| 1. |
- Ruilope, LM, et al.
(författare)
-
Design and Baseline Characteristics of the Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease Trial
- 2019
-
Ingår i: American journal of nephrology. - : S. Karger AG. - 1421-9670 .- 0250-8095. ; 50:5, s. 345-356
-
Tidskriftsartikel (refereegranskat)abstract
- <b><i>Background:</i></b> Among people with diabetes, those with kidney disease have exceptionally high rates of cardiovascular (CV) morbidity and mortality and progression of their underlying kidney disease. Finerenone is a novel, nonsteroidal, selective mineralocorticoid receptor antagonist that has shown to reduce albuminuria in type 2 diabetes (T2D) patients with chronic kidney disease (CKD) while revealing only a low risk of hyperkalemia. However, the effect of finerenone on CV and renal outcomes has not yet been investigated in long-term trials. <b><i>Patients and</i></b> <b><i>Methods:</i></b> The Finerenone in Reducing CV Mortality and Morbidity in Diabetic Kidney Disease (FIGARO-DKD) trial aims to assess the efficacy and safety of finerenone compared to placebo at reducing clinically important CV and renal outcomes in T2D patients with CKD. FIGARO-DKD is a randomized, double-blind, placebo-controlled, parallel-group, event-driven trial running in 47 countries with an expected duration of approximately 6 years. FIGARO-DKD randomized 7,437 patients with an estimated glomerular filtration rate ≥25 mL/min/1.73 m<sup>2</sup> and albuminuria (urinary albumin-to-creatinine ratio ≥30 to ≤5,000 mg/g). The study has at least 90% power to detect a 20% reduction in the risk of the primary outcome (overall two-sided significance level α = 0.05), the composite of time to first occurrence of CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure. <b><i>Conclusions:</i></b> FIGARO-DKD will determine whether an optimally treated cohort of T2D patients with CKD at high risk of CV and renal events will experience cardiorenal benefits with the addition of finerenone to their treatment regimen. Trial Registration: EudraCT number: 2015-000950-39; ClinicalTrials.gov identifier: NCT02545049.
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
- Guédron, S., et al.
(författare)
-
Reconstructing two millennia of copper and silver metallurgy in the Lake Titicaca region (Bolivia/Peru) using trace metals and lead isotopic composition
- 2021
-
Ingår i: Anthropocene. - : Elsevier. - 2213-3054. ; 34
-
Tidskriftsartikel (refereegranskat)abstract
- Copper, silver, and gold exploitation has been a foundation of economic and socio-cultural development of Andean societies, at least for the last three millennia. The main centers of pre-colonial metallurgy are well-known from archeological artifacts, but temporal gaps inherent in this record handicap a finer understanding of the modalities of ore exploitation by succeeding civilizations. A continuous record over time of trace metals emitted during ore smelting operations make lake sediments excellent candidates to fill those gaps. Two millennia of metallurgy were reconstructed from atmospherically derived metals together with lead (Pb) isotope ratios in two dated sediment cores from Lake Titicaca. The first evidence for metallurgy is found during the apogee of the Tiwanaku state (AD 800–1150), with a higher copper (Cu) accumulation that can be attributed to the smelting of local Cu ores, based on Pb isotopic fingerprinting. During the Late Intermediate Period (AD 1150–1450), recorded peaks in metal deposition that persisted for ∼ twenty years show that mining activities were intensive but discontinuous. Pb isotope ratios suggest diversified extractive activities, mainly located in the southern part of the central Altiplano. Finally, the most intense mining epoch began during the Inca Empire (ca. AD 1500) and lasted until the end of the Colonial Period (AD 1830), with unprecedented metal deposition over this interval. Pb isotope fingerprinting shows that mining operations occurred mainly in the Lake Titicaca and Potosi areas and were responsible for metal emissions recorded in the entire Altiplano, as evidenced by other studies.
|
|
| 6. |
- Barré, Benjamin P., et al.
(författare)
-
Intragenic repeat expansion in the cell wall protein gene HPF1 controls yeast chronological aging
- 2020
-
Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1088-9051 .- 1549-5469. ; 30:5, s. 697-710
-
Tidskriftsartikel (refereegranskat)abstract
- Aging varies among individuals due to both genetics and environment, but the underlying molecular mechanisms remain largely unknown. Using a highly recombined Saccharomyces cerevisiae population, we found 30 distinct quantitative trait loci (QTLs) that control chronological life span (CLS) in calorie-rich and calorie-restricted environments and under rapamycin exposure. Calorie restriction and rapamycin extended life span in virtually all genotypes but through different genetic variants. We tracked the two major QTLs to the cell wall glycoprotein genes FLO11 and HPF1. We found that massive expansion of intragenic tandem repeats within the N-terminal domain of HPF1 was sufficient to cause pronounced life span shortening. Life span impairment by HPF1 was buffered by rapamycin but not by calorie restriction. The HPF1 repeat expansion shifted yeast cells from a sedentary to a buoyant state, thereby increasing their exposure to surrounding oxygen. The higher oxygenation altered methionine, lipid, and purine metabolism, and inhibited quiescence, which explains the life span shortening. We conclude that fast-evolving intragenic repeat expansions can fundamentally change the relationship between cells and their environment with profound effects on cellular lifestyle and longevity.
|
|
| 7. |
- De Chiara, Matteo, et al.
(författare)
-
Domestication reprogrammed the budding yeast life cycle
- 2022
-
Ingår i: Nature Ecology & Evolution. - : Springer Science and Business Media LLC. - 2397-334X .- 2397-334X. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Domestication of plants and animals is the foundation for feeding the world human population but can profoundly alter the biology of the domesticated species. Here we investigated the effect of domestication on one of our prime model organisms, the yeast Saccharomyces cerevisiae, at a species-wide level. We tracked the capacity for sexual and asexual reproduction and the chronological life span across a global collection of 1,011 genome-sequenced yeast isolates and found a remarkable dichotomy between domesticated and wild strains. Domestication had systematically enhanced fermentative and reduced respiratory asexual growth, altered the tolerance to many stresses and abolished or impaired the sexual life cycle. The chronological life span remained largely unaffected by domestication and was instead dictated by clade-specific evolution. We traced the genetic origins of the yeast domestication syndrome using genome-wide association analysis and genetic engineering and disclosed causative effects of aneuploidy, gene presence/absence variations, copy number variations and single-nucleotide polymorphisms. Overall, we propose domestication to be the most dramatic event in budding yeast evolution, raising questions about how much domestication has distorted our understanding of the natural biology of this key model species.
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Li, Jing, et al.
(författare)
-
Shared Molecular Targets Confer Resistance over Short and Long Evolutionary Timescales
- 2019
-
Ingår i: Molecular Biology and Evolution. - : Oxford University Press (OUP). - 1537-1719 .- 0737-4038. ; 36:4, s. 691-708
-
Tidskriftsartikel (refereegranskat)abstract
- Pre-existing and de novo genetic variants can both drive adaptation to environmental changes, but their relative contributions and interplay remain poorly understood. Here we investigated the evolutionary dynamics in drug-treated yeast populations with different levels of pre-existing variation by experimental evolution coupled with time-resolved sequencing and phenotyping. We found a doubling of pre-existing variation alone boosts the adaptation by 64.1% and 51.5% in hydroxyurea and rapamycin, respectively. The causative pre-existing and de novo variants were selected on shared targets: RNR4 in hydroxyurea and TOR1, TOR2 in rapamycin. Interestingly, the pre-existing and de novo TOR variants map to different functional domains and act via distinct mechanisms. The pre-existing TOR variants from two domesticated strains exhibited opposite rapamycin resistance effects, reflecting lineage-specific functional divergence. This study provides a dynamic view on how pre-existing and de novo variants interactively drive adaptation and deepens our understanding of clonally evolving populations.
|
|
