| 1. |
- Li, Josephine H., et al.
(author)
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Identification of Genetic Variation Influencing Metformin Response in a Multiancestry Genome-Wide Association Study in the Diabetes Prevention Program (DPP)
- 2023
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In: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 72:8, s. 1161-1172
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Journal article (peer-reviewed)abstract
- Genome-wide significant loci for metformin response in type 2 diabetes reported elsewhere have not been repli-cated in the Diabetes Prevention Program (DPP). To as-sess pharmacogenetic interactions in prediabetes, we conducted a genome-wide association study (GWAS) in the DPP. Cox proportional hazards models tested associations with diabetes incidence in the metformin (MET; n = 876) and placebo (PBO; n = 887) arms. Multiple linear regression assessed association with 1-year change in metformin-related quantitative traits, adjusted for baseline trait, age, sex, and 10 ancestry principal compo-nents. We tested for gene-by-treatment interaction. No significant associations emerged for diabetes inci-dence. We identified four genome-wide significant variants after correcting for correlated traits (P < 9 × 1029). In the MET arm, rs144322333 near ENOSF1 (minor al-lele frequency [MAF]AFR = 0.07; MAFEUR = 0.002) was associated with an increase in percentage of glycated hemoglobin (per minor allele, b = 0.39 [95% CI 0.28, 0.50]; P = 2.8 × 10212). rs145591055 near OMSR (MAF = 0.10 in American Indians) was associated with weight loss (kilograms) (per G allele, b = 27.55 [95% CI 29.88, 25.22]; P = 3.2 × 10210) in the MET arm. Neither variant was significant in PBO; gene-by-treatment interaction was significant for both variants [P(G×T) < 1.0 × 1024 ]. Replication in individuals with diabetes did not yield significant findings. A GWAS for metformin response in prediabetes revealed novel ethnic-specific associations that require further investigation but may have implications for tailored therapy.
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| 2. |
- Weinstock, Joshua S, et al.
(author)
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Aberrant activation of TCL1A promotes stem cell expansion in clonal haematopoiesis.
- 2023
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In: Nature. - 1476-4687. ; 616:7958, s. 755-763
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Journal article (peer-reviewed)abstract
- Mutations in a diverse set of driver genes increase the fitness of haematopoietic stem cells (HSCs), leading to clonal haematopoiesis1. These lesions are precursors for blood cancers2-6, but the basis of their fitness advantage remains largely unknown, partly owing to a paucity of large cohorts in which the clonal expansion rate has been assessed by longitudinal sampling. Here, to circumvent this limitation, we developed a method to infer the expansion rate from data from a single time point. We applied this method to 5,071 people with clonal haematopoiesis. A genome-wide association study revealed that a common inherited polymorphism in the TCL1A promoter was associated with a slower expansion rate in clonal haematopoiesis overall, but the effect varied by driver gene. Those carrying this protective allele exhibited markedly reduced growth rates or prevalence of clones with driver mutations in TET2, ASXL1, SF3B1 and SRSF2, butthis effect was not seen inclones withdriver mutations in DNMT3A. TCL1A was not expressed in normal or DNMT3A-mutated HSCs, but the introduction of mutations in TET2 or ASXL1 led to the expression of TCL1A protein and the expansion of HSCs in vitro. The protective allele restricted TCL1A expression and expansion of mutant HSCs, as did experimentalknockdown of TCL1A expression. Forced expression of TCL1A promoted the expansion of human HSCs in vitro and mouse HSCs in vivo. Our results indicate that the fitness advantage of several commonly mutated driver genes in clonal haematopoiesis may be mediated by TCL1A activation.
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| 3. |
- Zhao, Haiguang, et al.
(author)
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Gram-scale synthesis of carbon quantum dots with a large Stokes shift for the fabrication of eco-friendly and high-efficiency luminescent solar concentrators
- 2021
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In: Energy & Environmental Science. - : Royal Society of Chemistry. - 1754-5692 .- 1754-5706. ; 14:1, s. 396-406
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Journal article (peer-reviewed)abstract
- Luminescent solar concentrators (LSCs) are large-area sunlight collectors coupled to small area solar cells, for efficient solar-to-electricity conversion. The three key points for the successful market penetration of LSCs are: (i) removal of light losses due to reabsorption during light collection; (ii) high light-to-electrical power conversion efficiency of the final device; (iii) long-term stability of the LSC structure related to the stability of both the matrix and the luminophores. Among various types of fluorophores, carbon quantum dots (C-dots) offer a wide absorption spectrum, high quantum yield, non-toxicity, environmental friendliness, low-cost, and eco-friendly synthetic methods. However, they are characterized by a relatively small Stokes shift, compared to inorganic quantum dots, which limits the highest external optical efficiency that can be obtained for a large-area single-layer LSC (>100 cm2) based on C-dots below 2%. Herein, we report highly efficient large-area LSCs (100–225 cm2) based on colloidal C-dots synthesized via a space-confined vacuum-heating approach. This one batch reaction could produce Gram-scale C-dots with a high quantum yield (QY) (∼65%) using eco-friendly citric acid and urea as precursors. Thanks to their very narrow size distribution, the C-dots produced via the space-confined vacuum-heating approach had a large Stokes shift of 0.53 eV, 50% larger than C-dots synthesized via a standard solvothermal reaction using the same precursors with a similar absorption range. The large-area LSC (15 × 15 × 0.5 cm3) prepared by using polyvinyl pyrrolidone (PVP) polymer as a matrix exhibited an external optical efficiency of 2.2% (under natural sun irradiation, 60 mW cm−2, uncharacterized spectrum). After coupling to silicon solar cells, the LSC exhibited a power conversion efficiency (PCE) of 1.13% under natural sunlight illumination (20 mW cm−2, uncharacterized spectrum). These unprecedented results were obtained by completely suppressing the reabsorption losses during light collection, as proved by optical spectroscopy. These findings demonstrate the possibility of obtaining eco-friendly, high-efficiency, large-area LSCs through scalable production techniques, paving the way to the lab-to-fab transition of this kind of devices.
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