = 0.21, P = 2.04 × 10 258). The C allele of rs10770791, in an intronic region of SLCO1B1, was associated with 0.11% (1.2 mmol/mol) greater reduction in HbA 1c (P = 4.80 × 10 28). In 1,183 human liver samples, the C allele at rs10770791 is a cis eQTL for reduced SLCO1B1 expression (P = 1.61 × 10 27), which, together with functional studies in cells expressing SLCO1B1, supports a key role for hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea transport. Further, a significant interaction between statin use and SLCO1B1 genotype was observed (P = 0.001). In statin nonusers, C allele homozygotes at rs10770791 had a large absolute reduction in HbA 1c (0.48 ± 0.12% [5.2 ± 1.26 mmol/mol]), equivalent to that associated with initiation of a dipeptidyl peptidase 4 inhibitor.Conclusions: We have identified clinically important genetic effects at genome-wide levels of significance, and important drug-drug-gene interactions, which include commonly prescribed statins. With increasing availability of genetic data embedded in clinical records these findings will be important in prescribing glucose-lowering drugs. </p
Clean hydrogen production with the Cu–Cl cycle – Progress of international consortium, II: Simulations, thermochemical data and materials
No full textThis second of two companion papers presents the latest advances of an international team on the thermochemical copper–chlorine (Cu–Cl) cycle of hydrogen production. It specifically focuses on simulations, thermochemical data, advanced materials, safety, reliability and economics of the Cu–Cl cycle. Aspen Plus simulations of various system configurations are performed to improve the cycle efficiency. In addition, simulations based on exergo-economic and exergy-cost-energy-mass (EXCEM) methods for system design are presented. Modeling of the linkage between nuclear and hydrogen plants demonstrates how the Cu–Cl cycle would be integrated with an SCWR (Super Critical Water Reactor; Canada’s Generation IV reactor). Chemical potentials, solubilities, formation of Cu(I) and Cu(II) complexes and properties of Cu2OCl2, Cu(I) and Cu(II) chloride species are reported. In addition, the development of new advanced materials with improved corrosion resistance is presented. In particular, the performance of new anode electrode structures and thermal spray coatings is presented. This companion set of two papers presents new advances in a range of key enabling technologies for the thermochemical copper–chlorine cycle.Atomic Energy of Canada LimitedOntario Research Excellence FundNatural Sciences and Engineering Research Council of Canada (NSERC)University Network of Excellence in Nuclear Engineering (UNENE)Canada Research Chairs (CRC
J-PLUS: Galaxy-star-quasar classification for DR3
No full textvon Marttens, R. et al.-- Full list of authors: von Marttens, R.; Marra, V.; Quartin, M.; Casarini, L.; Baqui, P. O.; Alvarez-Candal, A.; Galindo-Guil, F. J.; Fernández-Ontiveros, J. A.; del Pino, Andrés; Díaz-García, L. A.; López-Sanjuan, C.; Alcaniz, J.; Angulo, R.; Cenarro, A. J.; Cristóbal-Hornillos, D.; Dupke, R.; Ederoclite, A.; Hernández-Monteagudo, C.; Marín-Franch, A.; Moles, M.; Sodré, L.; Varela, J.; Vázquez Ramió, H..-- This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.The Javalambre Photometric Local Universe Survey (J-PLUS) is a 12-band photometric survey using the 83-cm JAST telescope. Data Release 3 includes 47.4 million sources. J-PLUS DR3 only provides star-galaxy classification so that quasars are not identified from the other sources. Given the size of the data set, machine learning methods could provide a valid alternative classification and a solution to the classification of quasars. Our objective is to classify J-PLUS DR3 sources into galaxies, stars, and quasars, outperforming the available classifiers in each class. We use an automated machine learning tool called TPOT to find an optimized pipeline to perform the classification. The supervised machine learning algorithms are trained on the crossmatch with SDSS DR18, LAMOST DR8, and Gaia. We checked that the training set of about 660 thousand galaxies, 1.2 million stars, and 270 thousand quasars is both representative and contain a minimal presence of contaminants (less than 1 per cent). We considered 37 features: The 12 photometric bands with respective errors, 6 colours, 4 morphological parameters, galactic extinction with its error, and the PSF relative to the corresponding pointing. With TPOT genetic algorithm, we found that XGBoost provides the best performance: The AUC for galaxies, stars, and quasars is above 0.99 and the average precision is above 0.99 for galaxies and stars and 0.96 for quasars. XGBoost outperforms the classifiers already provided in J-PLUS DR3 and also classifies quasars. © The Author(s) 2023.RvM thanks FAPES (Brazil) and the Programa de Capacitac¸ao˜
Institucional PCI/ON for financial support. VM thanks CNPq
(Brazil) and FAPES (Brazil) for partial financial support. MQ
is supported by the Brazilian research agencies CNPq, FAPERJ,
and CAPES. We acknowledge support from the CAPES-DAAD
bilateral project ‘Data Analysis and Model Testing in the Era of
Precision Cosmology’. LC acknowledges financial support from
CNPq. AAC acknowledges support from the State Agency for
Research of the Spanish MCIU through the ‘Centre of Excellence
Severo Ochoa’ award to the Instituto de Astrof´ısica de Andaluc´ıa
(SEV-2017-0709). JAFO acknowledges the financial support from
the Spanish Ministry of Science and Innovation and the European
Union – NextGenerationEU through the Recovery and Resilience
Facility project ICTS-MRR-2021-03-CEFCA. LADG acknowledges
financial support from the State Agency for Research of the Spanish
MCIU through the ‘Centre of Excellence Severo Ochoa’ award to
the Instituto de Astrof´ısica de Andaluc´ıa (SEV-2017-0709), and to
the PID2019-109067-GB100. LSJ acknowledges the support from
CNPq (308994/2021-3) and FAPESP (2011/51680-6). This work
made use of the Virgo Cluster at Cosmo-Ufes/UFES, which isfunded
by FAPES (Fundac¸ao˜ de Amparo a´ Pesquisa e Inovac¸ao˜ do Esp´ırito
Santo) and administered by Renan Alves de Oliveira.
Based on observations made with the JAST80 telescope and
T80Cam camera for the J-PLUS project at the Observatorio Astrof´ısico de Javalambre (OAJ), in Teruel, owned, managed, and
operated by the Centro de Estudios de F´ısica del Cosmos de Aragon´
(CEFCA). We acknowledge the OAJ Data Processing and Archiving
Unit (UPAD) for reducing and calibrating the OAJ data used in
this work. Funding for the J-PLUS project has been provided by
the Governments of Spain and Aragon´ through the Fondo de Inversiones de Teruel; the Aragonese Government through the Research Groups E96, E103, E16 17R, and E16 20R; the Spanish Ministry of Science, Innovation, and Universities (MCIU/AEI/FEDER,
UE) with grants PGC2018-097585-B-C21 and PGC2018-097585-
B-C22; the Spanish Ministry of Economy and Competitiveness
(MINECO/FEDER, UE) under grant number AYA2015-66211-
C2-1-P, AYA2015-66211-C2-2, AYA2012-30789, and ICTS-2009-
14; and European FEDER funding (grant no. FCDD10-4E-867,
FCDD13-4E-2685). The Brazilian agencies FAPERJ and FAPESP
as well as the National Observatory of Brazil have also contributed
to this project.
Funding for SDSS-III has been provided by the Alfred P. Sloan
Foundation, the Participating Institutions, the National Science
Foundation, and the U.S. Department of Energy Office of Science.
The SDSS-III web site is sdss3.org. SDSS-III is managed by the
Astrophysical Research Consortium for the Participating Institutions of the SDSS-III Collaboration including the University of
Arizona, the Brazilian Participation Group, Brookhaven National
Laboratory, Carnegie Mellon University, University of Florida, the
French Participation Group, the German Participation Group, Harvard University, the Instituto de Astrofisica deCanarias, the Michigan
State/Notre Dame/JINA Participation Group,Johns Hopkins University, Lawrence Berkeley National Laboratory, Max Planck Institute
for Astrophysics, Max Planck Institute for Extraterrestrial Physics,
New Mexico State University, New York University, Ohio State
University, Pennsylvania State University, University of Portsmouth,
Princeton University, the Spanish Participation Group, University
of Tokyo, University of Utah, Vanderbilt University, University of
Virginia, University of Washington, and Yale University.
This work has made use of data from the European Space Agency
(ESA) mission Gaia (www.cosmos.esa.int/0:italic Gaia/0:italic),
processed by the Gaia Data Processing and Analysis Consortium
(DPAC, www.cosmos.esa.int/web/0:italic Gaia/0:italic/dpac/con
sortium). Funding for the DPAC has been provided by national
institutions, in particular the institutions participating in the Gaia
Multilateral Agreement.
Guoshoujing Telescope (the LAMOST) is a National Major
Scientific Project built by the Chinese Academy of Sciences. Funding
for the project has been provided by the National Development
and Reform Commission. LAMOST is operated and managed by
the National Astronomical Observatories, Chinese Academy of
Sciences.With funding from the Spanish government through the "Severo Ochoa Centre of Excellence" accreditation (SEV2017-0709).Peer reviewe
Author Correction: Comparability of automated drusen volume measurements in age-related macular degeneration: a MACUSTAR study report
No full textGenome-Wide Meta-analysis Identifies Genetic Variants Associated With Glycemic Response to Sulfonylureas
No full textObjective:
Sulfonylureas, the first available drugs for the management of type 2 diabetes,
remain widely prescribed today. However there exists significant variability in glycaemic response to
treatment. We aimed to establish heritability of
sulfonylurea response and identify genetic variants and interacting treatments
associated with HbA1c reduction.
Research
design and methods: As an initiative of the Metformin Genetics Plus (MetGen
Plus) and the DIabetes REsearCh on patient straTification (DIRECT) consortia,
5,485 white Europeans with type 2 diabetes treated with sulfonylurea were
recruited from 6 referral centres in Europe and North America. We first
estimated heritability using generalized restricted
maximum likelihood (REML) and then undertook GWAS of glycemic response to sulfonylureas
measured as HbA1c reduction after 12 months of therapy followed by
meta-analysis. These results were supported by acute glipizide challenge in
humans who were naïve to type 2 diabetes medications, cis-eQTLs
and functional validation in cellular models. Finally, we examined for a
possible drug-drug-gene interactions.
Results: After establishing that
sulfonylurea response is heritable (37±11%), we identified two independent loci
near the GXYLT1 and SLCO1B1 genes associated with HbA1c reduction
at a genome-wide scale (p -8). The C-allele at rs1234032, near GXYLT1, was associated with
0.14% (1.5 mmol/mol), p=2.39×10−8)
lower reduction in HbA1c. Similarly, the C-allele was associated with higher
glucose trough levels (β=1.61, p=0.005) in healthy volunteers in the SUGAR-MGH
given glipizide (N = 857). In 3, 029 human whole blood samples, the C-allele is
a cis-eQTL for increased expression of GXYLT1 (β=0.21, p=2.04×10-58). The C-allele of rs10770791, in an
intronic region of SLCO1B1, was associated with 0.11%
(1.2 mmol/mol) greater reduction in HbA1c (p=4.80×10−8). In
1,183 human liver samples, the C-allele at rs10770791 is a cis-eQTL for reduced
SLCO1B1 expression (p=1.61×10−7) which, together with
functional studies in cells expressing SLCO1B1, supports a key role for
hepatic SLCO1B1 (encoding OATP1B1) in regulation of sulfonylurea
transport. Further, a significant interaction between statin use, sulfonylurea
response and SCLO1B1 genotype was observed (p=0.001). In statin
non-users, C-allele homozygotes at rs10770791 had a large absolute reduction in HbA1c
(0.48±0.12% (5.2±1.26 mmol/mol)), equivalent to initiating a DPP4 inhibitor.
Conclusion:
We have identified clinically important genetic
effects at genome wide levels of significance, and important drug-drug-gene
interactions, which include commonly prescribed statins. With increasing
availability of genetic data embedded in clinical records these findings will
be important when prescribing glucose-lowering drugs. </p
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