Frogs (Anura) are one of the most diverse groups of vertebrates and comprise nearly 90% of living amphibian species. Their worldwide distribution and diverse biology make them well-suited for ...assessing fundamental questions in evolution, ecology, and conservation. However, despite their scientific importance, the evolutionary history and tempo of frog diversification remain poorly understood. By using a molecular dataset of unprecedented size, including 88-kb characters from 95 nuclear genes of 156 frog species, in conjunction with 20 fossil-based calibrations, our analyses result in the most strongly supported phylogeny of all major frog lineages and provide a timescale of frog evolution that suggests much younger divergence times than suggested by earlier studies. Unexpectedly, our divergence-time analyses show that three species-rich clades (Hyloidea, Microhylidae, and Natatanura), which together comprise ∼88% of extant anuran species, simultaneously underwent rapid diversification at the Cretaceous–Paleogene (K–Pg) boundary (KPB). Moreover, anuran families and subfamilies containing arboreal species originated near or after the KPB. These results suggest that the K–Pg mass extinction may have triggered explosive radiations of frogs by creating new ecological opportunities. This phylogeny also reveals relationships such as Microhylidae being sister to all other ranoid frogs and African continental lineages of Natatanura forming a clade that is sister to a clade of Eurasian, Indian, Melanesian, and Malagasy lineages. Biogeographical analyses suggest that the ancestral area of modern frogs was Africa, and their current distribution is largely associated with the breakup of Pangaea and subsequent Gondwanan fragmentation.
The dynamic properties of mitochondria-including their fusion, fission, and degradation-are critical for their optimal function in energy generation. The interplay of fusion and fission confers ...widespread benefits on mitochondria, including efficient transport, increased homogenization of the mitochondrial population, and efficient oxidative phosphorylation. These benefits arise through control of morphology, content exchange, equitable inheritance of mitochondria, maintenance of high-quality mitochondrial DNA, and segregation of damaged mitochondria for degradation. The key components of the machinery mediating mitochondrial fusion and fission belong to the dynamin family of GTPases that utilize GTP hydrolysis to drive mechanical work on biological membranes. Defects in this machinery cause a range of diseases that especially affect the nervous system. In addition, several common diseases, including neurodegenerative diseases and cancer, strongly affect mitochondrial dynamics.
Dapagliflozin in Patients with Chronic Kidney Disease Heerspink, Hiddo J L; Stefánsson, Bergur V; Correa-Rotter, Ricardo ...
New England journal of medicine/The New England journal of medicine,
10/2020, Volume:
383, Issue:
15
Journal Article
Peer reviewed
Open access
Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 ...diabetes, is not known.
We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m
of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.
The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval CI, 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 95% CI, 15 to 27). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.
Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).
In the Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized, placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin ...significantly reduced risk of kidney failure and prolonged survival in patients with CKD with or without type 2 diabetes.
Adults with eGFR of 25-75 ml/min per 1.73 m
and urinary albumin-to-creatinine ratio of 200-5000 mg/g had been randomized to receive dapagliflozin 10 mg/d or placebo. Here, we conducted a prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR,30 ml/min per 1.73 m
) at baseline. The primary end point was a composite of time to ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Secondary end points were a kidney composite (same as the primary end point but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death.
A total of 293 participants with stage 4 CKD received dapagliflozin and 331 received placebo. Patients with stage 4 CKD randomized to dapagliflozin experienced a 27% (95% confidence interval 95% CI: -2 to 47%) reduction in the primary composite endpoint, and 29% (-2 to 51%), 17% (-53 to 55%), and 32% (-21 to 61%) reductions in the kidney, cardiovascular and mortality endpoints, respectively, relative to placebo. Interaction P-values were 0.22, 0.13, 0.63, and 0.95, respectively, comparing CKD stages 4 versus 2/3. The eGFR slope declined by 2.15 and 3.38 ml/min per 1.73 m
per year in the dapagliflozin and placebo groups, respectively (
=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest.
Among patients with stage 4 CKD and albuminuria, the effects of dapagliflozin were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.
The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient ...generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.
Suzuki-Miyaura cross-coupling reactions of heteroaryl polyhalides with aryl boronates are surveyed. Drawing on data from literature sources as well as bespoke searches of Pfizer's global chemistry ...RKB and CAS Scifinder® databases, the factors that determine the site-selectivity of these reactions are discussed with a view to rationalising the trends found.
This handbook looks to provide academics and students with a comprehensive and holistic understanding of the phenomenon of innovation. Innovation spans a number of fields within the social sciences ...and humanities: Management, Economics, Geography, Sociology, Politics, Psychology, and History. Consequently, the rapidly increasing body of literature on innovation is characterized by a multitude of perspectives based on, or cutting across, existing disciplines and specializations. Scholars of innovation can come from such diverse starting points that much of this literature can be missed, and so constructive dialogues missed. The editors of The Oxford Handbook of Innovation have carefully selected and designed twenty-one contributions from leading academic experts within their particular field, each focusing on a specific aspect of innovation. These have been organized into four main sections, the first of which looks at the creation of innovations, with particular focus on firms and networks. Section Two provides an account of the wider systematic setting influencing innovation and the role of institutions and organizations in this context. Section Three explores some of the diversity in the working of innovation over time and across different sectors of the economy, and Section Four focuses on the consequences of innovation with respect to economic growth, international competitiveness, and employment. An introductory overview, concluding remarks, and guide to further reading for each chapter, make this handbook a key introduction and vital reference work for researchers, academics, and advanced students of innovation. Available in OSO: http://www.oxfordhandbooks.com/oso/public/content/oho_business/9780199286805/toc.html Contributors to this volume - Jan Fagerberg, University of Oslo William Lazonick, INSEAD Walter W. Powell, Stanford University Keith Pavitt, SPRU Alice Lam, Brunel University Keith Smith, INTECH Charles Edquist, Linkoping David Mowery, University of California, Berkeley Mary O'Sullivan, INSEAD Ove Granstrand, Chalmers Bjorn Asheim, University of Lund Rajneesh Narula, Copenhagen Business School Antonello Zanfei, Urbino Kristine Bruland, University of Oslo Franco Malerba, University of Bocconi Nick Von Tunzelmann, SPRU Ian Miles, University of Manchester Bronwyn Hall, University of California, Berkeley Bart Verspagen , ECIS Francisco Louca, ISEG Manuel M. Godinho, ISEG Richard R. Nelson, Mario Pianta, Urbino Bengt-Ake Lundvall, Aalborg
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