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- Flannick, Jason, et al.
(author)
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Data Descriptor : Sequence data and association statistics from 12,940 type 2 diabetes cases and controls
- 2017
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In: Scientific Data. - : Springer Science and Business Media LLC. - 2052-4463. ; 4
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Journal article (peer-reviewed)abstract
- To investigate the genetic basis of type 2 diabetes (T2D) to high resolution, the GoT2D and T2D-GENES consortia catalogued variation from whole-genome sequencing of 2,657 European individuals and exome sequencing of 12,940 individuals of multiple ancestries. Over 27M SNPs, indels, and structural variants were identified, including 99% of low-frequency (minor allele frequency [MAF] 0.1-5%) non-coding variants in the whole-genome sequenced individuals and 99.7% of low-frequency coding variants in the whole-exome sequenced individuals. Each variant was tested for association with T2D in the sequenced individuals, and, to increase power, most were tested in larger numbers of individuals (> 80% of low-frequency coding variants in similar to ~82 K Europeans via the exome chip, and similar to ~90% of low-frequency non-coding variants in similar to ~44 K Europeans via genotype imputation). The variants, genotypes, and association statistics from these analyses provide the largest reference to date of human genetic information relevant to T2D, for use in activities such as T2D-focused genotype imputation, functional characterization of variants or genes, and other novel analyses to detect associations between sequence variation and T2D.
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| 2. |
- Fuchsberger, Christian, et al.
(author)
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The genetic architecture of type 2 diabetes
- 2016
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 536:7614, s. 41-47
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Journal article (peer-reviewed)abstract
- The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of the heritability of this disease. Here, to test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole-genome sequencing in 2,657 European individuals with and without diabetes, and exome sequencing in 12,940 individuals from five ancestry groups. To increase statistical power, we expanded the sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support the idea that lower-frequency variants have a major role in predisposition to type 2 diabetes.
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| 6. |
- Milner-Gulland, E. J., et al.
(author)
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Accounting for the Impact of Conservation on Human Well-Being
- 2014
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In: Conservation Biology. - : Wiley. - 0888-8892 .- 1523-1739. ; 28:5, s. 1160-1166
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Journal article (peer-reviewed)abstract
- Conservationists are increasingly engaging with the concept of human well-being to improve the design and evaluation of their interventions. Since the convening of the influential Sarkozy Commission in 2009, development researchers have been refining conceptualizations and frameworks to understand and measure human well-being and are starting to converge on a common understanding of how best to do this. In conservation, the term human well-being is in widespread use, but there is a need for guidance on operationalizing it to measure the impacts of conservation interventions on people. We present a framework for understanding human well-being, which could be particularly useful in conservation. The framework includes 3 conditions; meeting needs, pursuing goals, and experiencing a satisfactory quality of life. We outline some of the complexities involved in evaluating the well-being effects of conservation interventions, with the understanding that well-being varies between people and over time and with the priorities of the evaluator. Key challenges for research into the well-being impacts of conservation interventions include the need to build up a collection of case studies so as to draw out generalizable lessons; harness the potential of modern technology to support well-being research; and contextualize evaluations of conservation impacts on well-being spatially and temporally within the wider landscape of social change. Pathways through the smog of confusion around the term well-being exist, and existing frameworks such as the Well-being in Developing Countries approach can help conservationists negotiate the challenges of operationalizing the concept. Conservationists have the opportunity to benefit from the recent flurry of research in the development field so as to carry out more nuanced and locally relevant evaluations of the effects of their interventions on human well-being. Consideracion del Impacto de la Conservacion sobre el Bienestar Humano
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| 7. |
- Agarwala, Hemlata, et al.
(author)
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Alternating Metal-Ligand Coordination Improves Electrocatalytic CO2 Reduction by a Mononuclear Ru Catalyst**
- 2023
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In: Angewandte Chemie International Edition. - : Wiley. - 1433-7851 .- 1521-3773. ; 62:17
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Journal article (peer-reviewed)abstract
- Molecular electrocatalysts for CO2-to-CO conversion often operate at large overpotentials, due to the large barrier for C−O bond cleavage. Illustrated with ruthenium polypyridyl catalysts, we herein propose a mechanistic route that involves one metal center that acts as both Lewis base and Lewis acid at different stages of the catalytic cycle, by density functional theory in corroboration with experimental FTIR. The nucleophilic character of the Ru center manifests itself in the initial attack on CO2 to form [Ru-CO2]0, while its electrophilic character allows for the formation of a 5-membered metallacyclic intermediate, [Ru-CO2CO2]0,c, by addition of a second CO2 molecule and intramolecular cyclization. The calculated activation barrier for C−O bond cleavage via the metallacycle is decreased by 34.9 kcal mol−1 as compared to the non-cyclic adduct in the two electron reduced state of complex 1. Such metallacyclic intermediates in electrocatalytic CO2 reduction offer a new design feature that can be implemented consciously in future catalyst designs.
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| 8. |
- Agarwala, Hemlata, et al.
(author)
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An Elusive Intermediate Uncovered in the Pathway for Electrochemical Carbon Dioxide Reduction by Ruthenium Polypyridyl Catalyst - Combined Spectroscopic and Computational Investigation
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Other publication (other academic/artistic)abstract
- A scrutinous study of the catalytic cycle for electrochemical CO2 reduction by the ruthenium 2,2:6,2-terpyridine (tpy) 2,2-bipyridine (bpy) class of catalysts is presented. An unprecedented 2-(C,O)-carboxycarboxylatoruthenium(II) metalacyclic intermediate, critical for C-O bond dissociation at low overpotentials, so far precluded from mechanistic considerations of polypyridyl transition metal complex catalysts, is unearthed by infra-red spectroscopy coupled to controlled potential electrolysis in corroboration with density functional theory (DFT) investigations. Thermodynamic and kinetic analyses of the intermediate reveal the important role of the structural flexibility of polypyridyl ligands and fine electronic tunability of the metal center, along with kinetic trans effect, in propelling catalysis at lower overpotentials. The choice of metal center, Ru in the present case, points to the fact that the requirement of an additional Lewis acid to enhance C-O bond dissociation, hence increase the catalytic rate or turnover, can be circumvented.
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- Maison-Blanche, Pierre, et al.
(author)
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An open-label study to investigate the cardiac safety profile of cabazitaxel in patients with advanced solid tumors
- 2014
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In: Cancer Chemotherapy and Pharmacology. - : Springer Science and Business Media LLC. - 0344-5704 .- 1432-0843. ; 73:6, s. 1241-1252
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Journal article (peer-reviewed)abstract
- This study assessed the cardiovascular safety of cabazitaxel, based on thorough evaluation of QT and non-QT variables, and the relationship between pharmacokinetic and pharmacodynamic electrocardiographic (ECG) profiles and the occurrence of Grade a parts per thousand yen3 cardiovascular adverse events. Patients with advanced solid tumors were treated with cabazitaxel 25 mg/m(2) every 3 weeks. Digital ECG recordings were obtained during Cycle 1 over 24 h after dosing. The primary end point was effect of cabazitaxel on QT interval corrected by the Fridericia formula (QTcF). Secondary end points were additional ECG parameters (QT, PR and QRS intervals, and heart rate), plasma pharmacokinetics of cabazitaxel and overall clinical safety. The pharmacodynamic (ECG) population included 94 patients. In 63 patients with a full 24-h ECG evaluation, the maximum upper bound of 90 % confidence interval (CI) for mean QTcF change from baseline was 7.46 ms (mean 4.8 ms), occurring at 1 h 30 min post-infusion. The slope of QTcF change from baseline versus cabazitaxel concentration was slightly negative (-0.012 [95 % CI -0.017; -0.008], equivalent to a 1.2 ms decrease per 100 ng/mL increase in cabazitaxel concentration). For non-QT variables, no effect was noted. No Grade a parts per thousand yen3 cardiac adverse events were observed; Grade a parts per thousand yen3 hypotension and lymphocele occurred in two patients and one patient, respectively. These results suggest that cabazitaxel has no clinically significant cardiovascular adverse effects in patients with advanced solid tumors.
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| 13. |
- Villo, Piret, et al.
(author)
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Electroreductive Deoxygenative C−H and C−C Bond Formation from Non-Derivatized Alcohols Fueled by Anodic Borohydride Oxidation
- 2023
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In: ChemElectroChem. - : Wiley. - 2196-0216. ; 10:22
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Journal article (peer-reviewed)abstract
- Alcohols are one of the most common organic compound classes among natural and synthetic products. Thus, methods for direct removal of C−OH groups without the need for wasteful pre-functionalization are of great synthetic interest to unlock the full synthetic potential of the compound class. Herein, electroreductive C−OH bond activation and subsequent deoxygenative C−H and C−C bond formation of benzylic and propargylic alcohols are demonstrated along with mechanistic insights. Experimental and theoretical studies indicate that the reductive C−OH bond cleavage furnishes an open shell intermediate that undergoes a radical-polar crossover to the corresponding carbanion that subsequently undergoes protonation to furnish alkane products. Furthermore, we demonstrate that the carbanion can be trapped with CO2 to form arylacetic acids. The cathodic transformations are efficiently balanced by the anodic oxidation of sub-stoichiometric borohydride additives, a strategy that serves as a highly attractive alternative to the use of sacrificial metal anodes.
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