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Background Liver hepatocellular carcinoma (LIHC) ranks sixth among the most common types of cancer with a high mortality rate. Cuproptosis is a newly discovered type of cell death in tumor, which is characterized by accumulation of intracellular copper leading to the aggregation of mitochondrial lipoproteins and destabilization of proteins. Thus, understanding the exact effects of cuproptosis-related genes in LIHC and determining their prognosticvalue is critical. However, the prognostic model of LIHC based on cuproptosis-related genes has not been reported. Methods Firstly, we downloaded transcriptome data and clinical information of LIHC patients from TCGA and GEO (GSE76427), respectively. We then extracted the expression of cuproptosis-related genes and established a prognostic model by lasso cox regression analysis. Afterwards, the prediction performance of the model was evaluated by Kaplan–Meier survival analysis and receiver operating characteristic curve (ROC). Then, the prognostic model and the expression levels of the three genes were validated using the dataset from GEO. Subsequently, we divided LIHC patients into two subtypes by non-negative matrix factorization (NMF) classification and performed survival analysis. We constructed a Sankey plot linking different subtypes and prognostic models. Next, we calculate the drug sensitivity of each sample from patients in the high-risk group and low-risk group by the R package pRRophetic. Finally, we verified the function of LIPT1 in LIHC. Results Using lasso cox regression analysis, we developed a prognostic risk model based on three cuproptosis-related genes (GCSH, LIPT1 and CDKN2A). Both in the training and in the test sets, the overall survival (OS) of LIHC patients in the low-risk group was significantly longer than that in the high-risk group. By performing NMF cluster, we identified two molecular subtypes of LIHC (C1 and C2), with C1 subtype having significantly longer OS and PFS than C2 subtype. The ROC analysis indicated that our model had a precisely predictive capacity for patients with LIHC. The multivariate Cox regression analysis indicated that the risk score is an independent predictor. Subsequently, we identified 71 compounds with IC50 values that differed between the high-risk and low-risk groups. Finally, we determined that knockdown of LIPT1 gene expression inhibited proliferation and invasion of hepatoma cells. Conclusion In this study, we developed a novel prognostic model for hepatocellular carcinoma based on cuproptosis-related genes that can effectively predict the prognosis of LIHC patients. The model may be helpful for clinicians to make clinical decisions for patients with LIHC and provide valuable insights for individualized treatment. Two distinct subtypes of LIHC were identified based on cuproptosis-related genes, with different prognosis and immune characteristics. In addition, we verified that LIPT1 may promote proliferation, invasion and migration of LIHC cells. LIPT1 might be a new potential target for therapy of LIHC.

Sterically congested C–O and C–N bonds are ubiquitous in natural products, pharmaceuticals, and bioactive compounds. However, the development of a general method for the efficient construction of those sterically demanding covalent bonds still remains a formidable challenge. Herein, a photoredox-driven ring-opening C( sp 3 )–heteroatom bond formation of arylcyclopropanes is presented, which enables the construction of structurally diversified while sterically congested dialkyl ether, alkyl ester, alcohol, amine, chloride/fluoride, azide and also thiocyanate derivatives. The selective single electron oxidation of aryl motif associated with the thermodynamic driving force from ring strain-release is the key for this transformation. By this synergistic activation mode, C–C bond cleavage of otherwise inert cyclopropane framework is successfully unlocked. Further mechanistic and computational studies disclose a complete stereoinversion upon nucleophilic attack, thus proving a concerted S N 2-type ring-opening functionalization manifold, while the regioselectivity is subjected to an orbital control scenario. The development of new methodologies for the construction of C( sp 3 )–heteroatom bonds under mild conditions is desirable. Here the authors report the formation of C( sp 3 )–heteroatom bonds via ring opening of arylcyclopropanes enabled by photoredox catalysis.

Full-dose prednisone (FP) regimen in the treatment of high-risk immunoglobulin A nephropathy (IgAN) patients, is still controversial. The pulsed intravenous methylprednisolone combined with alternative low-dose prednisone (MCALP) might have a more favorable safety profile, which has not been fully investigated. Eighty-seven biopsy-proven IgAN adult patients and proteinuria between 1 and 3.5 g/24 h after ACEI/ARB for at least 90 days were randomly assigned to 6-month therapy: (1) MCALP group: 0.5 g of methylprednisolone intravenously for three consecutive days at the beginning of the course and 3rd month respectively, oral prednisone at a dose of 15 mg every other day for 6 months. (2) FP group: 0.8–1.0 mg/kg/days of prednisone (maximum 70 mg/day) for 2 months, then tapered by 5 mg every 10 days for the next 4 months. All patients were followed up for another 12 months. The primary outcome was complete remission (CR) of proteinuria at 12 months. The percentage of CR at 12th and 18th month were similar in the MCALP and FP groups (51% vs 58%, P  = 0.490, at 12th month; 60% vs 56%, P  = 0.714, at 18th month). The cumulative dosages of glucocorticoid were less in the MCALP group than FP group (4.31 ± 0.26 g vs 7.34 ± 1.21 g, P  < 0.001). The analysis of the correlation between kidney biopsy Oxford MEST-C scores with clinical outcomes indicated the percentages of total remission was similar between two groups with or without M1, E1, S1, T1/T2, and C1/C2. More patients in the FP group presented infections (8% in MCALP vs 21% in FP), weight gain (4% in MCALP vs 19% in FP) and Cushing syndrome (3% in MCALP vs 18% in FP). These data indicated that MCALP maybe one of the choices for IgAN patients with a high risk for progression into ESKD. Trial registration: The study approved by the Chinese Clinical Trial Registry (registration date 13/01/2018, approval number ChiCTR1800014442, https://www.chictr.org.cn/ ).

Anilines and phenols are recognized as challenging organic pollutants in industrial wastewater. Herein, the coupled treatment of aniline and phenol in water was achieved through electrochemical oxidation-induced copolymerization. After the electrolysis (1,300 mA for 10 h) in the solution of aniline and phenol (200 mL, each at a concentration of 5 g/L), the organic compounds were efficiently precipitated from their mixed solution by copolymerization. These insoluble copolymers could be easily separated by filtration and collected as brown powders, and the average removal rate of aniline and phenol was calculated as 0.6 mol/h m2 in this coupled electrolysis. The chemical oxygen demand (COD) test of the filtrates showed that it reached up to 98% of the COD removal ratio. Moreover, mixed solutions containing multiple aniline and phenol derivatives were also applicable for this coupled treatment strategy, and they were efficiently removed together after electrolysis.

Chemoselective functionalization of hetero- gem -dimetalloid represents an attractive strategy in terms of diversity-oriented synthesis. In particular, desilylative functionalization of gem- silylboronate esters remains a challenging task and existing solutions heavily relied on ionic reactions. Herein, we report a desilylative functionalization of allylic gem -silylboronate esters with aldehydes under synergistic photoredox and chromium(II) catalysis. With different substrates, both α- and γ-functionalization are realized with exclusive regioselectivity and diastereoselectivity, which is dictated by the chair-like transition state of predominant isomer of Cr III allyl intermediate. Moreover, γ-functionalization products bearing CF 2 unit are acquired when gem -difluoroalkene-containing substrates are employed. In the presence of chiral ligand, enantioselective allylation of aldehydes is successfully accomplished, affording alkenylated 1,2-diols after oxidative workup with excellent regio-, diastereo- and enantioselectivity. The current protocol displays wide substrate generality and broad functional group compatibility. In addition, diverse post-transformations converted obtained products into a variety of valuable structures. Chemoselective functionalization of hetero- gem -dimetalloid represents an attractive strategy in terms of diversity-oriented synthesis. Here, the authors report a desilylative functionalization of allylic gem -silylboronate esters with aldehydes under synergistic photoredox and chromium(II) catalysis.

AbstractHyperglycemia-induced oxidative stress in podocytes exerts a major role in the pathological process of diabetic nephropathy. Tripartite motif-containing protein 32 (TRIM32) has been reported to be a key protein in the modulation of cellular apoptosis and oxidative stress under various pathological processes. However, whether TRIM32 participates in the regulation of high glucose (HG)-induced injury in podocytes has not been investigated. This work aimed to assess the possible role of TRIM32 in mediating HG-induced apoptosis, oxidative stress, and inflammatory response in podocytes in vitro. Our results showed a marked increase in TRIM32 expression in HG-exposed podocytes and the glomeruli of diabetic mice. Loss-of-function experiments showed that TRIM32 knockdown improves the viability of HG-stimulated podocytes and suppresses HG-induced apoptosis, oxidative stress, and inflammatory responses in podocytes. Further investigation revealed that TRIM32 inhibition enhances the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which is associated with the modulation of the Akt/glycogen synthase kinase-3β (GSK-3β) axis in podocytes following HG exposure. However, Akt suppression abrogated the TRIM32 knockdown-mediated activation of Nrf2 in HG-exposed podocytes. Nrf2 knockdown also markedly abolished the protective effects induced by TRIM32 inhibition o in HG-exposed podocytes. In summary, this work demonstrated that TRIM32 inhibition protects podocytes from HG-induced injury by potentiating Nrf2 signaling through modulation of Akt/GSK-3β signaling. The findings reveal the potential role of TRIM32 in mediating podocyte injury during the progression of diabetic nephropathy.

The treatment of adult minimal change disease (MCD) is challenging due to the side effects of high-dose and long-term glucocorticoid therapy as well as the frequent relapsing of the disease. Clinically, there is a demand for regimens that ensure rapid response and lower relapse rates, such as calcineurin inhibitors could fulfill this role. This study aims to compare the efficacy and safety of tacrolimus combined with low-dose glucocorticoids high-dose glucocorticoids in the treatment of newly diagnosed adult MCD. A retrospective cohort study was conducted on 59 adult patients diagnosed with MCD renal biopsy at the Second Affiliated Hospital of Xi'an Jiaotong University, China. Patients were divided into two groups: the high-dose glucocorticoids group (GCs group, 39 patients, receiving 1 mg/kg/day prednisone) and the tacrolimus combined with low-dose glucocorticoid group (TAC group, 20 patients, receiving 0.05 mg/kg/day tacrolimus plus 10 mg/day prednisone). Both groups were followed for at least 24 weeks. The primary endpoint was the complete remission rate at 24 weeks, with secondary endpoints including relapse rates. And adverse events was analysed. At 24 weeks, the complete remission rates (90% . 100%, = 0.111) and cumulative relapse rates (5% . 25.6%, = 0.054) were comparable between the TAC and GCs groups. Patients receiving high-dose glucocorticoids were more likely to show incurred higher Cushingoid features (41% . 5%, = 0.004). Patients in the tacrolimus group had a higher risk of transient serum creatinine elevation (10% . 0%, = 0.045), resolving spontaneously. Longitudinal albumin recovery and estimated glomerular filtration rate (eGFR) stability were similar between groups. Tacrolimus combined with low-dose glucocorticoids demonstrates comparable efficacy to high-dose glucocorticoids in inducing remission for adult-onset MCD, with a more favorable safety profile.

With the extensive application of radiotherapy in various cancers, its side effects in tissues adjacent to cancers are garnering much attention. Intestines are sensitive to irradiation due to its rapid proliferation, and irradiation-induced enteric inflammation is common in patients with pelvic peritoneal tumors. Sirt1, class III protein deacetylase, could lead to transcriptional repression of various inflammation-associated genes, and our previous study has proved its relationship with interleukin (IL)-1β. Here we show that resveratrol, the activator of Sirt1, could alleviate the bowel inflammation induced by irradiation and the expression of Sirt1 is consistent with the inflammation level. We further identified in vivo that Sirt1 repress the expression of IL-1β by the repression of NLR Family, Pyrin Domain Containing protein 3 (NLRP3) expression. In conclusion, this study confirms resveratrol acts against radiation-induced inflammatory bowel disease via NLRP-3 inflammasome repression in mice and supports Sirt1 as a potential biomarker and therapy target in intestinal radiation protection.

Velocity map imaging (VMI) spectrometry is widely used to measure the momentum distribution of charged particles with the kinetic energy of a few tens of electronVolts. With the progress of femtosecond laser and X-ray free-electron laser, it becomes increasingly important to extend the electron kinetic energy to 1 keV. Here, we report on a recently built composite VMI spectrometer at the Shanghai soft X-ray free-electron laser, which can measure ion images and high-energy electron images simultaneously. In the SIMION simulation, we extended the electron kinetic energy to 1 keV with a resolution <2% while measuring the ions with the kinetic energy of 20 eV. The experimental performance is tested by measuring Ar 2p photoelectron spectra at Shanghai Synchrotron Radiation Facility, and O+ kinetic energy spectrum from dissociative ionization of O2 by 800 nm femtosecond laser. We reached a resolution of 1.5% at the electron kinetic energy of 500 eV. When the electron arm is set for 100 eV, a resolution of 4% is reached at the ion kinetic energy of 5.6 eV. This composite VMI spectrometer will support the experiment, such as X-ray multi-photon excitation/ionization, Auger electrons emission, attosecond streaking.