Affinity selection of double-click triazole libraries for rapid discovery of allosteric modulators for GLP-1 receptor.

The recently developed double-click reaction sequence [G. Meng et al., Nature 574, 86-89 (2019)] is expected to vastly expand the number and diversity of synthetically accessible 1,2,3-triazole derivatives. However, it remains elusive how to rapidly navigate the extensive chemical space created by double-click chemistry for bioactive compound discovery. In this study, we selected a particularly challenging drug target, the glucagon-like-peptide-1 receptor (GLP-1R), to benchmark our new platform for the design, synthesis, and screening of double-click triazole libraries. First, we achieved a streamlined synthesis of customized triazole libraries on an unprecedented scale (composed of 38,400 new compounds). By interfacing affinity-selection mass spectrometry and functional assays, we identified a series of positive allosteric modulators (PAMs) with unreported scaffolds that can selectively and robustly enhance the signaling activity of the endogenous GLP-1(9-36) peptide. Intriguingly, we further revealed an unexpected binding mode of new PAMs which likely act as a molecular glue between the receptor and the peptide agonist. We anticipate the merger of double-click library synthesis with the hybrid screening platform allows for efficient and economic discovery of drug candidates or chemical probes for various therapeutic targets.

13-Oxyingenol-dodecanoate inhibits the growth of non-small cell lung cancer cells by targeting ULK1.

Lung cancer is the leading cause of cancer deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all lung cancers. Euphorbia kansui yielded 13-oxyingenol-dodecanoate (13OD), an ingenane-type diterpenoid, which had a strong cytotoxic effect on NSCLC cells. The underlying mechanism and potential target, however, remained unknown. The study found that 13OD effectively inhibited the cell proliferation and colony formation of NSCLC cells (A549 and H460 cells), with less toxicity in normal human lung epithelial BEAS-2B cells. Moreover, 13OD can cause mitochondrial dysfunction, and apoptosis in NSCLC cells. Mechanistically, the transcriptomics results showed that differential genes were mainly enriched in the mTOR and AMPK signaling pathways, which are closely related to cellular autophagy, the related indicators were subsequently validated. Additionally, bafilomycin A1 (Baf A1), an autophagy inhibitor, reversed the mitochondrial damage caused by 13OD. Furthermore, the Omics and Text-based Target Enrichment and Ranking (OTTER) method predicted ULK1 as a potential target of 13OD against NSCLC cells. This hypothesis was further confirmed using molecular docking, the cellular thermal shift assay (CETSA), and Western blot analysis. Remarkably, ULK1 siRNA inhibited 13OD's toxic activity in NSCLC cells. In line with these findings, 13OD was potent and non-toxic in the tumor xenograft model. Our findings suggested a possible mechanism for 13OD's role as a tumor suppressor and laid the groundwork for identifying targets for ingenane-type diterpenoids.

Exploring the mechanism of daphne-type diterpenes against gastric cancer cells.

Gastric cancer is one of the common malignant tumors. It is reported that daphne-type diterpenes have inhibitory effects on gastric cancer cells, but the mechanism is still unknown. To explore the detailed mechanism of the anticancer effect of daphne-type diterpenes, we carried out an integrated network pharmacology prediction study and selected an effective component (yuanhuacine, YHC) for the following validation in silico and in vitro. The result showed that daphne-type diterpenes exerted an anti-tumor effect by targeting proto-oncogene tyrosine-protein kinase SRC as well as regulating the Ras/MAPK signaling pathway, which caused the apoptosis and mitochondrial damage in gastric cancer cells.

Dietary supplementation of water extract of Eucommia ulmoides bark improved caecal microbiota and parameters of health in white-feathered broilers.

Eucommia ulmoides has been used as a food and medicine homologue for a long time in China. We hypothesize that Eucommia ulmoides achieves its health-promoting effects via altering gut microbiota. Here, we investigated the effects of water extract of Eucommia ulmoides bark on caecal microbiota and growth performance, antioxidant activity, and immunity in white-feathered broilers treated for 42 days. A total of 108 one-day-old Cobb white-feathered broilers were randomly assigned to three treatment groups: control diet, 0.75% Eucommia ulmoides diet (EU Ⅰ) and 1.5% Eucommia ulmoides diet (EU Ⅱ). The results showed that EU Ⅱ treatment improved average body weight (ABW), thigh muscle quality and total length of intestines, and decreased the serum total triglycerides and total cholesterol (TC) (p < 0.05). Eucommia ulmoides supplementation increased serum superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant activities and content of immunoglobulins, and reduced levels of malondialdehyde and tumour necrosis factor-α (TNF-α) (p < 0.05). Moreover, the supplementation increased the diversity of caecal microbiota and reduced the pathogenic genera Escherichia Shigella and Helicobacter. The genera Ochrobactrum, Odoribater, Klebsiella, Enterobacter, Georgenia and Bifidobacterium were positively associated with the ABW, total intestinal length, serum levels of GSH-Px, SOD and immunoglobulins (p < 0.001) and negatively associated with the TC and TNF-α (p < 0.01), suggesting an association of the changes of gut microbiota and improvement of broiler health. Meanwhile, Eucommia ulmoides supplementation enriched the Kyoto Encyclopedia of Genes and Genomes pathway of exocrine secretion from the pancreas, circadian entrainment and inhibited lipopolysaccharide biosynthesis. In conclusion, Eucommia ulmoides water extract can be used as a feed additive to improve poultry industry production.

Analysis of Multimorbidity of Moderate to Severe Allergic Rhinitis in Children: A Real-World Study.

INTRODUCTION: Allergic rhinitis (AR) in children is associated with various comorbidities, posing challenges for treatment and management. There have been few investigations of these multimorbidities in Chinese children with AR. Here, we investigated the prevalence of multimorbidities in children with moderate to severe AR and analyzed the influencing factors using real-world data. METHODS: In total, 600 children who visited the outpatient clinic of our hospital and were diagnosed with moderate-severe AR were prospectively enrolled. All children underwent allergen detection and electronic nasopharyngoscopy. Parents or guardians completed a questionnaire that included age, sex, mode of delivery, feeding pattern, and familial history of allergy. The multimorbidities investigated included atopic dermatitis (AD), asthma, allergic conjunctivitis (AC), chronic rhinosinusitis (CRS), adenoid hypertrophy (AH), tonsil hypertrophy (TH), recurrent epistaxis, and recurrent respiratory tract infections (RRTIs). RESULTS: The AR multimorbidities reported in children were as follows: recurrent epistaxis (46.5%), AC (46.3%), AD (40.7%), asthma (22.5%), RRIs (21.3%), CRS (20.5%), AH (19.7%), and TH (12.5%). In univariate logistic regression analysis, age (<6 years), birth mode, familial history of allergy, and single dust mite allergy were associated with AR multimorbidity (p < 0.05). Multivariate logistic regression revealed that a familial history of allergy was an independent risk factor for AC (odds ratio [OR] = 1.539, 95% confidence interval [CI]: 1.104-2.145) and AH (OR = 1.506, 95% CI: 1.000-2.267) (p < 0.05). Age (<6 years) was independently associated with the risk of AD (OR = 1.405, 95% CI: 1.003-1.969) and RRTIs (OR = 1.869, 95% CI: 1.250-2.793) (p < 0.05), cesarean section with AR and CRS risk (OR = 1.678, 95% CI: 1.100-2.561), and single dust mite allergy with asthma (OR = 1.590, 95% CI: 1.040-2.432) and CRS (OR = 1.600, 95% CI: 1.018-2.515) risk (p < 0.05). Further, non-dust mite allergy was independently associated with AR and CRS (OR = 2.056, 95% CI: 1.084-3.899). CONCLUSION: AR was found to be accompanied by different comorbidities, including both allergic and non-allergic comorbidities, complicating disease treatment. These findings demonstrated that age (<6 years), familial history of allergy, types of allergens, and cesarean section were risk factors for different multimorbidities associated with AR.

SARS-CoV-2 BA.2 (Omicron) variant infection in pediatric liver transplanted recipients and cohabitants during 2022 Shanghai outbreak: a prospective cohort.

BACKGROUND: The Omicron variant BA.2 was the dominant variant in the COVID-19 outbreak in Shanghai since March 2022. We aim to investigate the characteristics of SARS-CoV-2 Omicron variant infection in pediatric liver-transplanted recipients. METHODS: We conducted a single-center, prospective, observational, single-arm study. We enrolled pediatric liver-transplanted patients infected with the Omicron variant BA.2 from March 19th to October 1st, 2022 and analyzed their demographic, clinical, laboratory, and outcome data. The management of COVID-19 was conducted according to the 9th trial edition of the Chinese guideline. The immunosuppressive therapy was tailored considering the patients' infection developments and liver functions. RESULTS: Five children were included. The primary diseases included Niemann-Pick disease, propionic acidemia, decompensated cirrhosis, biliary atresia, and Crigler-Najjar syndrome type I. All of the patients were onset with fever before or when getting RNA-positive results at the age of 3 (Range: 1-13) years. The infection duration was 29 (Range: 18-40) days. Three and two children were diagnosed with mild and moderate COVID-19 respectively. Two patients were tested RNA-positive within 14 days after having been tested negative. The immunosuppressants were paused or extenuated in four patients. Eight of all nine cohabitants were injected with at least two doses of inactivated SARS-CoV-2 vaccine. The disease courses were significantly longer than the patients (P < 0.05). CONCLUSIONS: Post-transplant immunosuppression slows down the virus clearance and increases the risk of relapse but does not affect symptom duration or infection severity in pediatric patients. Patients can usually gain a favorable outcome and prognosis by extenuating immunosuppressants.

Photochromic Supramolecular Isomers Derived from Pb(II)-Bipyridinedicarboxylate Complexes.

Photochromic metal-organic complexes (PMOCs) have received huge attention of chemists, thanks to their diverse structural characteristic and various available photo-modulate physicochemical functionalities. The organic ligand plays a crucial role in the quest of PMOCs with specific photo-responsive functionalities. The multiple coordination modes of polydentate ligands also provide possibilities for forming isomeric MOCs, which may open a new perspective on the research of PMOCs. The exploration of suitable PMOC systems is significant for the yield of isomeric PMOCs. Taking into account extant PMOCs based on polypyridines and carboxylate as electron acceptors (EAs) and donors (EDs), the covalent fusion of suitable pyridyl and carboxyl species may produce single functionalized ligands bearing ED and EA moieties for the building of novel PMOCs. In this study, the coordination assembly of bipyridinedicarboxylate (2,2'-bipyridine-4,4'-dicarboxylic acid, H2bpdc) and Pb2+ ions generate two isomeric MOCs, [Pb(bpdc)]·H2O (1 and 2), which have the same chemical compositions with main discrepancies in the coordination mode of bpdc2- ligands. As expected, supramolecular isomers 1 and 2 exhibited different photochromic performance, thanks to the distinct microscopic functional structural units. A schematic encryption and anti-counterfeiting device based on complexes 1 and 2 has also been studied. Compared with the extensively studied PMOCs supported by photoactive ligands like pyridinium and naphthalimide-derivatives and PMOCs derived from mixed electron-accepting polydentate N-ligands and electron-donating ligands, our work provides a new idea for building PMOCs based on pyridinecarboxylic acid ligands.

Clinical value of station 4R node dissection in esophageal squamous cell carcinoma.

BACKGROUND: Many controversies still exist concerning the optimal extent of lymphadenectomy during esophagectomy in esophageal squamous cell carcinoma (ESCC). The objective of this study was to explore the characteristics of 4R metastasis and evaluate the clinical value of 4R node dissection in ESCC. METHODS: A total of 736 ESCC patients who underwent radical esophagectomy between 2005 and 2013 were retrospectively collected, among which 393 ones underwent 4R dissection. Propensity score matching (PSM) method was applied to reduce the effects of confounding variables between the 4R dissection and non-dissection groups to analyze overall survival. RESULTS: Patients showed a low 4R metastasis rate of 5.1% (20/393) (5.2%, 5.8%, and 1.8% for upper, middle, and lower tumors, respectively). Correlation analyses identified that 4R metastasis was significantly associated with station 2R metastasis (p < 0.001) and pathologic tumor-node-metastasis (pTNM) stage (p < 0.001). All 4R metastases were observed in stages IIIB and IVA. Moreover, patients with station 4R dissection failed to achieve significantly improved overall survival compared with those without 4R dissection, regardless of tumor stage (overall: p = 0.696; stage 0-IIIA: p = 0.317; stage IIIB-IVA: p = 0.619). CONCLUSION: 4R metastasis is likely to be associated with more aggressive disease, and routine 4R node dissection might not be necessary for ESCC patients.

Role of Traditional Chinese Medicine for the Treatment of Lupus nephritis: Mechanisms and Applications.

Background: Lupus nephritis (LN), caused by Systemic lupus erythematosus, is a chronic autoimmune renal disease and a key risk factor for morbidity and fatality involving 50% damage to the kidney. LN is associated with aberrant functioning of the immune system, characterized by increased systemic inflammation, altered lymphocyte count, perivascular infiltration of inflammatory cells, and declined organ functioning. Current Therapies and Limitations: Conventional therapies to LN include high-dose glucocorticoids, immunosuppressants, calcineurin inhibitors, immune boosters, and targeted medicines that improve kidney functioning. However, these drugs triggered severe adverse side effects, and their prolonged usage resulted in drug resistance, accentuating LN complications. TCM in LN Treatment: Hence, safe and functional Traditional Chinese Medicines (TCM), with supporting clinical trials and observational studies, received significant recognition worldwide for the Treatment of LN. In the form of herbal extracts and preparations, TCM proved effective in treating immunodeficient disorders, including LN. Additionally, acupuncture as a TCM appeared promising in reducing LN-induced inflammation and joint pain. Mechanisms and Benefits: The therapeutic mechanisms included reduced antibody generation, pro-inflammatory cytokine release, immune complex formation, complement activation, extracellular matrix damage and proteinuria levels that played vital roles in chronic kidney diseases. They generated immunosuppressive effects by modulating apoptosis, oxidative stress, and inflammatory signaling pathways, such as JAK/STAT, NF-κB, AP-1 and MAPK and their cross-talk in LN and associated renal injury. These therapies improved blood circulation, alleviated renal pathological changes, restored glomerular capillary functioning, and regenerated renal tissues. However, an essential requisite for these therapies for LN included reduced side effects and improved hepatoprotection and detoxification. Clinical studies suggest that TCM formulations may demonstrate therapeutic benefits in alleviating the symptoms of LN, suggesting prospects of combined applications with Western medicine to enhance treatment efficiencies. Overall, TCM is beneficial for treating LN, and may serve as a potential alternative to conventional medicines.

Multi-omics analysis reveals Mn exposure affects ferroptosis pathway in zebrafish brain.

Manganese (Mn) accumulates in the central nervous system and can cause neurotoxicity, but the mechanisms of Mn-induced neurotoxicity remain unclear. We performed single-cell RNA sequencing (scRNA-seq) of zebrafish brain after Mn exposure and identified 10 cell types by marker genes: cholinergic neurons, dopaminergic (DA) neurons, glutaminergic neurons, GABAergic neurons, neuronal precursors, other neurons, microglia, oligodendrocyte, radial glia, and undefined cells. Each cell type has its distinct transcriptome profile. Pseudotime analysis revealed that DA neurons had a critical role in Mn-induced neurological damage. Combined with metabolomic data, chronic Mn exposure significantly impaired amino acid and lipid metabolic processes in the brain. Furthermore, we found that Mn exposure disrupted the ferroptosis signaling pathway in the DA neurons in zebrafish. Overall, our study employed joint analysis of multi-omics and revealed ferroptosis signaling pathway is a novel potential mechanism of Mn neurotoxicity.

The clinical relevance of epithelial-mesenchymal transition and its correlations with tumorigenic immune infiltrates in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a cancer with extremely high mortality. Epithelial-mesenchymal transition (EMT) may play an important role in the occurrence, invasion and prognosis of HCC; however, its relationship with immunity in HCC has not yet been studied. Therefore, we investigated the diagnostic and prognostic values of EMT and explored its potential connections with tumorigenic immune infiltrates in HCC. We first proposed a quantitative metric of EMT activity, the EMT score. After applying this metric to 20 datasets from the Integrative Molecular Database of Hepatocellular Carcinoma, the Cancer Genome Atlas, and the Gene Expression Omnibus, we explored the ability of the EMT score to stratify across sample types. We then applied the EMT score for survival analysis and to differentiate patients with/without vascular invasion to test its prognostic value. We also collected and calculated data on the abundance of immune cells and immune cell markers in HCC and investigated their correlations with EMT scores. Finally, we synthesized and analyzed 20 datasets and constructed an EMT-gene-immune linkage network. The results showed higher EMT scores in HCC samples than in cirrhotic and normal livers. The cases with higher EMT scores also showed poorer performance in terms of prognostic factors such as vascular invasion and overall survival time. Our research demonstrated a broad correlation between EMT and the tumor immune microenvironment, and we uncovered multiple potential linkers associated with both EMT and immunity. Studying EMT has clinical relevance and high diagnostic and prognostic value for HCC.

Decomposition-Reassembly Synthesis of a Silverton-Type Polyoxometalate 3D Framework: Semiconducting Properties and Photocatalytic Applications.

Polyoxometalate-based all-inorganic three-dimensional (3D) frameworks have recently attracted attention as a unique class of materials due to their unique physicochemical properties and a wide field of application with excellent prospects. We herein synthesized a novel all-inorganic 3D framework material based on cobalt-substituted Silverton-type polyoxometalate, H6{Co6W10O42[Co(H2O)4]3}·2H2O (Co9W10), which was successfully constructed using Na12[WCo3II(H2O)2(CoIIW9O34)2]·46-48H2O (Co5W19) and Co(NO3)2·6H2O as starting materials in a hydrothermal reaction via a decomposition-reassembly route together with the rational adjustment of pH values. Co9W10 has been structurally characterized using single-crystal X-ray diffraction. Photocurrent response, band-gap (Eg) value, and the VB-XPS spectrum have been measured to reveal the semiconducting property of Co9W10. Furthermore, we synthesized x% PTh/Co9W10 composites (PTh = polythiophene, x = 0.5, 1, 2, 5) for photodegradation of tetracycline hydrochloride (TH) to evaluate the photocatalytic activities of title composites. Due to the optimal molar ratio of hybrids and matching energy levels, 2% PTh/Co9W10 composites show the best photocatalytic activities among these composites.

Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists.

The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and ß-arrestin recruitment assays, which revealed that these compounds exhibited no ß-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.

Sesquiterpene lactones from Elephantopus scaber exhibit cytotoxic effects on glioma cells by targeting GSTP1.

Sesquiterpene lactones possess excellent anti-tumor activity in multiple cancer cell lines, including glioma, the most common type of malignant brain tumor with high mortality. However, the detailed mechanism of this type of constituent, especially the potential target for anti-glioma effect, is still unclear. Here, we collected 52 sesquiterpene lactones from Elephantopus scaber Linn. for network pharmacology analysis. The results demonstrated that the targets of the active components were markedly enriched on the pathways in cancer, which were closely related to cell proliferation regulation. Next, the Gene Expression Omnibus (GEO) and DisGeNET were analyzed by bioinformatics, and 429 glioma-related targets were obtained. Furtherly, 34 common targets of compounds and glioma were revealed, and they were significantly enriched in MAPK signaling pathway. Subsequently, we constructed a common target-compound network, and glutathione S-transferase Pi 1 (GSTP1) had the highest degree value, which explained its significance in the network. Therefore, we speculated that the compounds might exert an anti-glioma effect by targeting GSTP1. To verify the above results, we obtained part of sesquiterpene lactones isolated from E. scaber in our laboratory and evaluated their activities against glioma U87 cells. Among these sesquiterpene lactones (1-27), compounds 1 (elephantopinolide A), 2 (cis-scabertopin) and 3 (elephantopinolide F) exhibited the strongest inhibitory effect, and the IC50 values were 4.22 ± 0.14 µM, 4.28 ± 0.21 µM and 1.79 ± 0.24 µM, respectively. The results from molecular docking, cellular thermal shift assay (CETSA), as well as RT-PCR and Western blot analysis suggested that the compounds exerted an inhibitory effect by targeting GSTP1. Meanwhile, the compounds also activated JNK/STAT3 signaling pathway. Furthermore, we found that 1, 2 and 3 could suppress cell proliferation and also induce mitochondrial dysfunction as well as oxidative stress, eventually leading to cellular apoptosis. Taken together, this study revealed that sesquiterpene lactones from E. scaber could be a promising therapeutic strategy for the treatment of glioma by targeting GSTP1.

Tunable acoustic metasurface based on tunable piezoelectric composite structure.

Due to the potential engineering needs, the passive tunable metasurfaces with a high performance equivalent to the active phased array is worthy of research. Here, a passive ultrathin metasurface unit composed of a piezoelectric composite structure (PCS) connected to an external capacitor, which can modulate the phase of the transmitted acoustic waves at a deep subwavelength scale only by controlling the external capacitor but without changing the structure, is proposed. Then, a tunable acoustic metasurface composed of 20 identical PCSs is introduced to realize three acoustic functions, beam steering, beam focusing, and tweezer-like beam generating, just by changing the external capacitors. The phase-control abilities of the PCS unit and three functions of the designed metasurface are proved both numerically and experimentally. This study provides the possibility to design ultrathin tunable acoustic metasurfaces with the ability of precise control and passive materials.

On-chip programmable optical switch based on CdS multibranched nanowire arrays.

Micro/nano optoelectronic devices are widely studied as basic building blocks for on-chip integrated microsystem and multichannel logic units with excellent optoelectronic properties that are especially important part for interconnection route construction. Here, based on anisotropic waveguides, an optical switch with an on/off ratio of 2.14 is built up in a 2D CdS branched nanowire array. Because the branches are obliquely distributed at the same side of the trunk in a highly ordered form, the guided photoluminescence (PL) intensity from the trunk into the branch tightly relates to its angle. Based on the different intensity of the guided PL emitted from the end of each branch, the position of the incident spot in the backbone area can be identified accurately, making a feasible construction of an on-chip position-sensitive detector to realize an all-optical information process.

USP37 downregulation elevates the Chemical Sensitivity of Human Breast Cancer Cells to Adriamycin.

Background: The evolution of adriamycin (ADR) resistance in the treatment of breast cancer often leads to a poor prognosis in patients. Ubiquitin-specific peptidase 37 (USP37) has been recently identified as a modulator in regulating the stemness of breast cancer cells, but its underlying mechanism remains unclear. In this study, we investigated whether USP37 knockdown could hamper the chemical resistance of MCF-7 and MCF-7/ADR cells to adriamycin and elucidated the potential mechanism. Methods: Immunohistochemistry, western blotting, and RT-qPCR assays were performed to detect the USP37 expression in MCF-7 and MCF-7/ADR cells. The efficiency of USP37 knockdown in breast cancer cells was confirmed by western blotting and RT-qPCR assays. We also performed CCK-8 assay, flow cytometry, western blotting, and TUNEL assays to evaluate cell viability and apoptosis in breast cancer cells. In vivo study was performed to detect the tumorigenicity of MCF-7/ADR cells transfected with shScramble or shUSP37#1 under adriamycin treatment. Results: Bioinformatic analysis indicated that USP37 overexpression was positively correlated with adriamycin resistance. The expression levels of USP37 in both MCF-7 and MCF-7/ADR cells increased significantly with the exposure to adriamycin in a dose-dependent manner. It was verified by the observation that USP37 downregulation elevated the inhibitory effects of adriamycin on breast cancer cells, suppressed cell proliferation caused by cell cycle arrest in G1/S transition, as well as induced apoptosis. Furthermore, in vivo study showed that knockdown of USP37 expression also decreased tumorigenicity of MCF-7/ADR cells in mice. TUNEL assay and observation of cell morphology magnified USP37 knockdown synergized with Adriamycin could elevate the apoptosis of MCF-7 and MCF-7/ADR cells. Western blotting assay illustrated that the combination of USP37 knockdown with adriamycin treatment significantly upregulated the expression levels of cleaved caspase 3 and Bax, whereas the expression level of Bcl-2 was inhibited. Conclusion: Knockdown of USP37 gene expression can reverse the resistance of breast cancer cells to adriamycin, and down-regulating USP37 might be a valuable strategy against ADR resistance in breast cancer therapy.

Postoperative Complications Associated with Moderate Sedation in Endoscopic Procedures Among Patients with Cirrhosis.

BACKGROUND Moderate sedation for endoscopic intervention has become common and offers increased safety and comfort. Patients with cirrhosis are sicker and at increased risk for complications related to sedation. However, postoperative complications associated with moderate sedation and their risk factors have not been adequately studied in this population. MATERIAL AND METHODS This retrospective study included cirrhotic patients who underwent endoscopic procedures with moderate sedation and were admitted to the First Affiliated Hospital, Zhejiang University School of Medicine, between January 1, 2015, and December 31, 2019. A mixed-effects multivariate logistic regression model determined odds ratios between variables and complications, adjusting for potential confounders. The model was validated with 51 patients admitted from August 28, 2020, to October 12, 2020, at 3 hospitals. RESULTS Among 232 cirrhotic patients, complications were recorded for 40 patients (17.2%). These patients had a significantly longer hospital length of stay (P<0.05), and postprocedural complications (35/40; 87.5%) were the most common type of complication. Moderate sedation-associated postoperative complications were significantly associated with portal hypertension history (odds ratio [OR] 2.201; 95% confidence interval [CI] 0.903, 5.364) and the procedure being performed in the evening (OR 1.971; 95% CI 0.946, 4.106). The area under the receiver-operating characteristic curve was 0.627 (95% CI, 0.534 to 0.719, P=0.012) in the validated subgroup, and the predicted accordance rate was 70%. CONCLUSIONS Moderate sedation-associated postoperative complications were relatively high among cirrhotic patients undergoing endoscopic procedures. Complications were associated with sicker patients who underwent endoscopic procedures in the evening, suggesting the potential need for more intensive care of perioperative management in this population, including anesthesia monitoring.

Helical Higher-Order Topological States in an Acoustic Crystalline Insulator.

The topological states in quantum Hall insulators and quantum spin Hall insulators that emerge helical are considered nondissipative. However, in crystalline systems without spin-orbit couplings, the existing higher-order topological states are considered not helical, and the energy suffers from dissipation during propagation. In this work, by introducing the intrinsic pseudospin degree of freedom, we theoretically and experimentally present the existence of the helical higher-order topological states in the C_{6}-symmetric topological crystalline insulators based on the acoustic samples. Crucially, rather than considering the global interaction of the large bulk, we further intuitively reveal the impacts of the geometries of the crystal on the generation mechanisms and natural behaviors of these states based on the simple equivalent models. These results provide a versatile way for guiding the design of the desired topological materials.

The Warburg effect promoted the activation of the NLRP3 inflammasome induced by Ni-refining fumes in BEAS-2B cells.

Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.