(Cyclopentadienone)iron-Catalyzed Transfer Dehydrogenation of Symmetrical and Unsymmetrical Diols to Lactones

Air-stable iron carbonyl compounds bearing cyclopentadienone ligands with varying substitution were explored as catalysts in dehydrogenative diol lactonization reactions using acetone as both the solvent and hydrogen acceptor. Two catalysts with trimethylsilyl groups in the 2- and 5-positions, [2,5-(SiMe3)2-3,4-(CH2)4(η4-C4C═O)]Fe(CO)3 (1) and [2,5-(SiMe3)2-3,4-(CH2)3(η4-C4C═O)]Fe(CO)3 (2), were found to be the most active, with 2 being the most selective in the lactonization of diols containing both primary and secondary alcohols. Lactones containing five-, six-, and seven-membered rings were successfully synthesized, and no over-oxidations to carboxylic acids were detected. The lactonization of unsymmetrical diols containing two primary alcohols occurred with catalyst 1, but selectivity was low based on alcohol electronics and modest based on alcohol sterics. Evidence for a transfer dehydrogenation mechanism was found, and insight into the origin of selectivity in the lactonization of 1°/2° diols was obtained. Additionally, spectroscopic evidence for a trimethylamine-ligated iron species formed in solution during the reaction was discovered

Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

Purpose: Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. Methods: We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. Results: We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and >= 1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed >= 1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. Conclusion: Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance

De Novo Truncating Variants in ASXL2 Are Associated with a Unique and Recognizable Clinical Phenotype

The ASXL genes (ASXL1, ASXL2, and ASXL3) participate in body patterning during embryogenesis and encode proteins involved in epigenetic regulation and assembly of transcription factors to specific genomic loci. Germline de novo truncating variants in ASXL1 and ASXL3 have been respectively implicated in causing Bohring-Opitz and Bainbridge-Ropers syndromes, which result in overlapping features of severe intellectual disability and dysmorphic features. ASXL2 has not yet been associated with a human Mendelian disorder. In this study, we performed whole-exome sequencing in six unrelated probands with developmental delay, macrocephaly, and dysmorphic features. All six had de novo truncating variants in ASXL2. A careful review enabled the recognition of a specific phenotype consisting of macrocephaly, prominent eyes, arched eyebrows, hypertelorism, a glabellar nevus flammeus, neonatal feeding difficulties, hypotonia, and developmental disabilities. Although overlapping features with Bohring-Opitz and Bainbridge-Ropers syndromes exist, features that distinguish the ASXL2-associated condition from ASXL1- and ASXL3-related disorders are macrocephaly, absence of growth retardation, and more variability in the degree of intellectual disabilities. We were also able to demonstrate with mRNA studies that these variants are likely to exert a dominant-negative effect, given that both alleles are expressed in blood and the mutated ASXL2 transcripts escape nonsense-mediated decay. In conclusion, de novo truncating variants in ASXL2 underlie a neurodevelopmental syndrome with a clinically recognizable phenotype. This report expands the germline disorders that are linked to the ASXL genes

Dissolved organic carbon reduces uranium toxicity to the unicellular eukaryote Euglena gracilis

The influence of dissolved organic carbon (DOC), in the form of Suwannee River fulvic acid (SRFA), on uranium (U) toxicity to the unicellular eukaryote, Euglena gracilis (Z strain), was investigated at pH 6. In a background medium without SRFA, exposure of E. gracilis to 57 μg L U resulted in a 50% reduction in growth (IC50). The addition of 20 mg L DOC (as SRFA), reduced U toxicity 4 to 5-fold (IC increased to 254 μg L U). This reduction in toxicity was also evident at more sensitive effect levels with a 10% reduction in growth (IC ) occurring at 5 μg L U in the background medium and at 17 μg L U in the SRFA medium, respectively. This amelioration of toxicity with the addition of SRFA was linked to a decrease in the bioavailability of U, with geochemical speciation modelling predicting 84% of U would be complexed by SRFA. The decrease in bioavailability of U in the presence of SRFA was also evident from the 11-14 fold reduction in the cellular concentration of U compared to that of E. gracilis in the background medium. Stepwise multiple linear regression analyses indicated that UO alone explained 51% of the variation in measured U toxicity to E. gracilis. Preliminary U exposures to E. gracilis in the presence of a reactive oxygen species probe, suggest exposure to ≥60 μg L U may induce oxidative stress, but this endpoint was not considered to be a sensitive biological indicator

Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial (vol 321, pg 2292, 2019)

status: publishe

Effect of Intraoperative High Positive End-Expiratory Pressure (PEEP) With Recruitment Maneuvers vs Low PEEP on Postoperative Pulmonary Complications in Obese Patients: A Randomized Clinical Trial.

IMPORTANCE An intraoperative higher level of positive end-expiratory positive pressure (PEEP) with alveolar recruitment maneuvers improves respiratory function in obese patients undergoing surgery, but the effect on clinical outcomes is uncertain