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Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
Rapid decline of glomerular filtration rate estimated from creatinine (eGFRcrea) is associated with severe clinical endpoints. In contrast to cross-sectionally assessed eGFRcrea, the genetic basis for rapid eGFRcrea decline is largely unknown. To help define this, we meta-analyzed 42 genome-wide association studies from the Chronic Kidney Diseases Genetics Consortium and United Kingdom Biobank to identify genetic loci for rapid eGFRcrea decline. Two definitions of eGFRcrea decline were used: 3 mL/min/1.73m(2)/year or more ("Rapid3"; encompassing 34,874 cases, 107,090 controls) and eGFRcrea decline 25% or more and eGFRcrea under 60 mL/min/1.73m(2) at follow-up among those with eGFRcrea 60 mL/min/1.73m(2) or more at baseline ("CKDi25"; encompassing 19,901 cases, 175,244 controls). Seven independent variants were identified across six loci for Rapid3 and/or CKDi25: consisting of five variants at four loci with genome-wide significance (near UMOD-PDILT (2), PRKAG2, WDR72, OR2S2) and two variants among 265 known eGFRcrea variants (near GATM, LARP4B). All these loci were novel for Rapid3 and/or CKDi25 and our bioinformatic follow-up prioritized variants and genes underneath these loci. The OR2S2 locus is novel for any eGFRcrea trait including interesting candidates. For the five genome-wide significant lead variants, we found supporting effects for annual change in blood urea nitrogen or cystatin-based eGFR, but not for GATM or (LARP4B). Individuals at high compared to those at low genetic risk (8-14 vs. 0-5 adverse alleles) had a 1.20-fold increased risk of acute kidney injury (95% confidence interval 1.08-1.33). Thus, our identified loci for rapid kidney function decline may help prioritize therapeutic targets and identify mechanisms and individuals at risk for sustained deterioration of kidney function.
The combination of a highly stereoselective tethered olefin metathesis reaction and a Julia-Kocienski olefination is presented as a strategy for the synthesis of conjugated polyenes with at least one Z-configured C=C bond. The strategy is exemplified by the synthesis of the marine natural product (+)-bretonin B.
Prenylated flavanones were obtained from ortho-allyloxy chalcones through a one-pot sequence of Claisen rearrangement and 6-endo-trig cyclization, followed by olefin cross metathesis of the intermediate allyl flavanones with 2-methyl-2-butene. The synthetic utility of this route is illustrated for the synthesis of several naturally occurring prenyl flavanones.
In this communication the development of an online course on the topic organic chemistry for nonmajor chemistry students is described and discussed. For this online course, the existing classroom course was further developed. New elements such as podcasts, task navigators, and a forum for discussing the solving of tasks or problems with the content were added. This new online course was evaluated. Therefore, a questionnaire was developed. This consists of questions with regard to the longtime learning behavior of the students and to the online learning. The results of this evaluation show that a preference for online learning and a preference for classroom teaching can be measured separately in two scales. Students values on the scale representing a preference for online learning correlate positively and significantly with confidence in the choice of the study subject, enthusiasm about the subject, and the ability to organize their learning, learning environment, and time management. They correlate also with the satisfaction concerning the materials provided. Students values for one of those teaching methods also correlate with their rating with regard to their exam preparation. Values representing a preference for online teaching correlate positively with students better feeling of exam preparation. Values representing a preference for classroom teaching show negative correlations with the values representing students similar or even better preparation for the exams as a result of online teaching. It is therefore not surprising that the ratings for the two scales correlate with the wish for a combination of online teaching and classroom teaching in the future. As a solution, a new course concept for the time after the corona virus crisis that suits all students is outlined in the outlook.
Total syntheses of prenylated isoflavones from Erythrina sacleuxii and their antibacterial activity
(2020)
The prenylated isoflavones 5-deoxyprenylbiochanin A (7-hydroxy-4'-methoxy-3'-prenylisoflavone) and erysubin F (7,4'-dihydroxy-8,3'-diprenylisoflavone) were synthesized for the first time, starting from mono-or di-O-allylated chalcones, and the structure of 5-deoxy-3'-prenylbiochanin A was corroborated by single-crystal X-ray diffraction analysis. Flavanones are key intermediates in the synthesis. Their reaction with hypervalent iodine reagents affords isoflavones via a 2,3-oxidative rearrangement and the corresponding flavone isomers via 2,3-dehydrogenation. This enabled a synthesis of 7,4'-dihydroxy-8,3'-diprenylflavone, a non-natural regioisomer of erysubin F. Erysubin F (8), 7,4'-dihydroxy-8,3'-diprenylflavone (27), and 5-deoxy-3'prenylbiochanin A (7) were tested against three bacterial strains and one fungal pathogen. All three compounds are inactive against Salmonella enterica subsp. enterica (NCTC 13349), Escherichia coli (ATCC 25922), and Candida albicans (ATCC 90028), with MIC values greater than 80.0 mu M. The diprenylated natural product erysubin F (8) and its flavone isomer 7,4'-dihydroxy-8,3'diprenylflavone (27) show in vitro activity against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300) at MIC values of 15.4 and 20.5 mu M, respectively. In contrast, the monoprenylated 5-deoxy-3'-prenylbiochanin A (7) is inactive against this MRSA strain.
The Quaternary volcanic fields of the Eifel (Rhineland-Palatinate, Germany) had their last eruptions less than 13,000 years ago. Recently, deep low-frequency (DLF) earthquakes were detected beneath one of the volcanic fields showing evidence of ongoing magmatic activity in the lower crust and upper mantle. In this work, seismic wide- and steep-angle experiments from 1978/1979 and 1987/1988 are compiled, partially reprocessed and interpreted, together with other data to better determine the location, size, shape, and state of magmatic reservoirs in the Eifel region near the crust-mantle boundary. We discuss seismic evidence for a low-velocity gradient layer from 30-36 km depth, which has developed over a large region under all Quaternary volcanic fields of the Rhenish Massif and can be explained by the presence of partial melts. We show that the DLF earthquakes connect the postulated upper mantle reservoir with the upper crust at a depth of about 8 km, directly below one of the youngest phonolitic volcanic centers in the Eifel, where CO(2)originating from the mantle is massively outgassing. A bright spot in the West Eifel between 6 and 10 km depth represents a Tertiary magma reservoir and is seen as a model for a differentiated reservoir beneath the young phonolitic center today. We find that the distribution of volcanic fields is controlled by the Variscan lithospheric structures and terrane boundaries as a whole, which is reflected by an offset of the Moho depth, a wedge-shaped transparent zone in the lower crust and the system of thrusts over about 120 km length.