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Background: Aldosterone-producing adenoma (APA) is a benign adrenal tumor with autonomous aldosterone production which causes hypertension and excess cardiovascular risk. Protein phosphorylation regulates aldosterone secretion from adrenal cortical cells, but how signaling networks are remodeled in APA remains unknown. Methods: We performed an integrated proteomic and phosphoproteomic profiling of 15 APA and 10 matched nonfunctioning adrenocortical tumors (NFAT) based on the 4-dimensional label-free technique. We further validated our main findings in enlarged APA samples, mice, and adrenocortical cell line. Results: The proteomic and phosphoproteomic profiling of APA and NFAT quantified 5989 proteins and 9011 phosphopeptides. We highlighted differentially expressed and phosphorylated proteins which modulated aldosterone synthesis and secretion from APA. As intracellular calcium is the central signal for aldosterone synthesis, our integrated calcium signaling network implicated wolframin in the control of calcium influx and CYP11B2 (aldosterone synthase) activation in APA (ratio of wolframin expression in APA to NFAT: 6.411, P Conclusions: Wolframin is a regulatory protein in aldosterone hypersecretion. Remodeled calcium transportation and mitochondrial function are involved in wolframin-related aldosterone secretion.

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 (Csub30/sub) was significantly negatively correlated with %EWL (β = -.37, Plt; .001) and %TWL (β = -.28, P = .011). Univariate logistic regression analysis showed that preoperative Csub30/subwas associated with %EWL ≥75% and %TWL ≥35% after LSG. According to multiple logistic regression analysis, patients with a low preoperative Csub30/subhad an 8-fold higher %TWL ≥35% after LSG than those with a high Csub30/sub(odds ratio: 8.41 [95% confidence interval: 1.46-48.58], P = .017). Similarly, patients with a low preoperative Csub30/subhad a 7-fold higher EWL% ≥75% after LSG than patients with a high Csub30/sub(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.

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.

β-Fluorinated amine is highly desirable for biological and pharmaceutical science, because replacing a C-H bond with a C-F bond can change the physical and chemical properties of the parent molecule to a large extent but not significantly alter its overall geometry. Herein, the highly stereoselective nucleophilic monofluoromethylation of imines have been developed. It is proposed that the chelated transition state enables the chiral induction by the dynamic kinetic resolution of the chiral α-fluoro carbanions.

Current guidelines recommend adrenal venous sampling (AVS) to identify unilateral primary aldosteronism (UPA) before offering adrenalectomy. However, AVS is costly and technically challenging, limiting its use to expert centres.To establish a model to predict UPA, and therefore, bypass the need for AVS prior to surgery.The model was developed in a Chinese cohort and validated in an Australian cohort. Previously published prediction models of UPA were also tested.primary aldosteronism patients with a definite subtyping diagnosis based on AVS and/or surgery.Diagnostic value of the model.In the development cohort (268 UPA and 88 bilateral primary aldosteronism), combinations of different levels of low serum potassium (≤3.0 or 3.5 mmol/l), high PAC (≥15-30 ng/dl), low PRC (≤2.5-10 μIU/ml) and presence of unilateral nodule on adrenal CT (8-15 mm in diameter) showed specificity of 1.00 and sensitivity of 0.16-0.52. The model of serum potassium 3.5 mmol/l or less, PAC at least 20 ng/dl, PRC 5 μIU/ml or less plus a unilateral nodule at least 10 mm had the highest sensitivity of 0.52 (0.45-0.58) and specificity of 1.00 (0.96-1.00). In the validation cohort (84 UPA and 117 bilateral primary aldosteronism), the sensitivity and specificity of the model were 0.13 (0.07-0.22) and 1.00 (0.97-1.00), respectively. Ten previous models were tested, and only one had a specificity of 1.00 in our cohorts but with a very low sensitivity [0.07 (0.04-0.10) and 0.01 (0.00-0.06) in our development and validation cohorts, respectively].A combination of high PAC, low PRC, low serum potassium and unilateral adrenal nodule could accurately determine primary aldosteronism subtype in 13-52% of patients with UPA and obviate the need for AVS before surgery.

As a cytoplasmic sensor of double-stranded DNA (dsDNA), the cyclic GMP-AMP synthase–stimulator of IFN genes (STING) pathway plays an important role in antitumor immunity. In this study, we investigated the effect of Src homology-2 domain-containing protein tyrosine phosphatase-2 (SHP2) on tumor cell–intrinsic STING pathway activity and DNA repair in colon cancer. SHP2 interacted with and dephosphorylated PARP1 after DNA damage. PARP1 inhibition by SHP2 resulted in reduced DNA repair and accumulation of dsDNA in cells, thus promoting hyperactivation of the STING pathway. The SHP2 agonist lovastatin was able to enhance SHP2 activity and promote STING pathway activation. Moreover, lovastatin significantly enhanced the efficacy of chemotherapy in colon cancer models, in part via STING pathway-mediated antitumor immunity. These findings suggest that SHP2 exacerbates STING pathway activation by restricting PARP1-mediated DNA repair in tumor cells, providing a basis for the combined use of lovastatin and chemotherapy in the treatment of colon cancer.Significance:Dephosphorylation of PARP1 by SHP2 simultaneously suppresses DNA repair and enhances STING pathway-mediated antitumor immunity, highlighting SHP2 activation as a potential therapeutic approach in colon cancer.

Primers used for qPCR.

Supplementary Figure S1-5.

Wood-derived carbons have been demonstrated to have large specific capacities as the anode materials of lithium-ion batteries (LIBs). However, these carbons generally show low tap density and minor volumetric capacity because of high specific surface area and pore volume. Combination with metal oxide is one of the expected methods to alleviate the obstacles of wood-derived carbons. In this work, the composites of MnO loaded wood-derived carbon fibers (CF@MnO) were prepared via a simple and environmentally friendly method, showing decreased specific surface area due to the generation of MnO nanoparticles on carbon fibers. Furthermore, the CF@MnO compostites exhibit superior electrochemical performance as anode materials of LIBs, which show high reversible capacity in the range of 529–734 mAh/g at a current density of 100 mA/g. The optimal CF@MnO product (MnO:carbon = 1:2) delivers reversible capacity of 734 and 265.3 mAh/g at current density of 100 and 2000 mA/g, respectively. Besides, the material presents outstanding stability with coulombic efficiency around 100% after 200 cycles at a high current density of 400 mA/g, revealing a potential as promising anode materials for high-performance LIBs.

The TMSCF3-derived CuCF2CF3 species has been successfully applied in pentafluoroethylation of organoboronates and terminal alkynes.

A high 5-HMF yield of 85.4% was achieved in polar aprotic oxygen-containing solvent with strong electrophilic maleic acid by quenching DHH.

An efficient trifluoromethylation reaction of vinyldiazoacetates under mild reaction conditions was depicted.

Trifluoromethyl phenyl sulfone is traditionally a nucleophilic trifluoromethylating agent.

Objectives The saline suppression test (SST) serves to confirm the diagnosis of primary aldosteronism (PA), while adrenal vein sampling (AVS) is used to subtype PA as unilateral or bilateral. Criteria that can accurately identify those with bilateral PA based on SST results could reduce the need for AVS. We previously demonstrated that a combination of plasma aldosterone concentration (PAC) < 300 pmol L−1 and a reduction in aldosterone-to-renin ratio (ARR) following recumbent SST had high specificity for predicting bilateral PA in an Australian cohort of 92 patients with PA who have undergone AVS. We sought to validate our predictive criteria in larger, independent cohorts of patients with PA. Design An international, multi-centre cohort study. Methods Data from 55 patients at Monash Health, Victoria, Australia, 106 patients from the First Affiliated Hospital of Chongqing Medical University, China, and 105 patients from Nihon University Itabashi Hospital, Japan were analysed. Results A combination of PAC Conclusion In patients undergoing the recumbent SST, a post-saline PAC

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 difluoromethylene (CF2) insertions lies in the well-defined formation of 2,2-difluoroenolsilyl ether and 2,2,3,3tetrafluorocyclopropanolsilyl 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 have been achieved, which offer a new platform to explore other unknown chemical space.

The selective introduction of perfluoro

Perfluoro-tert-butylation reaction has long remained a challenging task. We now report the use of 1,1-dibromo-2,2-bis(trifluoromethyl)ethylene (DBBF) as a practical reagent for perfluoro-tert-butylation reactions for the first time. Through a consecutive triple-fluorination process with DBBF and CsF, the (CF3 )3 C- species can be liberated and observed, which is able to serve as a robust nucleophilic perfluoro-tert-butylating agent for various electrophiles. The power of this synthetic protocol is evidenced by the efficient synthesis of structurally diverse perfluoro-tert-butylated molecules. Multiple applications demonstrate the practicability of this method, as well as the superiority of perfluoro-tert-butylated compounds as sensitive probes. The perfluoro-tert-butylated product was successfully applied in 1 H- and 19 F-magnetic resonance imaging (MRI) experiment with an ultra-low field (ULF) MRI system.

Metal–organic frameworks (MOFs) have received great attention in environmental remediation application. In particular, one-dimensional (1D) MOF materials have excellent catalytic degradation perfor...

The ring-opening difluoromethylation-halogenation of cyclic (thio)ethers is reported through a simple strategy relying on carbon-chalcogen bond activation with difluorocarbene. The reaction proceeds through in situ protonation of the previously little-known difluoromethylene oxonium or sulfonium ylide intermediate followed by ring-opening with halide ion to afford halogenated acyclic difluoromethyl (thio)ethers that can then be employed for further elaboration. TMSCF2 X (X=Br, Cl) are unique reagents to achieve this synthetic purpose, which serve as both the difluorocarbene source and the halide ion source.