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BackgroundHand, foot, and mouth disease (HFMD) is a common infectious disease in children. Enterovirus A71 (EV71) and coxsackievirus A16 (CA16) have been identified as the predominant pathogens for several decades. In recent years, coxsackievirus A6 (CA6) and coxsackievirus A10 (CA10) have played increasingly important roles in a series of HFMD outbreaks. We performed a retrospective analysis of the epidemiology of HFMD and the spectrum of different viral serotypes, to elucidate the genetic and phylogenetic characteristics of the main serotypes in the Jiashan area during 2016 to 2022.MethodsDescriptive epidemiological methods were used to analyze the time and population distribution of HFMD in Jiashan during 2016 to 2022 based on surveillance data. Molecular diagnostic methods were performed to identify the viral serotypes and etiological characteristics of HFMD. Phylogenetic analyses was based on VP1 region of CA16 and CA6.ResultsThe average annual incidence rate of HFMD fluctuated from 2016 to 2022. Children aged 1–5 years accounted for 81.65% of cases and boys were more frequently affected than girls. Except when HFMD was affected by the COVID-19 epidemic in 2020 and 2022, epidemics usually peak in June to July, followed by a small secondary peak from October to December and a decline in February. Urban areas had a high average incidence and rural areas had the lowest. Among 560 sample collected in Jiashan, 472 (84.29%) were positive for enterovirus. The most frequently identified serotypes were CA6 (296, 52.86%), CA16 (102, 18.21%), EV71 (16, 2.86%), CA10 (14, 2.50%) and other enteroviruses (44, 7.86%). There were 71 and 142 VP1 sequences from CA16 and CA6, respectively. Substitution of N218D, A220L and V251I was detected in CA16 and may have been related to viral infectivity. Phylogenetic analysis showed that CA16 could be assigned to two genogroups, B1a and B1b, while all the CA6 sequences belonged to the D3a genogroup.ConclusionCA6 and CA16 were the two major serotypes of enteroviruses circulating in the Jiashan area during 2016 to 2022. Continuous and comprehensive surveillance for HFMD is needed to better understand and evaluate the prevalence and evolution of the associated pathogens.

Antimicrobial resistance (AMR) is commonly associated with the inappropriate use of antibiotics during meat-rabbit production, posing unpredictable risks to rabbit welfare and public health. However, there is limited research on the epidemiological dynamics of antibiotic resistance among bacteria indicators derived from local healthy meat-rabbits. To bridge the knowledge gap between antibiotic use and AMR distribution, a total of 75 Escherichia coli (E. coli) and 210 Enterococcus spp. strains were successfully recovered from fecal samples of healthy meat-rabbits. The results revealed that diverse AMR phenotypes against seven commonly used antimicrobials, including ampicillin (AMP), amoxicillin-clavulanic acid (A/C), doxycycline (DOX), enrofloxacin (ENR), florfenicol (FFC), gentamicin (GEN), and polymycin B (PMB), were observed among most strains of E. coli and Enterococcus spp. in two rabbit farms, although the distribution pattern of antibiotic resistance between young and adult rabbits was similar. Among them, 66 E. coli strains showed resistance against 6 antimicrobials except for PMB. However, 164 Enterococcus spp. strains only exhibited acquired resistance against DOX and GEN. Notably, the DOX-based AMR phenotypes for E. coli and Enterococcus spp. strains were predominant, indicating the existing environmental stress conferred by DOX exposure. The MICs tests suggested elevated level of antibiotic resistance for resistant bacteria. Unexpectedly, all GEN-resistant Enterococcus spp. strains resistant high-level gentamicin (HLGR). By comparison, the blaTEM, tetA, qnrS and floR were highly detected among 35 multi-resistant E. coli strains, and aac[6']-Ie-aph[2']-Ia genes widely spread among the 40 double-resistant Enterococcus spp. strains. Nevertheless, the presence of ARGs were not concordant with the resistant phenotypes for a portion of resistant bacteria. In conclusion, the distribution of AMR and ARGs are prevalent in healthy meat-rabbits, and the therapeutic antimicrobials use in farming practice may promote the antibiotic resistance transmission among indicator bacteria. Therefore, periodic surveillance of antibiotic resistance in geographic locations and supervisory measures for rational antibiotic use are imperative strategies for combating the rising threats posed by antibiotic resistance, as well as maintaining rabbit welfare and public health.

Summary: Background: Urine cytology is an important non-invasive examination for urothelial carcinoma (UC) diagnosis and follow-up. We aimed to explore whether artificial intelligence (AI) can enhance the sensitivity of urine cytology and help avoid unnecessary endoscopy. Methods: In this multicentre diagnostic study, consecutive patients who underwent liquid-based urine cytology examinations at four hospitals in China were included for model development and validation. Patients who declined surgery and lacked associated histopathology results, those diagnosed with rare subtype tumours of the urinary tract, or had low-quality images were excluded from the study. All liquid-based cytology slides were scanned into whole-slide images (WSIs) at 40 × magnification and the WSI-labels were derived from the corresponding histopathology results. The Precision Urine Cytology AI Solution (PUCAS) was composed of three distinct stages (patch extraction, features extraction, and classification diagnosis) and was trained to identify important WSI features associated with UC diagnosis. The diagnostic sensitivity was mainly used to validate the performance of PUCAS in retrospective and prospective validation cohorts. This study is registered with the ChiCTR, ChiCTR2300073192. Findings: Between January 1, 2018 and October 31, 2022, 2641 patients were retrospectively recruited in the training cohort, and 2335 in retrospective validation cohorts; 400 eligible patients were enrolled in the prospective validation cohort between July 7, 2023 and September 15, 2023. The sensitivity of PUCAS ranged from 0.922 (95% CI: 0.811–0.978) to 1.000 (0.782–1.000) in retrospective validation cohorts, and was 0.896 (0.837–0.939) in prospective validation cohort. The PUCAS model also exhibited a good performance in detecting malignancy within atypical urothelial cells cases, with a sensitivity of over 0.84. In the recurrence detection scenario, PUCAS could reduce 57.5% of endoscopy use with a negative predictive value of 96.4%. Interpretation: PUCAS may help to improve the sensitivity of urine cytology, reduce misdiagnoses of UC, avoid unnecessary endoscopy, and reduce the clinical burden in resource-limited areas. The further validation in other countries is needed. Funding: National Natural Science Foundation of China; Key Program of the National Natural Science Foundation of China; the National Science Foundation for Distinguished Young Scholars; the Science and Technology Planning Project of Guangdong Province; the National Key Research and Development Programme of China; Guangdong Provincial Clinical Research Centre for Urological Diseases.

Abstract Non‐small‐cell lung cancer (NSCLC) is a highly lethal tumor that often develops resistance to targeted therapy. It is shown that Tank‐binding kinase 1 (TBK1) phosphorylates AGO2 at S417 (pS417‐AGO2), which promotes NSCLC progression by increasing the formation of microRNA‐induced silencing complex (miRISC). High levels of pS417‐AGO2 in clinical NSCLC specimens are positively associated with poor prognosis. Interestingly, the treatment with EGFR inhibitor Gefitinib can significantly induce pS417‐AGO2, thereby increasing the formation and activity of oncogenic miRISC, which may contribute to NSCLC resistance to Gefitinib. Based on these, two therapeutic strategies is developed. One is jointly to antagonize multiple oncogenic miRNAs highly expressed in NSCLC and use TBK1 inhibitor Amlexanox reducing the formation of oncogenic miRISC. Another approach is to combine Gefitinib with Amlexanox to inhibit the progression of Gefitinib‐resistant NSCLC. This findings reveal a novel mechanism of oncogenic miRISC regulation by TBK1‐mediated pS417‐AGO2 and suggest potential therapeutic approaches for NSCLC.

Abstract Arginine and lysine, frequently appearing as a pair on histones, have been proven to carry diverse modifications and execute various epigenetic regulatory functions. However, the most context‐specific and transient effectors of these marks, while significant, have evaded study as detection methods have thus far not reached a standard to capture these ephemeral events. Herein, a pair of complementary photo‐arginine/δ‐photo‐lysine (R‐dz/K‐dz) probes is developed and involve these into histone peptide, nucleosome, and chromatin substrates to capture and explore the interactomes of Arg and Lys hPTMs. By means of these developed tools, this study identifies that H3R2me2a can recruit MutS protein homolog 6 (MSH6), otherwise repelDouble PHD fingers 2 (DPF2), Retinoblastoma binding protein 4/7 (RBBP4/7). And it is disclosed that H3R2me2a inhibits the chromatin remodeling activity of the cBAF complex by blocking the interaction between DPF2 (one component of cBAF) and the nucleosome. In addition, the novel pairs of H4K5 PTMs and respective readers are highlighted, namely H4K5me‐Lethal(3)malignant brain tumor‐like protein 2 (L3MBTL2), H4K5me2‐L3MBTL2, and H4K5acK8ac‐YEATS domain‐containing protein 4 (YEATS4). These powerful tools pave the way for future investigation of related epigenetic mechanisms including but not limited to hPTMs.

Background Interferons (IFNs) are essential for activating an effective immune response and play a central role in immunotherapy-mediated immune cell reactivation for tumor regression. Type III IFN (λ), related to type I IFN (α), plays a crucial role in infections, autoimmunity, and cancer. However, the direct effects of IFN-λ on the tumor immune microenvironment have not been thoroughly investigated.Methods We used mouse MB49 bladder tumor models, constructed a retroviral vector expressing mouse IFN-λ3, and transduced tumor cells to evaluate the antitumor action of IFN-λ3 in immune-proficient tumors and T cell-deficient tumors. Furthermore, human bladder cancer samples (cohort 1, n=15) were used for immunohistochemistry and multiplex immunoflurescence analysis to assess the expression pattern of IFN-λ3 in human bladder cancer and correlate it with immune cells’ infiltration. Immunohistochemistry analysis was performed in neoadjuvant immunotherapy cohort (cohort 2, n=20) to assess the correlation between IFN-λ3 expression and the pathological complete response rate.Results In immune-proficient tumors, ectopic Ifnl3 expression in tumor cells significantly increased the infiltration of cytotoxic CD8+ T cells, Th1 cells, natural killer cells, proinflammatory macrophages, and dendritic cells, but reduced neutrophil infiltration. Transcriptomic analyses revealed significant upregulation of many genes associated with effective immune response, including lymphocyte recruitment, activation, and phagocytosis, consistent with increased antitumor immune infiltrates and tumor inhibition. Furthermore, IFN-λ3 activity sensitized immune-proficient tumors to anti-PD-1/PD-L1 blockade. In T cell-deficient tumors, increased Ly6G–Ly6C+I-A/I-E+ macrophages still enhanced tumor cell phagocytosis in Ifnl3 overexpressing tumors. IFN-λ3 is expressed by tumor and stromal cells in human bladder cancer, and high IFN-λ3 expression was positively associated with effector immune infiltrates and the efficacy of immune checkpoint blockade therapy.Conclusions Our study indicated that IFN-λ3 enables macrophage-mediated phagocytosis and antitumor immune responses and suggests a rationale for using Type III IFN as a predictive biomarker and potential immunotherapeutic candidate for bladder cancer.

Summary: Artificial intelligence (AI) has been found to assist in optical differentiation of hyperplastic and adenomatous colorectal polyps. We investigated whether AI can improve the accuracy of endoscopists’ optical diagnosis of polyps with advanced features. We introduced our AI system distinguishing polyps with advanced features with more than 0.870 of accuracy in the internal and external validation datasets. All 19 endoscopists with different levels showed significantly lower diagnostic accuracy (0.410–0.580) than the AI. Prospective randomized controlled study involving 120 endoscopists into optical diagnosis of polyps with advanced features with or without AI demonstration identified that AI improved endoscopists’ proportion of polyps with advanced features correctly sent for histological examination (0.960 versus 0.840, p

Steel fiber reinforced concrete (SFRC) is one of the fastest growing and most widely used fiber concrete as engineering structural material. Considering the importance of steel fiber concrete in tunneling applications, this paper reviews and discusses the damage mechanism of concrete and the crack arresting effect of steel fiber, and further investigates the application of SFRC in tunneling based on the reinforcement theory of SFRC. It was obvious that (1) steel fiber can not only delay the cracking damage of concrete, but also improve the deformation capacity of concrete, SFRC has excellent impact resistance and high tensile strength; (2) all the reinforcement theories can be considered to be developed on the basis of composite mechanics theory and fiber spacing theory by comprehensive improvement, but still need to further explore the reinforcement theory reflecting; (3) the combination of steel reinforcement and steel fiber will reduce the use of tunnel reinforcement, which is proven to be a better choice, because the content of steel fibers in SFRC has a certain degree of unevenness, so steel fibers can not completely replace the application of steel; and (4) SFRC applied to the node part of the tunnel structure is more effective, but the relevant research is less, in addition, steel fiber concrete tunnel node seismic resistance will be an important direction for future research. The relevant research in this paper can provide reference for the practical application of SFRC in tunnel engineering and other research directions.

It has been shown that exposure to hexavalent Chromium, Cr (Ⅵ), via nasal cavity can have neurotoxicological effects and induces behavioral impairment due to the fact that blood brain barrier (BBB) does not cover olfactory bulb. But whether Cr (Ⅵ) can cross the BBB and have a toxicological effects in central nervous system (CNS) remains unclear. Therefore, we investigated the effects of Cr (Ⅵ) on mice treated with different concentrations and exposure time (14 days and 28 days) of Cr (Ⅵ) via intraperitoneal injection. Results revealed that Cr accumulated in hypothalamus (HY) in a timely dependent manner. Much more severer neuropathologies was observed in the group of mice exposed to Cr (Ⅵ) for 28 days than that for 14 days. Gliosis, neuronal morphological abnormalities, synaptic degeneration, BBB disruption and neuronal number loss were observed in HY. In terms of mechanism, the Nrf2 related antioxidant stress signaling dysfunction and activated NF-κB related inflammatory pathway were observed in HY of Cr (Ⅵ) intoxication mice. And these neuropathologies and signaling defects appeared in a timely dependent manner. Taking together, we proved that Cr (Ⅵ) can enter HY due to weaker BBB in HY and HY is the most vulnerable CNS region to Cr (Ⅵ) exposure. The concentration of Cr in HY increased along with time. The accumulated Cr in HY can cause BBB disruption, neuronal morphological abnormalities, synaptic degeneration and gliosis through Nrf2 and NF-κB signaling pathway. This finding improves our understanding of the neurological dysfunctions observed in individuals who have occupational exposure to Cr (Ⅵ), and provided potential therapeutic targets to treat neurotoxicological pathologies induced by Cr (Ⅵ).

Background: The coexistence of autoimmune encephalitis (AE) with multiple neural auto-antibodies is of great clinical significance because overlying antibodies may cause superposition or variation of clinical syndrome, which increases the difficulty of diagnosis and treatment of the disease. To the best of our knowledge, the coexistence of anti-N-methyl d-aspartate Receptor (NMDAR) and anti-IgLON5 antibodies in AE has not been published previously. Case presentation: A 38-year-old female patient presented to our hospital due to headache and abnormal psychiatric behavior. Based on her clinical manifestations (psychiatric and behavioral abnormalities, involuntary limb movements, and sleep disorders) and laboratory assessment results (positive human leukocyte antigen (HLA)-DQB1*05:01 haplotype, anti-NMDAR, and anti-IgLON5 antibodies), she was diagnosed as AE with coexisting anti-NMDAR and anti-IgLON5 antibodies. After treatment with intravenous methylprednisolone and immunoglobulin, as well as plasmapheresis, her symptoms gradually improved with exception for the sleep disorders. Although oral prednisone acetate and mycophenolate mofetil were continued after discharge, her symptoms of sleep disorders did not improve at 6-month follow-up. Conclusion: This is the first case of AE co-existing with anti-NMDAR and anti-IgLON5 antibodies. Co-existence of neural auto-antibodies should be considered when patients present with overlapping or atypical symptoms. Special attention should be paid to the treatment of these patients as some anti-IgLON5 encephalitis patients may not benefit from immunotherapy treatment.

In recent years, nanoplastics (NPs) and triclosan (TCS, a pharmaceutical and personal care product) have emerged as environmental pollution issues, and their combined presence has raised widespread concern regarding potential risks to organisms. However, the combined toxicity and mechanisms of NPs and TCS remain unclear. In this study, we investigated the toxic effects of polystyrene NPs and TCS and their mechanisms on KGN cells, a human ovarian granulosa cell line. We exposed KGN cells to NPs (150 μg/mL) and TCS (15 μM) alone or together for 24 hours. Co-exposure significantly reduced cell viability. Compared with exposure to NPs or TCS alone, co-exposure increased reactive oxygen species (ROS) production. Interestingly, co-exposure to NPs and TCS produced synergistic effects. We examined the activity of superoxide dismutase (SOD) and catalase (CAT), two antioxidant enzymes; it was significantly decreased after co-exposure. We also noted an increase in the lipid oxidation product malondialdehyde (MDA) after co-exposure. Furthermore, co-exposure to NPs and TCS had a more detrimental effect on mitochondrial function than the individual treatments. Co-exposure activated the NRF2–KEAP1–HO-1 antioxidant stress pathway. Surprisingly, the expression of SESTRIN2, an antioxidant protein, was inhibited by co-exposure treatments. Co-exposure to NPs and TCS significantly increased the autophagy-related proteins LC3B-II and LC3B-Ⅰ and decreased P62. Moreover, co-exposure enhanced CASPASE-3 expression and inhibited the BCL-2/BAX ratio. In summary, our study revealed the synergistic toxic effects of NPs and TCS in vitro exposure. Our findings provide insight into the toxic mechanisms associated with co-exposure to NPs and TCS to KGN cells by inducing oxidative stress, activations of the NRF2-KEAP1-HO-1 pathway, autophagy, and apoptosis.

Drug nephrotoxicity has high fatality rates and complications. To study this conditional, traditionally, Gentamicin (GM) is used to induce acute injury and establish a nephrotic syndrome model. Baicalin, a flavonoid derived from baicalin with potent anti-inflammatory and antioxidant activity, has been used to treat various inflammatory diseases. This study aims to investigate the process of baicalin-2-ethoxyethyl ester (BAE) synthesis and its therapeutic effect on GM-induced acute kidney injury (AKI). Briefly, baicalin was processed by various reactions to yield BAE. A GM-induced AKI model was established for in vivo evaluation of the protective effect and mechanism of BAE. The results indicated that BAE reduced serum creatinine and urea nitrogen levels and improved pathological alterations, inflammatory responses, and oxidative stress in renal tissues. Furthermore, it was revealed that BAE might exert anti-inflammatory and anti-oxidative responses during AKI via the NF-κB signaling pathway regulation. The findings imply that BAE has a protective impact on the kidneys and might serve as a potent medicine for treating renal damage.

Asthma is a heterogeneous respiratory disease characterized by airway inflammation occurring in the bronchus. Direct delivery of targeted treatments to the bronchus for asthma has the potential to optimize therapeutic efficacy. Inhaled corticosteroids are cornerstone therapy for persistent asthma, however, there remain challenges in designing effective formulations for the inhaled route and minimizing long-term corticosteroid side effects. Here, a nanogel delivery system with good bio-adhesion based on alginate crosslinked with zinc ions was designed. The prepared alginate nanogel particles (ALG-NPs) effectively delivered icariin (ICA) which possesses anti-inflammatory and antioxidant activities, to the bronchus through ultrasonic aerosol inhalation, thereby ameliorating asthmatic symptoms and attenuating bronchial inflammation. The ALG-NPs exhibited favorable biological safety and could be deposited in the bronchus to control the release of ICA, enabling targeted treatment of asthma. In addition, ICA loaded ALG-NPs significantly reduced airway inflammation by modulating key targets associated with asthm (Th1 transcription factor and Th2 transcription factor) while also inducing eosinophilic apoptosis by regulating the Bax/Bcl-2 ratio expression. This study suggests that the ultrasonic aerosol inhalation of ICA loaded ALG-NPs was a promising strategy of treating asthma.

Left ventricular noncompaction cardiomyopathy (LVNC) is a cardiovascular disease characterized by arrhythmia and heart failure. In this study, LVNC myocardial samples were collected from patients who underwent heart transplantation and were analyzed using exome sequencing. Approximately half of the LVNC patients carried SCN5A variants, which are associated with clinical symptoms of ventricular tachycardia. To investigate the electrophysiological functions of these SCN5A variants and the underlying mechanism by which they increase arrhythmia susceptibility in LVNC patients, functional evaluations were conducted in CHO–K1 cells and human embryonic stem cell-derived cardiomyocytes (hESC-CMs) using patch-clamp or microelectrode array (MEA) techniques. These findings demonstrated that these SCN5A mutants exhibited gain-of-function properties, leading to increased channel activation and enhanced fast inactivation in CHO–K1 cells. Additionally, these mutants enhanced the excitability and contractility of the cardiomyocyte population in hESC-CMs models. All SCN5A variants induced fibrillation-like arrhythmia and increased the heart rate in cardiomyocytes. However, the administration of Lidocaine, an antiarrhythmic drug that acts on sodium ion channels, was able to rescue or alleviate fibrillation-like arrhythmias and secondary beat phenomenon. Based on these findings, it is speculated that SCN5A variants may contribute to susceptibility to arrhythmia in LVNC patients. Furthermore, the construction of cardiomyocyte models with SCN5A variants and their application in drug screening may facilitate the development of precise therapies for arrhythmia in the future.

ABSTRACT: Objectives: Carbapenem-resistant hypermucoviscous Klebsiella pneumoniae (CR-HMKP) poses unprecedented public health challenges. However, genomic information regarding the CR-HMKP K2-ST375 strain is scarce. The aim of this study was to characterize the whole genome sequence of the CR-HMKP K2-ST375 strain Kp0179 isolated from a male patient in China. Methods: The whole genome of Kp0179 was sequenced using the DNBSEQ and Pacific Biosciences RSII platforms. The capsular serotype, multilocus sequence typing (MLST), antimicrobial resistance genes, and virulence factors were determined using available databases and bioinformatics tools. Conjugation experiments were performed using rifampicin-resistant Escherichia coli C600 as the recipient. Results: The Kp0179 strain with hypermucoviscous phenotype was resistant to almost all β-lactams, including ertapenem and imipenem. Whole genome sequencing revealed that Kp0179 belonged to K2-ST375 and contained blaNDM-IncX3 and a virulence plasmid ca. 121 kb. Kp0179 contained 5146 coding genes, 88 tRNAs, 25 rRNAs and 38 non-coding RNA genes. Among the six acquired antibiotic resistance genes, blaSHV-99, fosA, oqxAB were located on the chromosome, whereas blaNDM-1, qnrS1 and blaSHV-12 were located on the conjugative plasmid pNDM-Kp0179 (IncX3 type). Virulence gene analysis indicated that pLVPK-Kp0179 carried multiple virulence-encoding genes, such as iroBCDN, iucABCDiutA, rmpA and rmpA2. In addition to carrying a virulence plasmid, capsule formation (kvgA) and the type 3 fimbriae operon (mrkABCDFHIJ) were located on the chromosome of Kp0179. Conclusion: To our knowledge, this is the first report of a CR-HMKP K2-ST375 strain with a blaNDM-harboured conjugative IncX3 plasmid and a pLVPK-like virulence plasmid from a patient in China. Therefore, the spread of CR-HMKP K2-ST375 isolates in China should be closely monitored.

ObjectiveTo investigate the prevalence of chronic kidney disease (CKD) and the association of obesity with CKD among hypertension patients registered at community health service centers in suburb of Shanghai. MethodsThe participants of the study were 3 600 hypertensive patients randomly recruited from chronic disease patients registered at two community health service centers in a suburban district of Shanghai city. Face-to-face interview with a self-designed questionnaire and the International Physical Activity Questionnaire, physical examination, laboratory tests were conducted among the participants during October – December 2021. Unconditional multivariate logistics regression model was adopted to analyze the association between body mass index [BMI] and CKD. ResultsOf the 2 991 participants finally included in the analysis, 1 037 (34.67%) were identified as having CKD and the number (proportion) of the participants with decreased estimated glomerular filtration (eGFR), proteinuria, and hematuria were 464 (15.51%), 677 (22.63%), and 99 (3.31%), respectively. After adjusting for age, sex, education, smoking, alcohol drinking, physical activity, diabetes, blood lipids and blood pressure control, unconditional multivariate logistic regression analysis revealed that the participants with obesity (BMI ≥ 28.0) were at a significantly increased risk of having CKD (odds ratio [OR] = 1.498，95% confidence interval [95%CI]: 1.203 – 1.866), decreased estimated glomerular filtration (OR = 1.340，95%CI: 1.001 – 1.793), and proteinuria (OR = 1.388，95%CI: 1.088 – 1.771) compared to those with normal or low body weight (≤ 23.9). Conclusion The prevalence of CKD was high and positively correlated with obesity among hypertension patients registered at community health service centers in suburb of Shanghai.

This study explored a more precise association between androgens and glycolipid metabolism in healthy women of different ages. Body mass index (BMI), waist circumference (WC), and waist-to-hip ratio were used as body fat indicators. High-density lipoprotein (HDL), low-density lipoprotein, triglycerides, and total cholesterol were used as lipid markers. Fasting blood glucose (FBG), fasting insulin, and the homeostatic model assessment of insulin resistance were used to assess insulin resistance and glucose metabolism. Liquid chromatography-tandem mass spectrometry was used to measure androgen indicators, including testosterone, sex hormone-binding globulin (SHBG), free testosterone (FT), dihydrotestosterone (DHT), androstenedione (A4), dehydroepiandrosterone (DHEA), and dehydroepiandrosterone sulfate (DHEAS). DHEAS levels varied across age groups. Correlation analyses with Spearman’s coefficient showed that the free androgen index correlated positively with WC (p = 0.040), FT correlated positively with BMI (p = 0.033) and WC (p = 0.049), SHBG correlated positively with HDL (p = 0.013), and A4 correlated positively with FBG (p = 0.017). Multiple linear regression analysis showed that among healthful women aged 36–40 years, A4 increased with FBG, and SHBG increased with HDL. Even within healthy, nonobese women, lipid and glucose metabolism were robustly correlated with androgens. Yearly metabolic assessments are necessary, particularly for FBG and HDL, since these markers can predict the likelihood of hyperandrogenemia, enabling timely interventions.

Abstract Sharp steering-braking at a high speed exposes sport utility vehicles with high gravity centers and narrow wheel tracks to the risks of tire locking, sideslip and rollover. To avoid these risks and ensure braking safety, yaw stability and roll stability upon steering-braking, a braking-yaw-roll stability integrated control strategy was proposed, which consists of a supervisor, an upper and a lower controller for the front and rear axle independent drive electric vehicle. In the supervisor, a nonlinear vehicle predictive model was constructed and four control modes were proposed according to the vehicle status and rollover indexes. The weight coefficients between braking force, yaw stability and roll stability are determined dynamically by the control mode and output to the upper controller. The upper controller used a nonlinear model predictive control to determine the longitudinal braking force distribution of the four wheels. And in the lower controller, the regenerative braking torque and friction braking torque of each wheel were distributed. Finally, simulation verifications were carried out on the high and low adhesion roads. The results show that the control strategy proposed in this study can effectively prevent the vehicle from rollover while ensuring braking safety and yaw stability.

Abstract When manually polishing blades, skilled workers can quickly machine a blade by observing the characteristics of the polishing sparks. To help workers better recognize spark images, we used an industrial charge-coupled device (CCD) camera to capture the spark images. Firstly, the spark image region detected by yolo5, then segment from the background. Secondly, the target region was further segmented and refined in a fully connected conditional random field (CRF), from which the complete spark image obtained. Experimental results showed that this method could quickly and accurately segment whole spark image. The test results showed that this method was better than other image segmentation algorithms. Our method could better segment irregular image, improve recognition and segmentation efficiency of spark image, achieve automatic image segmentation, and replace human observation.

Abstract During the process of coal mining, there is a violent appearance of mining stress when the initial weighting occurs. To guarantee the safety of the gob-side entry formed automatically by roof-cutting (EFARC) in an inclined coal seam, a study was conducted on the initial weighting mechanism and appearance characteristics through field monitoring and theoretical analysis. The findings reveal that, upon the initial breaking of the main roof in the non-pillar mining stope of an inclined coal seam, the deflection of the thin plate structure exhibits asymmetric distribution, with the maximum position situated in the middle-upper part of the thin plate. As the main roof thin plate reaches its limit interval, the tensile fracture first occurs in the middle-upper part of the coal wall in front and back of the stope. Once broken, the thin plate changes to a simply supported state. The analysis of field data reveals that the mine pressure in the non-pillar stope of EFARC shows an asymmetric weighting phenomenon. The periodic weighting interval at the ends of the working face increases, and the weighting intensity decreases. These results can serve as theoretical support for controlling mine pressure in non-pillar mining through EFARC in inclined coal seams and can serve as a basis for further investigations in this area.

Abstract Background Mesenchymal stem cells (MSCs) have shown promising potential in allograft survival. However, few reports have focused on comparing the immunosuppressive capacity of MSCs from different sources and administered via different routes in inhibiting transplant rejection. Moreover, virtually nothing is known about the role of MSCs in the regulation of graft neovascularization and lymphangiogenesis. In this study, we compared the efficacy of human adipose MSCs (hAD-MSCs) and human umbilical cord MSCs (hUC-MSCs) in vitro and in corneal transplantation models to explore the underlying molecular mechanisms and provide a powerful strategy for future clinical applications. Methods hAD-MSCs and hUC-MSCs were generated, and their self-renewal and multi-differentiation abilities were evaluated. The inhibitory effect of human MSCs (hMSCs) was examined by T-cell proliferation assays with or without transwell in vitro. Two MSCs from different sources were separately adoptively transferred in mice corneal transplantation (5 × 105 or 1 × 106/mouse) via topical subconjunctival or intravenous (IV) routes. Allograft survival was evaluated every other day, and angiogenesis and lymphomagenesis were quantitatively analyzed by immunofluorescence staining. The RNA expression profiles of hMSCs were revealed by RNA sequencing (RNA-seq) and verified by quantitative real-time PCR (qRT‒PCR), western blotting or ELISA. The function of the differentially expressed gene FAS was verified by a T-cell apoptosis assay. Results hAD-MSCs induced stronger immunosuppression in vitro than hUC-MSCs. The inhibitory effect of hUC-MSCs but not hAD-MSCs was mediated by cell–cell contact-dependent mechanisms. Systemic administration of a lower dose of hAD-MSCs showed better performance in prolonging corneal allograft survival than hUC-MSCs, while subconjunctival administration of hMSCs was safer and further prolonged corneal allograft survival. Both types of hMSCs could inhibit corneal neovascularization, while hAD-MSCs showed greater superiority in suppressing graft lymphangiogenesis. RNA-seq analysis and confirmation experiments revealed the superior performance of hAD-MSCs in allografts based on the lower expression of vascular endothelial growth factor C (VEGF-C) and higher expression of FAS. Conclusions The remarkable inhibitory effects on angiogenesis/lymphangiogenesis and immunological transplantation effects support the development of hAD-MSCs as a cell therapy against corneal transplant rejection. Topical administration of hMSCs was a safer and more effective route for application than systemic administration.

Abstract Transmembrane ion channels frequently regulate ion permeation by forming bundle crossing of the pore-lining helices when deactivated. The resulting physical constriction is believed to serve as the de facto gate that imposes the major free energy barrier to ion permeation. Intriguingly, many ion channels also contain highly hydrophobic inner pores enclosed by bundle crossing, which can undergo spontaneous dewetting and give rise to a “vapor barrier” to block ion flow even in the absence of physical constriction. Using atomistic simulations, we show that hydrophobic gating and bundle-crossing mechanisms co-exist and complement one and another in the human TRPV4 channel. In particular, a single hydrophilic mutation in the lower pore can increase pore hydration and reduce the ion permeation free energy barrier by about half without affecting the bundle crossing. We believe that hydrophobic gating may play a key role in other bundle-crossing ion channels with hydrophobic inner pores.

Abstract Among CRISPR-Cas genome editing systems, Streptococcus pyogenes Cas9 (SpCas9), sourced from a human pathogen, is the most widely used. Here, through in silico data mining, we have established an efficient plant genome engineering system using CRISPR-Cas9 from probiotic Lactobacillus rhamnosus. We have confirmed the predicted 5’-NGAAA-3’ PAM via a bacterial PAM depletion assay and showcased its exceptional editing efficiency in rice, wheat, tomato, and Larix cells, surpassing LbCas12a, SpCas9-NG, and SpRY when targeting the identical sequences. In stable rice lines, LrCas9 facilitates multiplexed gene knockout through coding sequence editing and achieves gene knockdown via targeted promoter deletion, demonstrating high specificity. We have also developed LrCas9-derived cytosine and adenine base editors, expanding base editing capabilities. Finally, by harnessing LrCas9’s A/T-rich PAM targeting preference, we have created efficient CRISPR interference and activation systems in plants. Together, our work establishes CRISPR-LrCas9 as an efficient and user-friendly genome engineering tool for diverse applications in crops and beyond.

Abstract Background Chronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer. Methods Breast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry. Results Breast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases. Conclusions Chronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

Amidst the backdrop of rural revitalization and cultural renaissance, there is a surge in the construction demand for replica traditional vernacular dwellings. Traditional cost estimation methods struggle to meet the need for rapid and precise estimation due to the complexity inherent in their construction. To address this challenge, this study aims to enhance the accuracy and efficiency of cost estimation by innovatively developing an Adaptive Self-Explanatory Convolutional Neural Network (ASCNN) model, tailored to meet the specific cost estimation needs of replica traditional vernacular dwellings in the Huizhou region. The ASCNN model employs a Random Forest model to filter key features, inputs these into the CNN for cost estimation, and utilizes Particle Swarm Optimization (PSO) to optimize parameters, thereby improving predictive accuracy. The decision-making process of the model is thoroughly interpreted through SHAP value analysis, ensuring credibility and transparency. During the construction of the ASCNN model, this study collected and analyzed bidding control price data from 98 replica traditional vernacular dwellings. The empirical results demonstrate that the ASCNN model exhibits outstanding predictive performance on the test set, with a Root Mean Square Error (RMSE) of 9828.06 yuan, a Mean Absolute Percentage Error (MAPE) of 0.6%, and a Coefficient of Determination (R2) as high as 0.989, confirming the model’s high predictive accuracy and strong generalization capability. Through SHAP value analysis, this study further identifies key factors such as floor plan layout, roof area, and column material coefficient that are central to cost prediction. The ASCNN model proposed in this study not only significantly improves the accuracy of cost estimation for Huizhou replica traditional vernacular dwellings, but also enhances its transparency and credibility through model interpretation methods, providing a reliable basis for related investment decisions. The findings of this study also offer valuable references and insights for rapid and precise cost estimation of replica buildings in other regions worldwide.

Glass-fiber-reinforced polymer (GFRP)–steel composite bar, a novel building material, is a promising longitudinal reinforcement for marine engineering in harsh environments. Previous research has primarily focused on altering individual parameters to assess their influence on the performance of composite bars, lacking a systematic and in-depth exploration. In this paper, the tensile properties of composite bars have been investigated by adequate experimental testing considering the type of inner steel bar and the thickness of the GFRP layer. Results show that although composite bars undergo elasticity, hardening, and failure stages under tensile loading, due to differences in interfacial bonding forces, the ultimate failure mode for composite bars with HPB300 inner steel bars is relative slippage, while for those with HRB400 inner steel bars, it is fracturing. While ensuring that composite bars have good initial elastic modulus and durability, it is preferable for the thickness of the external GFRP layer to be as small as possible. However, the thickness of the external GFRP layer of composite bars should not be less than 2 mm to prevent misalignment of the inner steel bars, which can negatively impact the tangent modulus during the hardening stage and the ultimate tensile strength. Furthermore, a stress–strain constitutive model for this composite bar was developed and validated. This model offers a universal framework for accurately representing the mechanical properties of the material across a wide range of research parameters.

Box beams constructed earlier were prone to inadequate bending capacity owing to low construction standards, overloading, and environmental degradation. To resolve the challenge, three full-scale box slab beams in service for 15 years were strengthened with a high-strength mortar layer and an ultra-high-performance concrete (UHPC) layer in this paper. The flexural performances of unstrengthened beams (control beam) and strengthened beams (mortar beam, UHPC beam) were investigated by in situ four-point bending tests and numerical simulations. The experimental results showed that the cracking of box beams, strengthened with high-strength mortar and UHPC layers, was effectively mitigated. In comparison to the control beam, the cracking load of the mortar beam and the UHPC beam increased by 20%, and the ultimate load increased by 23.5% and 35.3%, respectively. The high-strength mortar layer had little influence on the elastic-phase stiffness of box beams. In contrast, the stiffness of the elastic phase of the box beam, strengthened by the UHPC layer, increased by 32.9%. In the numerical simulations, the load-deflection curves obtained from finite elements and tests coincided well. The characteristic loads showed relatively good agreement with the test results, with errors below 10%. Combined with the tests and numerical analyses, the proposed equations for predicting the ultimate bearing capacities of the control beam, mortar beam, and UHPC beam were presented with a better prediction accuracy.

The main active component of Polygonatum sibiricum (P. sibiricum) rhizome is Polygonatum sibiricum Polysaccharide (PsP) with antioxidant function. At present, only the mature rhizome of P. sibiricum is used to extract PsP, while the young rhizome of by-product is discarded directly as waste, resulting in significant wastage of P. sibiricum resources. We used ultrasound-assisted extraction-deep eutectic solvents (UAE-DESs) method to extract PsP of young and mature rhizomes, respectively. The extraction rate, structure composition and antioxidant ability of PsP between young and mature rhizomes were compared, so as to provide references for comprehensive utilization of P. sibiricum resources. The PsP extraction rate (33.88 ± 1.95%) of young rhizome was close to that (45.08 ± 1.92%) of mature rhizomes. The main component (PsP-2) of the PsP in young rhizome contained six kinds of monosaccharides, which belonged to acidic polysaccharides. The above characteristics of the PsP of young rhizome were similar to those of mature rhizome. The PsP of young rhizome also exhibited similar biological activity to that of the mature rhizome, which indicated even more advantages in DPPH free radical scavenging ability. The results of this study support the utility of the young rhizome, consequently helping to avoid unnecessary waste and provide reference for comprehensive utilization of P. sibiricum.

Abstract Background This study aimed to investigate the association between baseline serum tumor markers (STMs) (carcinoembryonic antigen [CEA], neuron-specific enolase [NSE], cytokeratin-19 fragment [CYFRA21-1], carbohydrate antigen 19–9 [CA19-9], and carbohydrate antigen 125 [CA125]) and the efficacy of first-line immunotherapy in patients with advanced non-small cell lung cancer. Methods This multicenter retrospective study evaluated patients who received first-line immunotherapy between July 2017 and July 2022. The endpoints were progression-free survival (PFS) and overall survival (OS), as defined by the Response Evaluation Criteria in Solid Tumors version 1.1. We divided the patients into three groups based on STM levels: Group A ≥ threefold upper limit of normal, threefold upper limit of normal > Group B > upper limit of normal, and Group C ≤ upper limit of normal. Results In total, 716 patients were included in this study. In Cox proportional hazards analyses, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung adenocarcinoma (LUAD). Except for CA19-9 level, the STM levels in Group C were independently associated with superior PFS and OS in patients with lung squamous carcinoma (LUSC). Except for CEA and CA19-9 levels, the levels in Group A were independently associated with inferior PFS and OS in patients with LUAD and LUSC. Conclusions Serum CEA, NSE, CYFRA21-1, and CA125 levels can predict PFS and OS in patients with LUAD and LUSC, and serum CA19-9 levels can predict PFS and OS in patients with LUAD. The higher the serum NSE, CYFRA21-1, and CA125 levels, the worse the PFS and OS in patients with LUAD and LUSC. In addition, the higher the serum CA19-9 level, the worse the OS in patients with LUAD.

Abstract Background Osteoarthritis (OA) is a prevalent disease plaguing the elderly. Recently, chondrocyte ferroptosis has been demonstrated to promote the progression of OA. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important factor in maintaining cartilage health. However, the relationship between PPARγ and chondrocyte ferroptosis in OA and its mechanism is completely unclear. Methods We established a surgically induced knee OA rat model to investigate PPARγ and chondrocyte ferroptosis in OA. Rat knee specimens were collected for Safranin O/Fast Green staining and immunohistochemical staining after administered orally placebo or pioglitazone (PPARγ agonist) for 4 weeks. We used RSL3 to establish a chondrocyte ferroptosis model cultured in vitro to study the role of PPARγ activation toward ferroptosis, mitochondrial function, and PTEN-induced putative kinase 1 (Pink1)/Parkin-dependent mitophagy. GW9662 (PPARγ antagonist), Mdivi-1 (mitophagy inhibitor), and chloroquine (mitophagy inhibitor) were employed to investigate the mechanism of PPARγ-Pink1/Parkin-dependent mitophagy in the inhibition of ferroptosis. Results We found that PPARγ activation by pioglitazone attenuated not only OA but also inhibited the expression of the ferroptosis marker acyl-CoA synthetase long-chain family member 4 (ACSL4) at the same time in rats. Furthermore, in vivo and in vitro data indicated that PPARγ activation restored Pink1/Parkin-dependent mitophagy, improved mitochondrial function, inhibited chondrocyte ferroptosis, and delayed the progression of OA. Conclusions The present study demonstrated that PPARγ activation attenuates OA by inhibiting chondrocyte ferroptosis, and this chondroprotective effect was achieved by promoting the Pink1/Parkin-dependent mitophagy pathway.

Abstract Urothelial bladder cancer (UBC) is one of the most prevalent malignancies worldwide, with striking tumor heterogeneity. Elucidating the molecular mechanisms that can be exploited for the treatment of aggressive UBC is a particularly relevant goal. Protein ubiquitination is a critical post-translational modification (PTM) that mediates the degradation of target protein via the proteasome. However, the roles of aberrant protein ubiquitination in UBC development and the underlying mechanisms by which it drives tumor progression remain unclear. In this study, taking advantage of clustered regularly interspaced short palindromic repeats (CRISPR)-CRISPR-associated protein (Cas) 9 technology, we identified the ubiquitin E3 ligase ANAPC11, a critical subunit of the anaphase-promoting complex/cyclosome (APC/C), as a potential oncogenic molecule in UBC cells. Our clinical analysis showed that elevated expression of ANAPC11 was significantly correlated with high T stage, positive lymph node (LN) metastasis, and poor outcomes in UBC patients. By employing a series of in vitro experiments, we demonstrated that ANAPC11 enhanced the proliferation and invasiveness of UBC cells, while knockout of ANAPC11 inhibited the growth and LN metastasis of UBC cells in vivo. By conducting immunoprecipitation coupled with mass spectrometry, we confirmed that ANAPC11 increased the ubiquitination level of the Forkhead transcription factor FOXO3. The resulting decrease in FOXO3 protein stability led to the downregulation of the cell cycle regulator p21 and decreased expression of GULP1, a downstream effector of androgen receptor signaling. Taken together, these findings indicated that ANAPC11 plays an oncogenic role in UBC by modulating FOXO3 protein degradation. The ANAPC11–FOXO3 regulatory axis might serve as a novel therapeutic target for UBC.

Abstract Background Circular RNAs (circRNAs) circularized by back-splicing of pre-mRNA are widely expressed and affected the proliferation, invasion and metastasis of bladder cancer (BCa). However, the mechanism underlying circRNA biogenesis in mediating the distant metastasis of BCa still unexplored. Methods RNA sequencing data between BCa and normal adjacent tissues was applied to identify the differentially expressed circRNAs. The functions of circNIPBL in BCa were investigated via a series of biochemical experiments. The Clinical significance of circNIPBL was examined in a cohort of larger BCa tissues. Results In the present study, we identified a novel circRNA (hsa_circ_0001472), circNIPBL, which was significantly upregulated and had great influence on the poor prognosis of patients with BCa. Functionally, circNIPBL promotes BCa metastasis in vitro and in vivo. Mechanistically, circNIPBL upregulate the expression of Wnt5a and activated the Wnt/β-catenin signaling pathway via directly sponged miR-16-2-3p, leading to the upregulation of ZEB1, which triggers the EMT of BCa. Moreover, we revealed that ZEB1 interacted with the flanking introns of exons 2–9 on NIPBL pre-mRNA to trigger circNIPBL biogenesis, thus forming a positive feedback loop. Importantly, circNIPBL overexpression significantly facilitated the distant metastasis of BCa in the orthotopic bladder cancer model, while silencing ZEB1 remarkably blocked the effects of metastasis induced by circNIPBL overexpression. Conclusions Our study highlights that circNIPBL-induced Wnt signaling pathway activation triggers ZEB1-mediated circNIPBL biogenesis, which forms a positive feedback loop via the circNIPBL/miR-16-2-3p/Wnt5a/ZEB1 axis, supporting circNIPBL as a novel therapeutic target and potential biomarker for BCa patients. Graphical Abstract

Abstract Objective Bladder cancer is the 13th most common cancer in China with the predominant histologic type being urothelial carcinoma (UC). Locally advanced and metastatic (la/m) UC accounts for 12% of UC and the five‐year survival rate is only 39.4%, imposing a significant disease and economic burden on the patients. The aim of this scoping review is to synthesize existing evidence of epidemiology, the landscape of treatment options and associated efficacy and safety profiles, as well as treatment‐related biomarkers among Chinese la/mUC patients. Methods A systematic search was conducted on five databases (PubMed, Web of Science, Embase, Wanfang, and CNKI) from January 2011 to March 2022 based on the scoping review criteria in accordance with the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis Extension for Scoping Reviews. Results A total of 6211 records were identified, and further review resulted in 41 relevant studies that met all criteria. Additional searches were conducted on epidemiology and treatment‐related biomarkers of bladder cancer to supplement the evidence. Among 41 studies, 24 reported on platinum‐based chemotherapy, eight on non‐platinum‐based chemotherapy, six on immunotherapy, two on targeted therapy, and one on surgery. Efficacy outcomes were summarized by line of therapy. Treatment‐related biomarkers including PD‐L1, HER2, and FGFR3 alterations were identified, and the alteration rate of FGFR3 of Chinese UC patients was lower than that of the western patients. Conclusions Despite chemotherapy has been the main treatment choice for decades, appealing new therapeutic strategies including ICIs, targeted therapies and ADCs were applied in clinical practice. Further research on epidemiology and treatment‐related biomarkers of la/mUC patients is needed given only a limited number of studies have been identified thus far. High genomic heterogeneity and complexity of molecular features were observed among la/mUC patients; thus, further studies are required to identify critical drivers and promote potential precise therapies.

The heterogeneous Fenton process is a strategy for overcoming the greatest shortcomings of traditional homogeneous Fenton, i.e. the high generation of ferric hydroxide sludge and effectivity in a limited pH range. In this study, we constructed a heterogeneous Fenton system with natural iron-bearing clay mineral (nontronite) and dimethoxyhydroquinone (DMHQ) to degrade lincomycin (LCM) without the addition of H2O2. The degradation mechanism was derived from the hydroxyl radicals (•OH) produced from the oxygenation of Fe(II) in nontronites, which was reduced by DMHQ. Acidic conditions and low concentrations of LCM were favourable for LCM degradation. When the solution pH increased from 3 to 7, the final LCM removal ratio decreased from 95 to 46%. However, LCM can still be degraded by 46% under neutral conditions and 20% at the LCM concentration of 500 μmol/L. The nontronite has good reusability, and the LCM degradation efficiency in the fourth cycle still exceeded 90% of the original efficiency. The degradation sites of LCM mainly occurred in the methyl thioether moiety and the aliphatic amine group on the pyrrolidine ring, with the final product of CO2. This research presents a new eco-friendly and cost-effective method for the heterogenous Fenton process without external H2O2. HIGHLIGHTS 2,6-DMHQ could reduce structural Fe(III) to form Fe(II) to react with O2 and yield •OH.; LCM could be effectively degraded in the nontronite/2,6-DMHQ reaction system.; The nontronite was efficient with good reusability material.; The clay mineral not only provides iron but also a constrained reaction environment.; The reaction system is efficient, simple, and does not need H2O2 addition.;

Highlights A non-corrosive and air-stable hydrated eutectic electrolyte is developed. The electrolyte is composed of aluminum perchlorate nonahydrate and methylurea. The unique solvation structure enables reversible deposition/stripping of Al. The Al-ion battery in this electrolyte shows good charge/discharge performance.

Docynia has been treated as a separate genus or merged into Cydonia or Docyniopsis. Our phylogenomic evidence from 797 single-copy nuclear genes and plastomes confirmed the sister relationship between Docynia and Docyniopsis. By integrating the phylogenomic and morphological evidence, we propose to accept a broad generic concept of Malus and merge Docynia into Malus. Three new combinations are also made here: Malus delavayi (Franch.) B.B.Liu, M. indica (Wall.) B.B.Liu and M. longiunguis (Q.Luo & J.L.Liu) B.B.Liu.

Abstract Sterol carrier protein 2 (SCP2) is highly expressed in human osteoarthritis (OA) cartilage, accompanied by ferroptosis hallmarks, especially the accumulation of lipid hydroperoxides (LPO). However, the role of SCP2 in chondrocyte ferroptosis remains unexplored. Here, we identify that SCP2 transports cytoplasmic LPO to mitochondria in RSL3-induced chondrocyte ferroptosis, resulting in mitochondrial membrane damage and release of reactive oxygen species (ROS). The localization of SCP2 on mitochondria is associated with mitochondrial membrane potential, but independent of microtubules transport or voltage-dependent anion channel. Moreover, SCP2 promotes lysosomal LPO increase and lysosomal membrane damage through elevating ROS. However, SCP2 is not directly involved in the cell membrane rupture caused by RSL3. Inhibition of SCP2 markedly protects mitochondria and reduces LPO levels, attenuating chondrocyte ferroptosis in vitro and alleviating the progression of OA in rats. Our study demonstrates that SCP2 mediates the transport of cytoplasmic LPO to mitochondria and the spread of intracellular LPO, accelerating chondrocyte ferroptosis.

Abstract Lymphatic metastasis is the most common pattern of bladder cancer (BCa) metastasis and has an extremely poor prognosis. Emerging evidence shows that ubiquitination plays crucial roles in various processes of tumors, including tumorigenesis and progression. However, the molecular mechanisms underlying the roles of ubiquitination in the lymphatic metastasis of BCa are largely unknown. In the present study, through bioinformatics analysis and validation in tissue samples, we found that the ubiquitin-conjugating E2 enzyme UBE2S was positively correlated with the lymphatic metastasis status, high tumor stage, histological grade, and poor prognosis of BCa patients. Functional assays showed that UBE2S promoted BCa cell migration and invasion in vitro, as well as lymphatic metastasis in vivo. Mechanistically, UBE2S interacted with tripartite motif containing 21 (TRIM21) and jointly induced the ubiquitination of lipoma preferred partner (LPP) via K11-linked polyubiquitination but not K48- or K63-linked polyubiquitination. Moreover, LPP silencing rescued the anti-metastatic phenotypes and inhibited the epithelial-mesenchymal transition of BCa cells after UBE2S knockdown. Finally, targeting UBE2S with cephalomannine distinctly inhibited the progression of BCa in cell lines and human BCa-derived organoids in vitro, as well as in a lymphatic metastasis model in vivo, without significant toxicity. In conclusion, our study reveals that UBE2S, by interacting with TRIM21, degrades LPP through K11-linked ubiquitination to promote the lymphatic metastasis of BCa, suggesting that UBE2S represents a potent and promising therapeutic target for metastatic BCa.

Abstract Purpose To clarify the necessity and effect of a single intraoperative instillation of chemotherapy during radical cystectomy. Methods Patients who underwent radical cystectomy for bladder cancer between January 2013 and April 2019 were retrospectively evaluated and divided into a non‐instillation group and an instillation group according to the intraoperative instillation of chemotherapy. Univariate and multivariate Cox regression was used to determine the clinical predictors of overall survival and disease‐free survival. Kaplan–Meier analysis and log‐rank tests were performed to analyze overall survival and disease‐free survival. Results Of the 320 patients who were enrolled in the study, 113 underwent radical cystectomy with intraoperative instillation of chemotherapy. Univariate Cox analysis showed that intraoperative instillation was not a risk factor for overall survival or disease‐free survival (HR: 1.04, 95% CI: 0.66–1.63, p = 0.864; HR: 1.11, 95% CI: 0.76–1.62, p = 0.602, respectively). As shown in the Kaplan–Meier analysis, no significant differences were noted in overall survival (p = 0.857) and disease‐free survival (p = 0.600) between the two groups. A subgroup analysis demonstrated that intraoperative instillation was not associated with a statistically better overall survival and disease‐free survival in the nonmuscle invasive (p = 0.852 and 0.836) and muscle‐invasive (p = 0.929 and 0.805) patients. Conclusion A single intraoperative instillation of chemotherapy during radical cystectomy was not related to better disease‐free survival or overall survival. It is unnecessary to consider single instillation of chemotherapy as a regular procedure during radical cystectomy.

Abstract Background Programmed cell death‐1/ligand 1 inhibitors are a new treatment strategy for advanced urothelial carcinoma. Therefore, a comparative evaluation of their efficacy and toxicity compared with chemotherapy is necessary. Methods We comprehensively searched PubMed, Web of Science, Embase, and Cochrane Library databases and performed a meta‐analysis of randomized controlled trials up to July 2021. We considered overall survival as the primary outcome, and progression‐free survival, objective response rate, and treatment‐related adverse events as secondary outcomes. Results Overall, 3584 patients from five studies were evaluated. Compared with first‐line chemotherapy, programmed cell death‐1/ligand 1 inhibitors were significantly associated with worse progression‐free survival (p

Abstract Fibroadenomas (FAs) are the most common breast tumors in women. No pharmacological agents are currently approved for FA intervention owing to its unclear mechanisms and a shortage of reproducible human models. Here, using single-cell RNA sequencing of human FAs and normal breast tissues, we observe distinct cellular composition and epithelial structural changes in FAs. Interestingly, epithelial cells exhibit hormone-responsive functional signatures and synchronous activation of estrogen-sensitive and hormone-resistant mechanisms (ERBB2, BCL2 and CCND1 pathways). We develop a human expandable FA organoid system and observe that most organoids seem to be resistant to tamoxifen. Individualized combinations of tamoxifen with ERBB2, BCL2 or CCND1 inhibitors could significantly suppress the viability of tamoxifen-resistant organoids. Thus, our study presents an overview of human FA at single-cell resolution that outlines the structural and functional differences between FA and normal breast epithelium and, in particular, provides a potential therapeutic strategy for breast FAs.

Abstract Cannabidiol (CBD), a major non-psychoactive phytocannabinoid in cannabis, is an effective treatment for some forms of epilepsy and pain. At high concentrations, CBD interacts with a huge variety of proteins, but which targets are most relevant for clinical actions is still unclear. Here we show that CBD interacts with Nav1.7 channels at sub-micromolar concentrations in a state-dependent manner. Electrophysiological experiments show that CBD binds to the inactivated state of Nav1.7 channels with a dissociation constant of about 50 nM. The cryo-EM structure of CBD bound to Nav1.7 channels reveals two distinct binding sites. One is in the IV-I fenestration near the upper pore. The other binding site is directly next to the inactivated “wedged” position of the Ile/Phe/Met (IFM) motif on the short linker between repeats III and IV, which mediates fast inactivation. Consistent with producing a direct stabilization of the inactivated state, mutating residues in this binding site greatly reduced state-dependent binding of CBD. The identification of this binding site may enable design of compounds with improved properties compared to CBD itself.

Abstract Performance of Susceptible-Infected-Recovered (SIR) model in the early stage of a novel epidemic may be hindered by data availability. Additionally, the traditional SIR model may oversimplify the disease progress, and knowledge about the virus and transmission is limited early in the epidemic, resulting in a greater uncertainty of such modelling. We aimed to investigate the impact of model inputs on the early-stage SIR projection using COVID-19 as an illustration to evaluate the application of early infection models. We constructed a modified SIR model using discrete-time Markov chain to simulate daily epidemic dynamics and estimate the number of beds needed in Wuhan in the early stage of COVID-19 epidemic. We compared eight scenarios of SIR projection to the real-world data (RWD) and used root mean square error (RMSE) to assess model performance. According to the National Health Commission, the number of beds occupied in isolation wards and ICUs due to COVID-19 in Wuhan peaked at 37,746. In our model, as the epidemic developed, we observed an increasing daily new case rate, and decreasing daily removal rate and ICU rate. This change in rates contributed to the growth in the needs of bed in both isolation wards and ICUs. Assuming a 50% diagnosis rate and 70% public health efficacy, the model based on parameters estimated using data from the day reaching 3200 to the day reaching 6400 cases returned a lowest RMSE. This model predicted 22,613 beds needed in isolation ward and ICU as on the day of RWD peak. Very early SIR model predictions based on early cumulative case data initially underestimated the number of beds needed, but the RMSEs tended to decline as more updated data were used. Very-early-stage SIR model, although simple but convenient and relatively accurate, is a useful tool to provide decisive information for the public health system and predict the trend of an epidemic of novel infectious disease in the very early stage, thus, avoiding the issue of delay-decision and extra deaths.

Abstract Voltage-gated sodium (Nav) channels are targeted by a number of widely used and investigational drugs for the treatment of epilepsy, arrhythmia, pain, and other disorders. Despite recent advances in structural elucidation of Nav channels, the binding mode of most Nav-targeting drugs remains unknown. Here we report high-resolution cryo-EM structures of human Nav1.7 treated with drugs and lead compounds with representative chemical backbones at resolutions of 2.6-3.2 Å. A binding site beneath the intracellular gate (site BIG) accommodates carbamazepine, bupivacaine, and lacosamide. Unexpectedly, a second molecule of lacosamide plugs into the selectivity filter from the central cavity. Fenestrations are popular sites for various state-dependent drugs. We show that vinpocetine, a synthetic derivative of a vinca alkaloid, and hardwickiic acid, a natural product with antinociceptive effect, bind to the III-IV fenestration, while vixotrigine, an analgesic candidate, penetrates the IV-I fenestration of the pore domain. Our results permit building a 3D structural map for known drug-binding sites on Nav channels summarized from the present and previous structures.

Abstract Objectives Aberrantly expressed circular RNAs (circRNAs) have been detected in many types of tumors. Hence, they are currently investigated as candidate biomarkers for diagnostic and potential targets for therapy in cancers. The objective of this study was to assess the expression profile of circRNA in lung adenocarcinoma (LUAD). Methods This study included 14 pairs of postoperative lung adenocarcinoma specimens, including cancer tissues and matched adjacent tissues. Second‐generation sequencing was applied to the specimens to determine the circRNA expression in them among the 5242 distinct circRNAs detected. Results We identified a total of 18 significantly dysregulated circRNAs in the LUAD tissues: upregulation in four and downregulation in 14. ROC (The receiver operating characteristic curve) further suggested that hsa_circ_0120106, has_circ_0007342, has_circ_0005937, and circRNA_0000826 could potentially be used as biomarkers in the diagnosis of LUAD. Furthermore, study of the circRNA–microRNA (miRNA)–messenger RNA (mRNA) revealed interactions between the 18 dysregulated circRNA and several cancer‐related miRNAs. Finally, a further Kyoto Encyclopedia of Genes and Genomes analysis showed that the cell cycle phase transition, p53 signaling pathway, AMP‐activated protein kinase (AMPK) relative signaling pathway, and so on were key putative pathways in the process of LUAD. Conclusions These findings demonstrated the correlation between abnormality in circRNA expression and LUAD, which lays the foundation of making CircRNAs candidate biomarkers in the diagnosis of LUAD.

Background: Cancer is a significant global health problem that continues to cause a high number of deaths worldwide. Traditional cancer treatments often come with risks that can compromise the functionality of vital organs. As a potential alternative to these conventional therapies, Anticancer peptides (ACPs) have garnered attention for their small size, high specificity, and reduced toxicity, making them as a promising option for cancer treatments.Methods: However, the process of identifying effective ACPs through wet-lab screening experiments is time-consuming and requires a lot of labor. To overcome this challenge, a deep ensemble learning method is constructed to predict anticancer peptides (ACPs) in this study. To evaluate the reliability of the framework, four different datasets are used in this study for training and testing. During the training process of the model, integration of feature selection methods, feature dimensionality reduction measures, and optimization of the deep ensemble model are carried out. Finally, we explored the interpretability of features that affected the final prediction results and built a web server platform to facilitate anticancer peptides prediction, which can be used by all researchers for further studies. This web server can be accessed at http://lmylab.online:5001/.Results: The result of this study achieves an accuracy rate of 98.53% and an AUC (Area under Curve) value of 0.9972 on the ACPfel dataset, it has improvements on other datasets as well.