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We have developed a new strategy for controllable single and double difluoromethylene (CF2) formal insertions into C−H bonds of aldehydes with nearly full selectivity under transition‐metal‐free conditions. The key to the success of controllable CF2 insertions lies in the well‐defined formation of 2,2‐difluoroenolsilyl ether and 2,2,3,3‐tetrafluorocyclopropanolsilyl ether intermediates using difluorocarbene reagent TMSCF2Br (TMS=trimethylsilyl). These two intermediates can react with various electrophiles including proton sources and various halogenation reagents, allowing for the access to diverse arrays of ketones containing difluoromethylene (CF2) and tetrafluoroethylene (CF2CF2) units. The first synthesis of relatively stable 2,2,3,3‐tetrafluorocyclopropanolsilyl ethers has been achieved, which offers a new platform to explore other unknown chemical space. [ABSTRACT FROM AUTHOR]

The transition‐metal‐catalyzed carbonylation reaction is a useful approach for ketone synthesis. However, it is often problematic to use exogenous carbonyl reagents, such as gaseous carbon monoxide. In this manuscript, we report a novel palladium‐catalyzed coupling reaction of gem‐difluoroalkenes and aryl boronic acids that yields bioactive indane‐type ketones with an all‐carbon α‐quaternary center. Characterization and stoichiometric reactions of the key intermediates RCF2PdII support a water‐induced defluorination and cross‐coupling cascade mechanism. The vinyl difluoromethylene motif serves as an in situ carbonyl precursor which is unprecedented in transition‐metal‐catalyzed coupling reactions. It is expected to raise broad research interest from the perspectives of ketone synthesis, fluoroalkene functionalization, and rational design of new synthetic protocols based on the unique reactivity of difluoroalkyl palladium(II) species. [ABSTRACT FROM AUTHOR]

Abnormally hyperphosphorylated tau can be recognized by a variety of phosphoprotein‐binding domains (PBDs) to elicit downstream tau signaling in neuropathology, which has been found to have a potential association with subarachnoid hemorrhage. In this study, the genome‐wide binding behavior of tau phosphorylation sites (p‐sites) to PBDs involved in subarachnoid hyperphosphorylation events was systematically profiled at molecular level by integrating peptide docking, structural minimization, affinity scoring, and binding assay, from which a number of potent PBD–p‐site interaction pairs were identified. It was revealed that the PBD domains exhibit distinct binding preferences for phosphotyrosine, phosphoserine, and phosphothreonine p‐sites; the PBD‐recognition specificity of different tau p‐sites is not overlapped with each other, and their phosphorylations would therefore regulate varying biological functions in tau signaling. A number of PBD–p‐site pairs were identified to have potent binding potency as compared to others. The KCIP–pS[393–399] pair was found as a strong binder, which was further optimized with a rational peptide design protocol to derive a number of affinity‐improved phosphopeptides. Structural analysis revealed diverse noncovalent chemical forces across the complex interface of KCIP domain with a designed high‐affinity pS[393–399]‐d4, which confers both stability and specificity to the domain–peptide complex system, with affinity improved by 10.9‐fold relative to the native pS[393–399]. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease. Neutrophil extracellular traps (NETs) are a network structure composed of loose chromatin and embedded with multiple proteins. Here, we observed increased NETs deposition in the glomeruli of DKD patients and diabetic mice (streptozotocin-induced or db/db mice). After NETs were degraded with DNase I, diabetic mice exhibited attenuated glomerulopathy and glomerular endothelial cells (GECs) injury. We also observed alleviated glomerulopathy and GECs injury in peptidylarginine deiminase 4-knockout mice with streptozotocin-induced diabetes. In vitro, NETs-induced GECs pyroptosis was characterized by pore formation in the cell membrane, dysregulation of multiple genes involved in cell membrane function, and increased expression of pyroptosis-related proteins. Strengthening the GECs surface charge by oleylamine significantly inhibited NETs-induced GECs pyroptosis. These findings suggest that the GECs charge-related pyroptosis is involved in DKD progression, which is promoted by NETs. [ABSTRACT FROM AUTHOR]

Obesity has become a global problem that poses a serious threat to human health. Laparoscopic sleeve gastrectomy (LSG) is an effective long-term treatment. However, the weight loss of some patients after LSG is still insufficient. It is necessary to investigate the factors associated with inadequate weight loss after LSG. The objective of this study was to explore whether preoperative insulin secretion could be associated with weight loss after LSG in patients with obesity. This is a single-center prospective cohort study conducted in a university hospital. Patients from a prospective database who underwent LSG were analyzed. All 178 participants underwent a 75-g oral glucose tolerance test (OGTT) to assess preoperative insulin and c-peptide secretion before LSG. The areas under the curve (AUCs) for glucose, insulin, and c-peptide were determined in the OGTT. The percentage of excess weight loss (%EWL) and the percentage of total weight loss (%TWL) were used to estimate the effect of weight loss after LSG. Regression models were used to assess the correlation between preoperative insulin and c-peptide secretion with %EWL ≥75% and TWL ≥35% at 12 months after LSG. The AUCs of insulin and c-peptide were significantly lower in the %EWL ≥75% and %TWL ≥35% groups at 0–30 minutes, 0–60 minutes, and 0–120 minutes during the OGTT. At 30, 60, and 120 minutes during the OGTT, c-peptide levels were significantly lower in the %EWL ≥75% group and %TWL ≥35% group. The preoperative c-peptide level at 30 minutes during the OGTT (C 30) was significantly negatively correlated with %EWL (β = −.37, P <.001) and %TWL (β = −.28, P =.011). Univariate logistic regression analysis showed that preoperative C 30 was associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative C 30 had an 8-fold higher %TWL ≥35% after LSG than those with a high C 30 (odds ratio: 8.41 [95% confidence interval: 1.46–48.58], P =.017). Similarly, patients with a low preoperative C 30 had a 7-fold higher EWL% ≥75% after LSG than patients with a high C 30 (odds ratio: 7.25 [95% confidence interval: 1.11–47.50], P =.039). The rate of weight loss after LSG is low among patients with preoperative hyperinsulinemia. The preoperative c-peptide level at 30 minutes during the OGTT is associated with weight loss after LSG. • Early-phase insulin levels are associated with unrelieved obesity. • Hyperinsulinemia might predict inadequate weight loss after laparoscopic sleeve gastrectomy (LSG). • Preoperative C-peptide at 30 minutes after OGTT could be used as an independent predictor of weight loss outcome after LSG. [ABSTRACT FROM AUTHOR]

Trifluoromethyl phenyl sulfone is traditionally a nucleophilic trifluoromethylating agent. Herein, we report the first example of the use of trifluoromethyl phenyl sulfone as a trifluoromethyl radical precursor. Arylthiolate anions can form electron donor–acceptor (EDA) complexes with trifluoromethyl phenyl sulfone, which can undergo an intramolecular single electron transfer (SET) reaction under visible light irradiation, thus realizing the S-trifluoromethylation of thiophenols under photoredox catalyst-free conditions. Similar S-perfluoroethylation and S-perfluoro-iso-propylation of thiophenols are also achieved using the corresponding perfluoroalkyl phenyl sulfones. [ABSTRACT FROM AUTHOR]