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Abstract Double-lumen tubes (DLTs) are commonly used for one-lung ventilation (OLV) in thoracic surgery and the selection of an optimal size of DLTs is still a humongous task. The purpose of this study was to assess the feasibility and accuracy of the method for selecting an optimal size of DLTs in thoracic surgery. Sixty adult patients requiring a left side double-lumen tube (LDLT) for elective thoracoscopic surgery were included in this study. All patients were randomly allocated to the following two groups: Cuffs Collapsed group (CC group, n = 30) and Cuffs Inflated group (CI group, n = 30). In the Cuffs Collapsed group, the outer diameter of LDLT (the outer diameter of the tracheal and bronchial cuffs when they were collapsed as the outer diameter of the LDLT) matched with the inner diameter of the trachea and bronchus measured by the anesthesiologist on the chest CT slice; In the Cuffs Inflated group, the outer diameter of LDLT (the outer diameter of the tracheal and bronchial cuffs when they were inflated as the outer diameter of the LDLT) matched with the inner diameter of the trachea and bronchus measured by the anesthesiologist on the chest CT slice. The primary outcomes were the incidences of airway complications postoperative such as hoarseness and sore throat. The time of intubation and alignment, the incidences of LDLT displacement and adjustment, the peak airway pressure, the plateau airway pressure and the end-tidal carbon dioxide were also recorded. The incidences of airway complications postoperative such as sore throat and hoarseness were lower in the CI group than the CC group (P 0.05). The method which matched the inner diameter of the trachea and bronchus measured on chest CT slice with the outer diameter of the tracheal and bronchial cuffs when they were inflated to select an appropriate size of LDLT can reduce the incidence of airway complications. Trials registration: Clinical Trials: gov. no. NCT05739318. Registered at https://classic.clinicaltrials.gov 22/02/2023.

Objective To compare the effects of 10-methacryloyloxydecyl dihydrogen phosphate (10-MDP)- and silane-based primers with those of MDP-based primers on zirconia-resin bonding via multiple levels of aging. Methods Zirconia blocks were divided into 4 groups (n = 21) according to the primer used: MDP-based Z-Prime Plus (ZP), silane-based Monobond-S (MS), MDP- and silane-based Clearfil Ceramic Primer (CCP) and no primer (Blank). After pretreatment with or without the primers followed by bonding with cement Duo-Link, each group was subdivided into 3 subgroups (n = 7) according to aging level: 24 hours of water storage at 37 ℃ (24 h), 30 days of water storage at 37 ℃(30 d), and 30 d plus 3 000 thermal cycles (30 d/TC). After aging, shear bond strength (SBS) tests and failure mode analyses were conducted. Results ZP, MS and CCP groups had greater SBSs than did the BLANK group (PPPvs. 24 h, PPP = 0.029) but lower than that of MS at 30 d/TC (P = 0.037). From 30 d to 30 d/TC, the percent decrease in the bonding strength of ZP was significantly greater than that of MS (82.43% vs. 64.90%). Conclusion MDP-based primers function better for zirconia-resin bonding when they contain silane coupling agents.

Abstract The recommended bearing capacity of medium weathering mudstone foundation is less than the capacity of the rock structure to withstand loads in Southwest China. A comprehensive failure characterization of medium weathering mudstone in Chengdu has been performed including bearing plate test (BPT), binocular vision measurement (BVM) test, uniaxial compressive strength test, trial trench test of shallow rock surface and 3D imaging in this paper. Failure behavior of rock has been modeled with 3D imaging algorithm that utilizes Zhang’s calibration method in BVM system combination with trial trench test of shallow rock surface. The bearing capacity of medium weathering mudstone foundation were extracted from uniaxial experiments and BPT-BVM test by fitting relevant material properties to the data. The results revealed that: Bearing capacity of medium weathering mudstone of layered isotropic in Chengdu is undervalued. Specifically, the characteristic load carrying value is in the range 1500–2500 kP, that is 50% higher than in the local standard system. Failure process is different from Hoek–Brown Failure Criterion, presenting a wave peak transfer phenomenon of the increment displacement into the distance. Thus, it can be reduced to that of punching failures for thin bedded structures of Moudstone foundations. Compressive strength of soft rock proves to be main factor limiting the bearing capacity, a clear correlation between the uniaxial compressive strength reduction coefficient and the bearing capacity has been used to establish, leading to the proposal of a load bearing capacity prediction model.

Abstract Disc cutters are essential for full-section hard-rock tunnel boring machines. The performance of these devices directly affects tunnel engineering costs and duration. This paper proposes a sinusoidal variable cross-section (VCS) cutter ring and design method and establishes a digital model. Rock-like materials are simulated with a finite element model, and the model validity is verified via rock simulation mechanics tests. A disc cutter rolling rock simulation model for a linear cutting machine is also established, and simulation tests are performed for single- and three-cutter rolling using sinusoidal VCSs and constant cross-section (CCS) cutter models, respectively. The stress and energy changes for the cutters and rock-like material damage area were compared via simulation, confirming that some sinusoidal VCS cutter rings do less work on rock-like materials and cause larger crushing areas under the same engineering parameters; therefore, these cutter rings have smaller specific energies. The sinusoidal VCS cutter ring performance is 7% greater than that of CCS on average under single-cutter simulation, and the intermediate cutter performance of the intermediate cutter is 9% greater than that of CCS on average under three-cutter simulation. Thus, sinusoidal VCS cutter rings offer improved rock damage performance, and further research and application of this technology will improve the working efficiency of tunnel boring machines.

Abstract Parents’ beliefs and attitudes toward their children with Tourette syndrome (TS) influence treatment-seeking behaviors. This study aimed to explore and describe the Chinese parents’ perspectives on the causes of TS for their children. A qualitative study using semi-structured interviews was conducted with the parents of TS patients from a children’s hospital in western China from June to July 2021, and thematic analysis was performed to transcribe interviews and identify themes. A total of 13 participants were interviewed in this study. Five themes were developed in relation to the cognition of the causes of TS in parents, including physical problems, parenting and education problems, mental problems, bad habits, and neurological problems. Due to the insufficient awareness of TS, most parents repeatedly seek medical advice that they regarded the symptoms as physical problems or neurological problems. They generally felt guilty and blamed themselves for their parenting styles and education methods. And some parents attributed it to the poor psychological quality or the bad habits of children. Study findings showed a lack of scientific understanding of the causes of TS among parents further hindered the timely effective treatment for patients and affected the family relationships, which highlights the importance of public education and raising awareness of the disease.

Abstract Natural killer T cell lymphoma (NKTCL) is highly aggressive, with advanced stage patients poorly responding to intensive chemotherapy. To explore effective and safe treatment for newly diagnosed advanced stage NKTCL, we conducted a phase II study of anti-metabolic agent pegaspargase plus PD-1 antibody sintilimab (NCT04096690). Twenty-two patients with a median age of 51 years (range, 24–74) were enrolled and treated with induction treatment of pegaspargase 2500 IU/m2 intramuscularly on day 1 and sintilimab 200 mg intravenously on day 2 for 6 cycles of 21 days, followed by maintenance treatment of sintilimab 200 mg for 28 cycles of 21 days. The complete response and overall response rate after induction treatment were 59% (95%CI, 43–79%) and 68% (95%CI, 47–84%), respectively. With a median follow-up of 30 months, the 2 year progression-free and overall survival rates were 68% (95%CI, 45–83%) and 86% (95%CI, 63–95%), respectively. The most frequently grade 3/4 adverse events were neutropenia (32%, n = 7) and hypofibrinogenemia (18%, n = 4), which were manageable and led to no discontinuation of treatment. Tumor proportion score of PD-L1, peripheral blood high-density lipoprotein cholesterol, and apolipoprotein A-I correlated with good response, while PD-1 on tumor infiltrating lymphocytes and peripheral Treg cells with poor response to pegaspargase plus sintilimab treatment. In conclusion, the chemo-free regimen pegaspargase plus sintilimab was effective and safe in newly diagnosed, advanced stage NKTCL. Dysregulated lipid profile and immunosuppressive signature contributed to treatment resistance, providing an alternative therapeutic approach dual targeting fatty acid metabolism and CTLA-4 in NKTCL.

Background Currently, there is a lack of clinical competence evaluation tools applicable of general practitioners (GPs) practicing in rural settings in China, resulting in the lack of researches on the clinical competence evaluation of GPs in rural. Objective To explore reliability and validity of an evaluation index system for consultation competency of rural GPs developed previously, and provide an evaluation tool with high reliability and validity for scientific and objective assessment of consultation competence of GPs in rural settings. Methods Based on the evaluation system for consultation competency of rural GPs, a corresponding questionnaire was designed, and points were assigned to each option on a 5-point Likert scale. From September to December 2022, GPs or assistant general practitioners (AGPs) who were working in rural township health centers in Guangxi Province were recruited as the research subjects by using the purposive sampling and stratified sampling methods, the questionnaire was distributed through a national web-based survey platform-"WJX" to them. Cronbach's α coefficient, split-half coefficient, critical ratio (CR) and correlation coefficients were calculated based on questionnaire data. Confirmative factor analysis was employed to fit questionnaire data and assumed model, and calculate three categories of indicators, including preliminary fit criteria (PFC), overall model fit (OMF), and fit of internal structural model (FISM), to verify the degree of fit and structural validity of the measured data. Results A total of 600 questionnaires were distributed and 366 were validly collected, with an effective recovery rate of 61.0%, 86.1% were registered as GPs and 13.9% as AGPs, who came from five cities, including Nanning, Guilin, Wuzhou, Baise, and Guigang, and 204 township health centers in Guangxi Province. Cronbach'α coefficient for the whole questionnaire or for every section was higher than 0.700, and Guttman Split-Half coefficient was 0.931. The initial first-order model met the PFC well; except for goodness of fit index (GFI), adjusted goodness of fit index (AGFI), and normed fit index (NFI), other indicators related to the OMF reached for the best levels in the modified first-order model. Apart from R2 for 9 observable variables less than 0.5, the FISM for the modified first-order model showed good effects. The initial second-order model indicated as similar effects on the PFC as the initial first-order model; the modified second-order model shared similar OMF with the modified first-order model; the modified second-order model was inferior to the modified first-order model in terms of the FISM. Eventually, questionnaire data fitted the modified first-order model better. Conclusion The evaluation index system for consultation competency of rural GPs shows high reliability and validity, which can be used for research and practical work on the evaluation of consultation competence evaluation of GPs in rural settings.

Background Training general practitioners (GPs) and improving the practice competence of "GP-centered" primary health care personnel are important directions of the development of human resources for primary health care in China. At present, there is lack of an index system applicable to evaluate clinical competence of GPs in the circumstances of primary health care in China, which not only hampers accurate identification of gaps in clinical competence of GPs, but also impedes sustainable improvement of the education and training of GPs as well as primary health care personnel. Objective To develop an evaluation index system for consultation competency of GPs in the circumstances of primary health care in China based on the original version of Leicester Assessment Package (LAP), so as to provide an index model reference for the objective evaluation of consultation competency of GPs. Methods Between May to August in 2022, a total of 15 experts were invited by using the purposive sampling method to implement the Delphi method by correspondence, to evaluate the importance, feasibility, and textual representation of each index in the initial evaluation index system for consultation competency of GPs. Analytic hierarchy process was adopted to calculate weight and combined weight for the first-level and secondary-level indexes. Results A total of two rounds of Delphi were conducted. The positivity coefficient, familiarity level, judgment coefficient, and authority coefficient were 100%, 0.77, 0.91, and 0.84 in both rounds of consultation; the mean score of the importance and feasibility of each indicator was 3.5, and the variation coefficient was 0.3. The Kendall coefficients for the importance and feasibility of the indexes in the two rounds of consultation were statistically different (P

Abstract SARS-CoV-2 and its variants are widely prevalent worldwide. With frequent secondary and breakthrough infections, immune dysfunction in RA patients, and long-term use of immune preparations, SARS-CoV-2 infection poses a significant challenge to patients and rheumatologists. Whether SARS-CoV-2 infection causes RA flares and what factors aggravate RA flares are poorly studied. A questionnaire survey was conducted on RA patients infected with SARS-CoV-2 after December 7, 2022, in China through a multicenter and inter-network platform regarding general personal condition, primary disease, comorbidity, SARS-CoV-2 vaccination, viral infection, and impact on the primary disease. A total of 306 RA patients were included in this study, and the patient data were analyzed, in which the general condition of RA patients, medication use before SARS-CoV-2 infection and post-infection typing and manifestations, and medication adjustment did not affect the Flare of RA patients after SARS-CoV-2 infection. The control of disease before SARS-CoV-2 infection (OR = 2.10), RA involving pulmonary lesions (OR = 2.28), and the recovery time of COVID-19 (OR = 2.50) were risk factors for RA flare. RA involving pulmonary lesions, control status of disease before infection, and recovery time of COVID-19 disease are risk factors for RA flare after SARS-CoV-2 infection.

BackgroundPostinduction hypotension (PIHO) is a hemodynamic abnormality commonly observed during the induction of general anesthesia. Etomidate is considered a safer drug for the induction of anesthesia because it has only minor adverse effects on the cardiovascular and pulmonary systems. Recent evidence indicates that the novel benzodiazepine remimazolam has minimal inhibitory effects on the circulation and respiration. However, the efficacy and safety of remimazolam versus etomidate in the induction of anesthesia are unclear. ObjectiveTo further understand the potential of remimazolam in anesthesia induction, it is necessary to design a meta-analysis to compare its effects versus the classic safe anesthetic etomidate. The aim of this study is to determine which drug has more stable hemodynamics and a lower incidence of PIHO. Our study will also yield data on sedation efficiency, time to loss of consciousness, time to awakening, incidence of injection pain, and postoperative nausea and vomiting with the two drugs. MethodsWe plan to search the Web of Science, Cochrane Library, Embase, PubMed, China National Knowledge Infrastructure, and Wanfang databases from the date of their creation until March 31, 2025. The language is limited to English and Chinese. The search terms are “randomized controlled trials,” “etomidate,” and “remimazolam.” The incidence of PIHO is the primary outcome measure. Secondary outcomes include depth of anesthesia after induction, sedation success rate, time to loss of consciousness, hemodynamic profiles, recovery time, incidence of injection pain, and postoperative nausea and vomiting. Reviews, meta-analyses, case studies, abstracts from conferences, and commentaries will not be included. The heterogeneity of the results will be evaluated by sensitivity and subgroup analyses. RevMan software and Stata software will be used for data analysis. We will evaluate the quality of included studies using version 2 of the Cochrane risk-of-bias tool. The confidence of the evidence will be assessed through the Grading of Recommendations, Assessments, Developments, and Evaluations system. ResultsThe protocol was registered in the international PROSPERO (Prospective Register of Systematic Reviews) registry in November 2023. As of June 2024, we have performed a preliminary article search and retrieval for further review. The review and analyses are expected to be completed in March 2025. We expect to submit manuscripts for peer review by the end of June 2025. ConclusionsBy synthesizing the available evidence and comparing remimazolam and etomidate, we hope to provide valuable insights into the selection of anesthesia-inducing drugs to reduce the incidence of PIHO and improve patient prognosis. Trial RegistrationPROSPERO CRD42023463120; https://tinyurl.com/333jb8bm International Registered Report Identifier (IRRID)PRR1-10.2196/55948

Abstract Metabolic abnormalities constitute a significant characteristic of systemic lupus erythematosus (SLE). We utilised a two-sample Mendelian randomisation (MR) study to evaluate the potential causal association between 486 blood metabolites and SLE. Exposure data at the metabolite level were extracted from 7824 European Genome-wide association studies (GWAS). Preliminary analysis utilised SLE GWAS data from FinnGen. The primary method for causal analysis relied on random inverse variance weighting (IVW). To ensure robustness, sensitivity analyses included the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis. Steiger testing and linkage disequilibrium score regression were employed to validate the identified metabolites. This study identified 12 metabolites, comprising six known chemical structures: 1,5-anhydroglucitol(1,5-AG) [odds ratio (OR) = 0.100, 95% confidence interval (CI): 0.015–0.773, P = 0.027), gamma-glutamylthreonine (OR = 0.077, 95% CI: 0.010–0.574, P = 0.012), 5-dodecenoate(12:1n7) (OR = 0.205, 95% CI: 0.061–0.685, P = 0.010), linoleoylglycerophosphoethanolamine * (OR = 0.159, 95% CI: 0.027–0.933, P = 0.044), erythrose (OR = 88.331,95% CI:1.098–63.214, P = 0.040) and 1-, adrenate (22:4n6) (OR = 9.876, 95% CI: 1.753–55.639, P = 0.001)]. Additionally, we found associations between SLE and six unknown chemical structures: X-06351 (OR = 0.071, 95% CI: 0.006–0.817, P = 0.034), X-10810 (OR = 4.268 95% CI: 1.260–14.459, P = 0.020), X-11412 (OR = 5.418 95% CI: 1.068–27.487, P = 0.041), X-11905 (OR = 0.551, 95%CI: 0.304–0.997, P = 0.049), X-12038 (OR = 0.178 95%CI: 0.032–0.988, P = 0.045), X-12217 (OR = 0.174 95%CI: 0.044–0.680, P = 0.014). This study offers evidence supporting a causal relationship between SLE and 12 circulating metabolites, six of which have known chemical structures and six that remain unidentified. These findings introduce a new perspective for further exploration of SLE mechanisms.

Abstract The association between the systemic immune-inflammation index (SII) and the risk of sarcopenia has not yet been revealed. The purpose of this study was to investigate the relationship between the SII and sarcopenia in individuals aged 18–59 years. All data for this study are from the National Health and Nutrition Examination Survey (NHANES) database, including 7258 participants (age range: 18–59 years). We divided SII values by quartiles (quartiles 1–4: 0.3–3.1, 3.2–4.4, 4.4–6.2, and 6.2–58.5). We constructed a multivariate logistic regression model to assess the association between the SII and the risk of sarcopenia, and an interaction test was run to test the stability of the model and identify high-risk individuals with sarcopenia. Compared to nonsarcopenia participants, sarcopenia patients had a significantly higher SII value (weighted average: 6.65 vs. 5.16) (P = 0.002). Multivariate logistic regression results showed a positive linear relationship between the SII and sarcopenia (OR [odds ratio] = 1.12, 95% CI [confidence interval] 1.03–1.21). Compared to the quartile 1 group, the quartile 4 group was associated with a higher risk of sarcopenia (OR = 3.94, 95% CI 1.42–10.94). Compared with the quartile 1 group, the OR value of the quartile 2 to quartile 4 groups showed an upwards trend (P trend

Abstract Silicon is considered as the most promising anode material for high performance lithium-ion batteries due to its high theoretical specific capacity and low working potential. However, severe volume expansion problems existing during the process of (de)intercalation which seriously hinders its commercial progress. Binder can firmly adhere silicon and conductive agent to the current collector to maintain the integrity of the electrode structure, thereby effectively alleviating the silicon volume expansion and realizing lithium-ion batteries with high electrochemical performance. In this paper, citric acid (CA) and carboxymethyl cellulose (CMC) are adopted to construct a covalently crosslinked CA@CMC binder by an easy-to-scale-up esterification treatment. The Si@CA@CMC-1 electrode material shows an impressive initial coulombic efficiency (ICE) at 82.1% and after 510 cycles at 0.5 A/g, its specific capacity is still higher than commercial graphite. The excellent electrochemical performance of Si@CA@CMC-1 can be attributed to the ester bonds formed among CA@CMC binder and silicon particles. Importantly, by decoupling in situ EIS combining XPS at different cycles, it can be further proved that the CA@CMC binder can tune the component of SEI which provide a new-route to optimize the performance of silicon.

Abstract TP53 mutation (TP53 mut) occurs in 10–20% of diffuse large B-cell lymphoma (DLBCL) cases and serves as an unfavorable biomarker of DLBCL progression. It confers resistance to immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation, and anti-CD19 chimeric antigen receptor T-cell therapy. Therapeutic targeting of TP53 mut remains a significant challenge in DLBCL treatment. Here we assessed TP53 mut in 667 patients with newly diagnosed DLBCL, including 576 patients treated with immunochemotherapy rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and 91 patients with decitabine plus R-CHOP (DR-CHOP, NCT02951728 and NCT04025593). TP53 mut independently predicted an inferior prognosis in R-CHOP-treated DLBCL, although this could be mitigated by DR-CHOP treatment. In TP53 mut patients, multiple viral regulation pathways were repressed, resulting in the inhibition of immune modulation, as revealed by gene set enrichment analysis. TP53 mut DLBCL exhibited increased methyltransferase SUV39H1 expression and H3K9 trimethylation (H3K9me3), contributing to repression of endogenous retroviruses (ERVs) and immunosuppressive tumor microenvironment. In TP53 mut DLBCL cell lines, decitabine down-regulated SUV39H1, inhibited H3K9me3 occupancy on ERVs, and triggered ERV expression, thereby unleashing interferons program and CD4+T/CD8+T cell activation. Molecular silencing of SUV39H1 significantly abrogated decitabine-induced H3K9me3 inhibition and ERV expression. In TP53 mut patient-derived xenograft models and TP53 mut patients, the anti-tumor effect was improved upon the use of combined treatment of decitabine and doxorubicin via SUV39H1-H3K9me3-ERVs axis. Collectively, our findings highlight an ERV regulatory circuitry in TP53 mut DLBCL and the crucial roles ERVs for epigenetically reprogramming tumor microenvironment for treating TP53 mut-driven cancers.

Clematis Florida (CF) is a folk medicinal herb in the southeast of China, which is traditionally used for treating osteoarticular diseases. However, the mechanism of its action remains unclear. The present study used network pharmacology and experimental validation to explore the mechanism of CF in the treatment of rheumatoid arthritis (RA). Liquid chromatography–mass spectrometry (LC-MS/MS) identified 50 main compounds of CF; then, their targets were obtained from TCMSP, ETCM, ITCM, and SwissTargetPrediction databases. RA disease-related targets were obtained from DisGeNET, OMIM, and GeneCards databases, and 99 overlapped targets were obtained using a Venn diagram. The protein–protein interaction network (PPI), the compound–target network (CT), and the compound–potential target genes–signaling pathways network (CPS) were constructed and analyzed. The results showed that the core compounds were screened as oleanolic acid, oleic acid, ferulic acid, caffeic acid, and syringic acid. The core therapeutic targets were predicted via network pharmacology analysis as PTGS2 (COX-2), MAPK1, NF-κB1, TNF, and RELA, which belong to the MAPK signaling pathway and NF-κB signaling pathway. The animal experiments indicated that topical application of CF showed significant anti-inflammatory activity in a mouse model of xylene-induced ear edema and had strong analgesic effect on acetic acid-induced writhing. Furthermore, in the rat model of adjuvant arthritis (AA), topical administration of CF was able to alleviate toe swelling and ameliorate joint damage. The elevated serum content levels of IL-6, COX-2, TNF-α, IL-1β, and RF caused by adjuvant arthritis were reduced by CF treatment. Western blotting tests showed that CF may regulate the ERK and NF-κB pathway. The results provide a new perspective for the topical application of CF for treatment of RA.

Bone marrow-derived CD34-positive (CD34+) endothelial progenitor cells (EPCs) has unique functions in the mechanism of compensatory lung growth (CLG). The content of this study is mainly to describe the effect of microRNA (miR)-155 in the mechanisms of EPCs and CLG. Our study found that transfection of miR-155 mimic could promote EPC proliferation, migration and tube formation, while transfection of miR-155 inhibitor had the opposite effect. It was also found that transfection of pc-JARID2 inhibited EPC proliferation, migration and tube formation, while transfection of si-JARID2 had the opposite effect. miR-155 can target and negatively regulate JARID2 expression. Overexpression of JARID2 weakened the promoting effects of miR-155 mimic on EPC proliferation, migration, and tubular formation, while silencing JARID2 weakened the inhibitory effects of miR-155 inhibitors on EPC proliferation, migration, and tubular formation. Transplantation of EPCs transfected with miR-155 mimic into the left lung model effectively increased lung volume, total alveolar number, diaphragm surface area, and lung endothelial cell number, while transplantation of EPCs co-transfected with miR-155 mimic and pc-JARID2 reversed this phenomenon. Overall, we found that miR-155 activates CD34+ EPC by targeting negative regulation of JARID2 and promotes CLG.

Abstract Single image dehazing has received a lot of concern and achieved great success with the help of deep-learning models. Yet, the performance is limited by the local limitation of convolution. To address such a limitation, we design a novel deep learning dehazing model by combining the transformer and guided filter, which is called as Deep Guided Transformer Dehazing Network. Specially, we address the limitation of convolution via a transformer-based subnetwork, which can capture long dependency. Haze is dependent on the depth, which needs global information to compute the density of haze, and removes haze from the input images correctly. To restore the details of dehazed result, we proposed a CNN sub-network to capture the local information. To overcome the slow speed of the transformer-based subnetwork, we improve the dehazing speed via a guided filter. Extensive experimental results show consistent improvement over the state-of-the-art dehazing on natural haze and simulated haze images.

Abstract Giardia duodenalis is a gastrointestinal protozoan ubiquitous in nature. It is a confirmed zoonotic pathogen, and cattle are considered a source of giardiasis outbreaks in humans. This study aimed to evaluate the prevalence and multilocus genotype (MLG) of G. duodenalis in dairy cattle in Central Inner Mongolia. This study was based on the small subunit ribosomal RNA (SSU rRNA), glutamate dehydrogenase (gdh), triosephosphate isomerase (tpi), and beta-giardin (bg) genes of G. duodenalis. DNA extraction, polymerase chain reaction (PCR), and sequence analysis were performed on 505 dairy cattle fecal samples collected in 2021 from six sampling sites and four age groups in Central Inner Mongolia to determine the prevalence and MLG distribution of G. duodenalis. The PCR results of SSU rRNA revealed that the overall prevalence of G. duodenalis was 29.5% (149/505) and that the overall prevalence of the diarrhea and nondiarrhea samples was 31.5% (46/146) and 28.5% (103/359), respectively; the difference was not significant (p > 0.05). SSU rRNA sequence analysis revealed that G. duodenalis assemblage E (91.1%, 133/146) was primarily detected and that assemblage A (8.9%, 13/146) was detected in 13 samples. The G. duodenalis—positive samples were PCR amplified and sequenced for gdh, tpi, and bg, from which 38, 47, and 70 amplified sequences were obtained, respectively. A combination of G. duodenalis assemblages A and E were detected in seven samples. Multilocus genotyping yielded 25 different assemblage E MLGs, which formed six subgroups. To the best of our knowledge, this is the first report regarding G. duodenalis infection in dairy cattle in Inner Mongolia, China. This study revealed that Inner Mongolian cattle pose a risk of giardiasis transmission to humans and that the distribution of local cattle G. duodenalis assemblage E MLGs is diverse. The findings of this study can bridge the knowledge gap in the molecular epidemiological investigation of giardiasis in Central Inner Mongolia.

Abstract Esophageal stricture is a debilitating condition that negatively impacts patients' quality of life after undergoing endoscopic mucosal resection (EMR). Despite its significance, this disease remains underexplored due to the lack of a stable animal model. Under direct visualization with choledochoscopy, we retrogradely damaged the esophageal mucosal layer through the gastrostomy to create a rat model of esophageal stricture. The development of histological defects in the mucosal layer was assessed over a 2-week period after model induction. Then the models were evaluated using X-ray barium radiography, Hematoxylin–Eosin, Masson’s trichrome, Sirius red, and Victoria blue staining, multiphoton microscopic imaging. Additionally, the molecular mechanisms of esophageal stricture were explored by conducting RNA transcriptome sequencing, PCR, immunohistochemistry, and immunofluorescence staining. We successfully established fifteen rat models of esophageal stricture by injuring the mucosal layer. In the model group, the mucosal defect initially occurs and subsequently repaired. The epithelium was absent and was plastically remodeled by collagen during the acute inflammatory phase (Day 1), proliferation phase (Day 7), anaphase of proliferation (Day 10), and plastic remodeling phase (Day 14). We observed increased expression of COL1A1, acta2, FGF, IL-1, and TGF-β1 pathway in the model group. We established a highly repeatable rat model of esophageal stricture, and our results suggest that the mucosal defect of the esophagus is a critical factor in esophageal stricture development, rather than damage to the muscularis layer. We identified Atp4b, cyp1a2, and gstk1 as potential targets for treating esophageal stricture, while the TGF-β pathway was found to play an important role in its development.

Abstract Background Several COVID-19 vaccines are in widespread use in China. Few data exist on comparative immunogenicity of different COVID-19 vaccines given as booster doses. We aimed to assess neutralizing antibody levels raised by injectable and inhaled aerosolized recombinant adenovirus type 5 (Ad5)-vectored COVID-19 vaccine as a heterologous booster after an inactivated COVID-19 vaccine two-dose primary series. Methods Using an open-label prospective cohort design, we recruited 136 individuals who had received inactivated vaccine primary series followed by either injectable or inhaled Ad5-vectored vaccine and measured neutralizing antibody titers against ancestral SARS-CoV-2 virus and Omicron BA.1 and BA.5 variants. We also measured neutralizing antibody levels in convalescent sera from 39 patients who recovered from Omicron BA.2 infection. Results Six months after primary series vaccination, neutralizing immunity against ancestral SARS-CoV-2 was low and neutralizing immunity against Omicron (B.1.1.529) was lower. Boosting with Ad5-vectored vaccines induced a high immune response against ancestral SARS-CoV-2. Neutralizing responses against Omicron BA.5 were ≥ 80% lower than against ancestral SARS-CoV-2 in sera from prime-boost subjects and in convalescent sera from survivors of Omicron BA.2 infection. Inhaled aerosolized Ad5-vectored vaccine was associated with greater neutralizing titers than injectable Ad5-vectored vaccine against ancestral and Omicron SARS-CoV-2 variants. Conclusions These findings support the current strategy of heterologous boosting with injectable or inhaled Ad5-vectored SARS-CoV-2 vaccination of individuals primed with inactivated COVID-19 vaccine.

Abstract Background Accumulating data indicate that N6-methyladenosine (m6A) RNA methylation and lncRNA deregulation act crucial roles in cancer progression. Heterogeneous nuclear ribonucleoprotein A2B1 (HNRNPA2B1) as an m6A “reader” has been reported to be an oncogene in multiple malignancies. We herein aimed to elucidate the role and underlying mechanism by which HNRNPA2B1-mediated m6A modification of lncRNAs contributes to non-small cell lung cancer (NSCLC). Methods The expression levels of HNRNPA2B1 and their association with the clinicopathological characteristics and prognosis in NSCLC were determined by RT-qPCR, Western blot, immunohistochemistry and TCGA dataset. Then, the role of HNRNPA2B1 in NSCLC cells was assessed by in vitro functional experiments and in vivo tumorigenesis and lung metastasis models. HNRNPA2B1-mediated m6A modification of lncRNAs was screened by m6A-lncRNA epi-transcriptomic microarray and verified by methylated RNA immunoprecipitation (Me-RIP). The lncRNA MEG3-specific binding with miR-21-5p was evaluated by luciferase gene report and RIP assays. The effects of HNRNPA2B1 and (or) lncRNA MEG3 on miR-21-5p/PTEN/PI3K/AKT signaling were examined by RT-qPCR and Western blot analyses. Results We found that upregulation of HNRNPA2B1 was associated with distant metastasis and poor survival, representing an independent prognostic factor in patients with NSCLC. Knockdown of HNRNPA2B1 impaired cell proliferation and metastasis in vitro and in vivo, whereas ectopic expression of HNRNPA2B1 possessed the opposite effects. Mechanical investigations revealed that lncRNA MEG3 was an m6A target of HNRNPA2B1 and inhibition of HNRNPA2B1 decreased MEG3 m6A levels but increased its mRNA levels. Furthermore, lncRNA MEG3 could act as a sponge of miR-21-5p to upregulate PTEN and inactivate PI3K/AKT signaling, leading to the suppression of cell proliferation and invasion. Low expression of lncRNA MEG3 or elevated expression of miR-21-5p indicated poor survival in patients with NSCLC. Conclusions Our findings uncover that HNRNPA2B1-mediated m6A modification of lncRNA MEG3 promotes tumorigenesis and metastasis of NSCLC cells by regulating miR-21-5p/PTEN axis and may provide a therapeutic target for NSCLC.

Abstract This study aimed to help healthy adults achieve self-screening by analyzing the quantitative relationship between body composition index measurements (BMI, waist-to-hip ratio, etc.) and dyslipidemia and establishing a logical risk prediction model for dyslipidemia. We performed a cross-sectional study and collected relevant data from 1115 adults between November 2019 and August 2020. The least absolute shrinkage selection operator (LASSO) regression analysis was performed to select the best predictor variables, and multivariate logistic regression analysis was used to construct the prediction model. In this study, a graphic tool including 10 predictor variables (a "nomogram," see the precise definition in the text) was constructed to predict the risk of dyslipidemia in healthy adults. A calibration diagram, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA) were used to verify the model’s utility. Our proposed dyslipidemia nomogram showed good discriminative ability with a C-index of 0.737 (95% confidence interval, 0.70–0.773). In the internal validation, a high C-index value of 0.718 was achieved. DCA showed a dyslipidemia threshold probability of 2–45%, proving the value of the nomogram for clinical application for dyslipidemia. This nomogram may be useful for self-screening the risk of dyslipidemia in healthy adults.

Hashimoto's thyroiditis （HT） is an autoimmune disease triggered by environmental factors on the basis of genetic susceptibility. Trace elements are an important part of environmental factors， among which iodine excess， selenium deficiency， magnesium deficiency and vitamin D deficiency are the risk factors inducing the incidence and progression of HT. The mechanism of HT induced by these nutritional factors is related to the activation of thyroid autoimmune response， oxidative stress response and inflammatory response. For HT susceptible population and HT patients， rational dietary guidance should be given， and corresponding nutritional supplements should be delivered when necessary， aiming to delay the incidence and progression of HT.

Abstract Genetic classification helps to disclose molecular heterogeneity and therapeutic implications in diffuse large B-cell lymphoma (DLBCL). Using whole exome/genome sequencing, RNA-sequencing, and fluorescence in situ hybridization in 337 newly diagnosed DLBCL patients, we established a simplified 38-gene algorithm (termed ‘LymphPlex’) based on the information on mutations of 35 genes and rearrangements of three genes (BCL2, BCL6, and MYC), identifying seven distinct genetic subtypes: TP53 Mut (TP53 mutations), MCD-like (MYD88, CD79B, PIM1, MPEG1, BTG1, TBL1XR1, PRDM1, IRF4 mutations), BN2-like (BCL6 fusion, NOTCH2, CD70, DTX1, BTG2, TNFAIP3, CCND3 mutations), N1-like (NOTCH1 mutations), EZB-like (BCL2 fusion, EZH2, TNFRSF14, KMT2D, B2M, FAS, CREBBP, ARID1A, EP300, CIITA, STAT6, GNA13 mutations, with or without MYC rearrangement), and ST2-like (SGK1, TET2, SOCS1, DDX3X, ZFP36L1, DUSP2, STAT3, IRF8 mutations). Extended validation of 1001 DLBCL patients revealed clinical relevance and biological signature of each genetic subtype. TP53 Mut subtype showed poor prognosis, characterized by p53 signaling dysregulation, immune deficiency, and PI3K activation. MCD-like subtype was associated with poor prognosis, activated B-cell (ABC) origin, BCL2/MYC double-expression, and NF-κB activation. BN2-like subtype showed favorable outcome within ABC-DLBCL and featured with NF-κB activation. N1-like and EZB-like subtypes were predominated by ABC-DLBCL and germinal center B-cell (GCB)-DLBCL, respectively. EZB-like-MYC+ subtype was characterized by an immunosuppressive tumor microenvironment, while EZB-like-MYC- subtype by NOTCH activation. ST2-like subtype showed favorable outcome within GCB-DLBCL and featured with stromal-1 modulation. Genetic subtype-guided targeted agents achieved encouraging clinical response when combined with immunochemotherapy. Collectively, LymphPlex provided high efficacy and feasibility, representing a step forward to the mechanism-based targeted therapy in DLBCL.

Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG–dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.

Abstract Mounting evidence has demonstrated the considerable regulatory effects of long noncoding RNAs (lncRNAs) in the tumorigenesis and progression of various carcinomas. LncRNA Semaphorin 3B (SEMA3B) antisense RNA 1 (SEMA3B‐AS1) has been found to be dysregulated in a few carcinomas recently. However, its potential function and mechanism in colorectal carcinoma (CRC) have not yet been examined. Here we show that SEMA3B‐AS1 acts as a crucial regulator of CRC progression. We found that SEMA3B‐AS1 expression was downregulated in CRC cell lines and tissues. Downregulation of SEMA3B‐AS1 was significantly associated with poor survival in CRC patients. Overexpression of SEMA3B‐AS1 reduced the cell growth and metastasis of CRC in vivo and in vitro. In addition, SEMA3B‐AS1 promoted the expression of its sense‐cognate gene SEMA3B, a member of the Semaphorin family (SEMAs), by recruiting EP300 to induce H3K9 acetylation at the SEMA3B promoter. Furthermore, we proved that SEMA3B‐AS1 suppressed CRC angiogenesis by affecting the vascular endothelial growth factor signaling pathway activation which was regulated by the SEMA3B‐NRP1 axis. Our work unravels a novel mechanism of SEMA3B‐AS1 in the inhibition of CRC malignant progression and highlights its probability as a new promising diagnostic marker and therapeutic target for CRC interventions.

Neuronal hyperactivity is a key abnormality in early stage Alzheimer's disease (AD). Medial entorhinal cortex (mEC) plays a vital role in memory function and is affected early in AD. Growing evidence indicates benefits of regular exercise on memory and cognitive function in humans with AD, although, the underlying mechanisms are not clear. Therefore, this study was designed to test the effects of 16 weeks treadmill exercise on spatial learning memory and the underlying cellular mechanisms in 6-month-old 3xTg-AD mice. Whole-cell patch clamp was used to examine neuronal intrinsic excitability, spontaneous excitatory postsynaptic currents (sEPSCs) and spontaneous inhibitory postsynaptic currents (sIPSCs) of mEC layer II/III pyramidal neurons in the following groups: wild type (WT + sham), 3xTg-AD (AD+sham), WT receiving exercise (WT + Ex), and AD receiving exercise (AD+Ex). We found that at a behavioral level, treadmill exercise decreased working memory errors in radial arm maze (RAM) test in 6-month-old AD mice. At a cellular level, we found that treadmill exercise prevented the abnormal increase in mEC pyramidal neuron input resistance and action potential firing in 6-month-old 3xTg-AD mice compared with WT + sham and AD+Ex mice; further, sEPSC amplitude and frequency were normal in AD+Ex but overactive in AD+sham; additionally, GABAergic inhibition was normal in AD+Ex mice but reduced in AD+sham. In conclusion, our results indicate that treadmill exercise improves spatial learning memory and prevents network hyperexcitability in mEC by reducing pyramidal neuronal intrinsic excitability and normalizing excitatory and inhibitory synaptic transmission in 3xTg-AD mice.

Pathological features of Alzheimer's Disease (AD) include alterations in the structure and function of neurons as well as of myelin sheaths. Accumulated evidence shows that aerobic type of exercise can enhance neuroplasticity in mouse models of AD. However, whether and how aerobic exercise can affect myelin sheath repair and neuroprotection in the AD models remains unclear. In this study we tested the hypotheses that 1) myelin structural alterations in 3xTg-AD mice would be related to abnormalities in oligodendrocyte lineage cells, resulting in impaired learning and memory, and 2) a 6-month aerobic exercise intervention would have beneficial effects on such alterations. Two-month-old male 3xTg-AD mice were randomly assigned to a control (AC) or an exercise (AE) group, and age-matched male C57BL/6;129 mice were also randomly assigned to a normal control (NC) or an exercise (NE) group, with n = 12 in each group. Mice in the exercise groups were trained on a motor-drive treadmill, 60 min per day, 5 days per week for 6 months. Cognitive function was assessed at the end of the intervention period. Then, brain specimens were obtained for assessments of morphological and oligodendrocyte lineage cell changes. The results of electron microscopy showed that myelin ultrastructure demonstrated a higher percentage of loose and granulated myelin sheath around axons in the temporal lobe in the AC, as compared with the NC group, along with greater cognitive dysfunction at 8-months of age. These differences were accompanied by significantly greater myelin basic protein (MBP) expression and less neuron-glial antigen-2 (NG2) protein and mRNA levels in the AC, compared to the NC. However, there were no significant between-group differences in the G-ratio (the ratio of axon diameter to axon plus myelin sheath diameter) and 2′,3′-cyclic-nucleotide 3′-phosphodiesterase (CNPase) protein and mRNA levels. The aerobic exercise ameliorated cognitive deterioration and appeared to keep components of myelin sheath and oligodendrocyte precursor cells stabilized, resulting in a decrease in the percentage of loose and granulated myelin sheath and MBP protein, and an increase in NG2 protein and mRNA levels in the AE group. Therefore, the 6-month exercise intervention demonstrated beneficial effects on myelin lesions, abnormal differentiation of oligodendrocytes and general brain function in the 3xTg-AD mice, providing further insights into the role of aerobic exercise in management of neurodegeneration in AD by maintaining intact myelination.

Background There is an issue of mismatch between supply and demand of medical care resources in China. The implementation of contracted family doctor services is an effective measure to address the issue, and to improve the hierarchical diagnosis and treatment system. Therefore, it is urgent to speed up the training and ensure the training quality of general practice workforce. Objective To develop a comprehensive and systematic general practitioner (GP) competency model after analyzing the concept and structural domains of competencies (including inner competencies) required for GPs to deliver contracted healthcare services, providing insights into the realization of training eligible GPs in terms of quantity and quality, and the improvement of quality and efficiency of contracted services. Methods From December 2020 to September 2021, we conducted in-depth, semi-structured interviews with 38 GPs from 10 medical institutions in four cities (Zhenjiang, Taizhou and Suzhou in Jiangsu Province, and Foshan in Guangdong Province) , then treated the interview results applying the three-level coding and theoretical saturation used in the grounded theory. After that, we developed a General Practitioner Competency Model. Results The model consists of 10 items, which belong to four domains: general care capability, humanistic practice capability, team cooperation capability, learning and development capability. General care capability and learning and development capability belong to external competencies, which represent the external performance and driving force of competencies, and determine the level of competencies of GPs to provide contracted services. Humanistic practice capability and team cooperation capability reflect the internal traits and competencies, which belong to the inner competencies, and determine the potential of GPs to provide contracted services. Conclusion The model developed by us is complete and comprehensive, in which the inner competencies of GPs have been fully explored, which may be contributive to the training of GPs delivering contracted services, and to the development of a GP competency assessment system using quantitative empirical methods.

Abstract Health hazards from long-term exposure to microwaves, especially the potential for changes in cognitive function, are attracting increasing attention. The purpose of this study was to explore changes in spatial learning and memory and synaptic structure and to identify differentially expressed proteins in hippocampal and serum exosomes after long-term exposure to 2.856 and 9.375 GHz microwaves. The spatial reference learning and memory abilities and the structure of the DG area were impaired after long-term exposure to 2.856 and 9.375 GHz microwaves. We also found a decrease in SNARE-associated protein Snapin and an increase in charged multivesicular body protein 3 in the hippocampus, indicating that synaptic vesicle recycling was inhibited and consistent with the large increase in presynaptic vesicles. Moreover, we investigated changes in serum exosomes after 2.856 and 9.375 GHz microwave exposure. The results showed that long-term 2.856 GHz microwave exposure could induce a decrease in calcineurin subunit B type 1 and cytochrome b-245 heavy chain in serum exosomes. While the 9.375 GHz long-term microwave exposure induced a decrease in proteins (synaptophysin-like 1, ankyrin repeat and rabankyrin-5, protein phosphatase 3 catalytic subunit alpha and sodium-dependent phosphate transporter 1) in serum exosomes. In summary, long-term microwave exposure could lead to different degrees of spatial learning and memory impairment, EEG disturbance, structural damage to the hippocampus, and differential expression of hippocampal tissue and serum exosomes.

Background Previous studies have discussed the effects of grazing and house feeding on yaks during the cold season when forage is in short supply, but there is limited information on the effects of these feeding strategies on Jersey cows introduced to the Tibetan Plateau. The objective of this study was to use genomics and metabolomics analyses to examine changes in rumen microbiology and organism metabolism of Jersey cows with different feeding strategies. Methods We selected 12 Jersey cows with similar body conditions and kept them for 60 days under grazing (n = 6) and house-feeding (n = 6) conditions. At the end of the experiment, samples of rumen fluid and serum were collected from Jersey cows that had been fed using different feeding strategies. The samples were analyzed for rumen fermentation parameters, rumen bacterial communities, serum antioxidant and immunological indices, and serum metabolomics. The results of the study were examined to find appropriate feeding strategies for Jersey cows during the cold season on the Tibetan plateau. Results The results of rumen fermentation parameters showed that concentrations of acetic acid, propionic acid, and ammonia nitrogen in the house-feeding group (Group B) were significantly higher than in the grazing group (Group G) (P 0.05). Beta diversity analysis revealed no significant differences in the composition of the rumen microbiota between the two groups. Analysis of serum antioxidant and immune indices showed no significant differences in total antioxidant capacity between Group G and Group B (P > 0.05), while IL-6, Ig-M , and TNF-α were significantly higher in Group G than in Group B (P

Abstract Pseudostellaria heterophylla, also called Tai-zi-shen (TZS) in Traditional Chinese Medicine (TCM), is always used clinically to treat spleen deficiency symptoms. Polysaccharides in TZS have various pharmacological activities, including anti-diabetic, immune regulation, and myocardial protection. However, the relationship between the spleen-invigorating effects of TZS or its polysaccharides and intestinal flora are not clear. This study investigated the effects of TZS decoction (PHD) and polysaccharide (PHP) on immune function and intestinal flora in a rat model of spleen deficiency syndrome (SDS) induced by a decoction of raw rhubarb (RRD). PHD and PHP increased immune organ index, alleviated inflammatory cell filtration, and reduced the levels of pro-inflammatory cytokines in rats with spleen deficiency syndrome. In addition, the production of butyric acid was promoted in PHD and PHP groups. Moreover, 16S rRNA gene sequencing showed that PHD and PHP reduced the relative abundance of Firmicutes while increasing the one of Bacteroidetes; significantly increased the abundance of Lactobacillus and decreased the abundance of Rombutsia; and PHP significantly increased the abundance of Alloprevotella. And there was a significant positive correlation between the alleviation of SDS and short-chain fatty acids (SCFAs)-producing bacteria. These findings suggested PHD and PHP, especially PHP, has a potential to relieve spleen deficiency by reducing intestinal inflammation, modulating structure and composition of gut microbiota, and promoting the production of butyric acid.

Abstract Background Long non-coding RNAs (lncRNAs) are closely related to the occurrence and development of cancer. Abnormally expressed lncRNA can be used as a diagnostic marker for cancer. In this study, we aim to investigate the clinical significance of MIR99AHG expression in lung adenocarcinoma (LUAD), and its biological roles in LUAD progression. Methods The relative expression of MIR99AHG in LUAD tissues and cell lines was analyzed using public databases and RT-qPCR. The biological functions of MIR99AHG were investigated using a loss-of-function approach. The effect of MIR99AHG on lung fibrosis was assessed by scratch assay, invasion assay and lung fibrosis rat model. FISH, luciferase reporter assay and immunofluorescence were performed to elucidate the underlying molecular mechanisms. Results LncRNA MIR99AHG expression level was downregulated in LUAD tissues and cell lines. Low MIR99AHG levels were associated with poorer patient overall survival. Functional analysis showed that MIR99AHG is associated with the LUAD malignant phenotype in vitro and in vivo. Further mechanistic studies showed that, MIR99AHG functions as a competitive endogenous RNA (ceRNA) to antagonize miR-136-5p-mediated ubiquitin specific protease 4 (USP4) degradation, thereby unregulated the expression of angiotensin-converting enzyme 2 (ACE2), a downstream target gene of USP4, which in turn affected alveolar type II epithelial cell fibrosis and epithelial–mesenchymal transition (EMT). In summary, the MIR99AHG/miR-136-5p/USP4/ACE2 signalling axis regulates lung fibrosis and EMT, thus inhibiting LUAD progression. Conclusion This study showed that downregulated MIR99AHG leads to the development of pulmonary fibrosis. Therefore, overexpression of MIR99AHG may provide a new approach to preventing LUAD progression.

Objective To analyze the expression of SIRT5 in pan-cancer and its relationship with prognosis and to explore the mechanism of SIRT5 regulating breast cancer proliferation through aldehyde dehydrogenase 5 family member A1(ALDH5A1). Methods cBioPortal,TNMplot,GEPIA and The Kaplan-Meier Plotter were used to analyze the differential expression of SIRT5 in a variety of tumors and its correlation with prognosis. The interacting proteins co-precipitated with the SIRT5 were analyzed by mass spectrometry. Pathway enrichment was performed for the interaction proteome, and for the combined analysis of the interaction proteome and the acylation proteome. Finally, the ALDH5A1 was focused. Then, the interaction between SIRT5 and ALDH5A1 was determined by an in vivo and in vitro immunoprecipitation(IP).SIRT5 was over-expressed or knocked down to detect acylation level and enzyme activity of ALDH5A1. Finally, the effects of SIRT5 and ALDH5A1 on breast cancer proliferation were determined by cell proliferation and cloning experiments. Results SIRT5 was highly expressed in a variety of tumors such as breast cancer and was positively correlated with poor prognosis (P＜0.05). There were multiple overlaps between SIRT5 interacting proteins and acylomics and the overlapped proteins were mainly enriched in metabolic pathways such as amino acid metabolism. SIRT5 directly interacted with ALDH5A1. SIRT5 could enhance the enzyme activity of ALDH5A1 by inducing the desuccinylation of ALDH5A1, thus promoting the proliferation of breast cancer cells (P＜0.05). Conclusions The function of SIRT5 in tumors may be specific to a heterogeneous environment and it can play a tumor-promoting role through ALDH5A1 in breast cancer. The results reported here may provide a theoretical basis for subsequent clinical targeted therapy.

Abstract Chimeric antigen receptor (CAR) T-cell therapy has emerged as a promising novel therapeutic approach. However, primary and secondary resistance to CAR-T cell therapy is commonly encountered in various clinical trials. Despite the comprehensive studies to elucidate the mechanisms of resistance, effective resolution in clinical practice is still elusive. Inadequate persistence and subsequent loss of infused CAR-T cells are proposed major resistance mechanism associated with CAR-T cell treatment failure. Thus, we generated CAR-T cells armored with IL-7 to prolong the persistence of infused T-cells, particularly CD4 + T cells, and enhanced anti-tumor response. IL-7 increased CAR-T-cell persistence in vivo and contributed to the distinct T-cell cytotoxicity profile. Using mass cytometry (CyTOF), we further assessed the phenotypic and metabolic profiles of IL-7-secreting CAR-T cells, along with conventional CAR-T cells at the single-cell level. With in-depth analysis, we found that IL-7 maintained CAR-T cells in a less differentiated T-cell state, regulated distinct metabolic activity, and prevented CAR-T-cell exhaustion, which could be essential for CAR-T cells to maintain their metabolic fitness and anti-tumor response. Our findings thus provided clinical rationale to exploit IL-7 signaling for modulation and metabolic reprogramming of T-cell function to enhance CAR-T cell persistence and induce durable remission upon CAR-T cell therapy.

Objectives The hepatotoxicity of irinotecan has been widely implicated in the treatment of multiple solid tumours. However, there are few studies on the influencing factors of irinotecan-induced hepatotoxicity. Herein, we investigated the risk factors for irinotecan-induced liver injury among 421 patients receiving irinotecan-based regimens (IBRs).Design Retrospective multi-centre cross-sectional study.Setting This study surveyed four hospitals in China.Participants After excluding participants with missing variables, we retrospectively collected the demographic, clinical and therapeutic data of 421 patients who received IBRs in four hospitals between January 2020 and December 2021 and divided the patients into two groups: those without liver injury and those with liver injury.Results The 421 enrolled patients were grouped (liver injury group: n=92; control group: n=329) according to their hepatic biochemical monitoring parameters. In our study, the multivariate logistic regression results showed that three to four cycles of chemotherapy (OR (95% CI): 2.179 (1.272 to 3.733); p=0.005) and liver metastasis (OR (95% CI): 1.748 (1.079 to 2.833); p=0.023) were independent risk factors for irinotecan-induced liver injury. The Cox proportional hazards model demonstrated that alcohol consumption history (OR (95% CI): 2.032 (1.183 to 3.491); p=0.010) and a cumulative dose of irinotecan ≥1000 mg (OR (95% CI): 0.362 (0.165 to 0.792); p=0.011) were significantly correlated with the onset time of irinotecan-induced liver injury.Conclusions These findings suggest that patients with liver metastasis or who received three to four cycles of chemotherapy should undergo rigorous liver function monitoring to prevent or reduce the incidence of irinotecan-induced liver injury. Moreover, patients with a history of alcohol consumption should also be closely monitored.

Bacillus amyloliquefaciens is an interesting microbe in the food processing and manufacturing industries. Non-coding small RNAs (sRNAs) have been shown to play a crucial role in the physiology and metabolism of bacteria by post-transcriptionally regulating gene expression. This study investigated the function of novel sRNA FenSr3 by constructing fenSr3 deficient strain and complementary strains in B. amyloliquefaciens LPB-18 , which were named LPN-18N and LPB-18P, respectively. The result showed significant differences in fengycin yield between strain LPB -18N and LPB-18P. The production of fengycin was significantly enhanced in B. amyloliquefaciens LPB-18N, compared with that of the strain LPB-18 from 190.908 mg/L to 327.598 mg/L. Moreover, the production of fengycin decreased from 190.464 mg/L to 38.6 mg/L in B . amyloliquefaciens LPB-18P. A comparative transcriptome sequencing was carried out to better understand the complex regulatory mechanism. Transcription analysis revealed that 1037 genes were differentially expressed between B. amyloliquefaciens LPB-18 and B. amyloliquefaciens LPB-18N, including the key regulatory genes in fatty acid, amino acid biosynthesis, and central carbon metabolism, which could provide sufficient quantities of building precursors for fengycin biosynthesis. The biofilm formation and sporulation was also enhanced in the strain LPB-18N, which indicates that FenSr3 could play a vital role in stress resistance and promotes survival in B. amyloliquefaciens. Some sRNAs involved in stress response have been identified in the literature, but their regulatory roles in fengycin production remain unclear. The study will contribute a novel perspective to the regulation mechanism of biosynthesis and the optimization of key metabolites of B. amyloliquefaciens.

The use of essential oil (EO) in treating infected wounds is still challenging. A lot of effort has been made to make such an application more convenient. Recently, microneedles (MNDs) have been considered as a smart dermal delivery system to overcome the poor absorption and distribution, low bioavailability, and skin penetration of some drugs. The aim of our study is to evaluate the wound healing activity of juniper-EO-loaded MNDs (EO MNDs) against wounds with bacterial and fungal infection. The Polyvinylpyrrolidone (PVP) MNDs were prepared using the gel-filled mold technique and loaded with juniper EO. In vivo models were created and wounds on rats were infected with two clinically isolated bacterial strains Pseudomonas aeruginosa and Staphylococcus aureus. Furthermore, Candida albicans was used to mimic fungal infection and juniper EO MNDs were tested. The obtained results showed an improvement in wound healing which started from the third day after application of the juniper EO MNDs, and at the sixth day post-infection, the treated wounds were significantly smaller than untreated wounds. A complete healing was shown by the 12th day after infection. Furthermore, our cytotoxicity results showed a cytotoxic effect of juniper EO MNDs on epithelial cells, which explained the faster wound healing in rats. Our study showed that juniper EO MNDs represent a novel strategy in EO delivery with minimal invasion. Juniper EO MNDs demonstrated significant antimicrobial activity against both the bacterial strains Pseudomonas aeruginosa and Staphylococcus aureus and against one fungal strain, Candida albicans. Finally, application of juniper EO MNDs exerted promising activity in the treatment and healing of wound infection.

Objective To investigate whether depression is a potential risk factor for falls in the elderly in China. Methods Data were collected from the Subcohort of Rugao Longevity and Aging Study. Depression in the elderly was assessed by the GDS-15(Geriatric Depression Scale), and the occurrence of falls in the subjects at baseline in 2014 and the second follow-up in 2017 were collected and recorded. According to the depression status, subjects were divided into depression group and normal group, and the general information and occurrence of falls were compared between the two groups. Logistic regression was used to analyze whether depression increased the risk of falls in older adults. Results In the cross-sectional study of 1 548 subjects, the incidence of falls was 8.3%. The proportion of subjects in the “fall” group was higher in older age, lower education level and cognitive impairment. Compared with the normal group, the depressed group had a higher proportion of women, farmers, less education, unmarried, non-smokers, non-drinkers and cognitively disabled people. After adjusting for confounders, depression was associated with an increased risk of falls at baseline and 3 years later in older adults (P＜ 0.05). Conclusions Depression is a potential risk factor for falls among the elderly in the Chinese community.

Objective To investigate the expression of immune-related molecules and the infiltration of immune cells from mouse breast cancer stem cells (BCSCs). Methods Mouse BCSCs of 4T1 and 4T07 were enriched by spheroid culturing; the expression of immune checkpoint-and antigen presentation-associated genes in BCSCs was detected by RT-qPCR; the proportion of various types of immune cells in spleen or tumor tissue of orthotopic tumor model mouse was detected by flow cytometry. Results The mouse BCSCs 4T1 and 4T07 were successfully enriched by spheroid culturing; the expression of immune checkpoints-and antigen presentation-associated genes were significantly different as compared with the adherent cancer cells; the proportion of both CD4+ and CD8+ T cell increased. However, the proportion of macrophage (CD11b+/F480+) was decreased in tumors formed by spheroid cells as compared with that in the tumors formed by adherent cells. Conclusions The expression of immune checkpoint-and antigen presentation-associated genes in BCSCs were significantly different and the infiltration of T cells increased in tumors formed by BCSCs.

Objective To construct a mouse-derived tumor organoid that can retain various types of immune cells in the immune microenvironment without artificial reconstruction. Methods The mouse-derived tumor organoids were cultured and constructed by air-liquid interface method. The histological morphology of the tumor organoids was analyzed by hematoxylin and eosin(HE). The proportion of various types of immune cells in the tumor organoids was analyzed by flow cytometry. The interleukin-2 (IL-2) was used to maintain the number of T lymphocytes in tumor organoids. Results The tumor organoids from three tumor types of mouse CT26 colon cancer, Lewis lung cancer and MC38 colon cancer all retained the histomorphology of the original tumor. Compared with mouse CT26 colon cancer tumor tissues, the proportion of CD4+T cells, CD8+ T cells and B cells in tumor organoids didn't show significant change and the proportion of macrophages decreased from 66.7% to 44.3%. The proportion of dendritic cells decreased from 66.5% to 7.25%. Compared with mouse Lewis lung cancer tumor tissue, the proportion of CD4+T cells, macrophages, dendritic cells and B cells in tumor organoids remained unchanged and the proportion of CD8+ T cells decreased from 5.6% to 1.95%. Compared with mouse MC38 colon cancer tumor tissue, the proportion of CD4+T cells, CD8+ T cells and B cells in tumor organoids remained unchanged, the proportion of macrophages decreased from 33.5% to 17%, and the proportion of dendritic cells decreased from 46.8% to 1.2%. IL-2 could increase the tumor-infiltrating T lymphocytes in tumor organoids derived from three tumor types. Conclusions Mouse tumor organoids retain the histological morphology of the original tumor and the various types of immune cells are retained in a certain extent. IL-2 can increase the quantity of T lymphocytes.

Abstract Background Acute lung injury (ALI) caused by intestinal ischemia–reperfusion is a life-threatening disease. Interferon gene stimulator (STING) is a cytoplasmic DNA sensor that participates in the initiation of the inflammatory response. This study aims to establish whether C-176 (STING inhibitor) improves ALI under intestinal ischemia–reperfusion conditions. Methods To induce ALI, 72 male C57BL/6 mice were subjected to intestinal ischemia for 60 min and reperfusion for 3 h. Through intraperitoneal injection, C-176, a selective STING inhibitor, was injected 30 min before surgical treatment; meanwhile, compound C, an antagonist of adenosine monophosphate-activated protein kinase (AMPK), was administered 30 min after surgery. Based on immunofluorescence and Western blot assays, post-ALI assessments included lung water content (TLW), bronchoalveolar lavage fluid (BALF) protein, H&E staining, Masson staining, pulmonary pyroptosis [Gasdermin-D (GSDMD), cleaved caspase-1], and apoptosis (TUNEL, cleaved caspase-3). Results C-176 administration significantly attenuated intestinal ischemia–reperfusion-mediated ALI; this effect was reflected by exacerbated TLW and BALF protein, aggravated lung injury score, elevated degree of pulmonary fibrosis, increased TUNEL- and GSDMD-positive cells, and upregulated phospho-AMPK, cleaved caspase-1, cleaved caspase-3 and IFNβ mRNA expression. Moreover, C-176 increased phospho-AMPK under ALI conditions. Nonetheless, compound C partially reversed these beneficial effects. Conclusion C-176, a selective STING inhibitor, improves intestinal ischemia–reperfusion-mediated ALI, and its underlying mechanism may be associated with AMPK signal activation.

Abstracts Background Dietary phytoestrogens have been suggested to influence puberty timing, a critical stage for well-being in adulthood. We hypothesized that childhood soy intake might prospectively influence puberty timing and that dietary fibre and the key isoflavone metabolite equol might play roles. Methods Cox proportional hazard regression models were performed in 4781 children (2152 girls and 2629 boys) aged 6–8 years old from the Chinese Adolescent Cohort Study for whom a food frequency questionnaire at baseline and information about potential confounders were available. Anthropometry and pubertal status including age at Tanner stage 2 for breast development (B2) or age at the initiation of gonadal growth (G2), and age at menarche (M) or voice break (VB) were assessed annually. Equol excretion was determined by urine samples from 1311 participants. Results Among girls and boys, higher soy intake was associated with later puberty timing (hazard ratio (HR)-B2: 0.88 (95% CI, 0.80–0.96), p=0.02; HR-M, 0.87 (0.77–0.94), p=0.01; HR-G2, 0.91 (0.82–0.98), p=0.013; HR-VB, 0.90 (0.82–0.9), p=0.02), independent of prepubertal body fatness and fibre intake. These associations were more pronounced among children with a high urinary equol level (p for-interaction ≤ 0.04) or with a high cereal fibre intake (p for-interaction ≤ 0.06). Intake of dietary fibre or its subtype was not prospectively associated with puberty onset after adjusting for dietary soy intake (p≥0.06). Conclusion Higher childhood soy intake is prospectively associated with later puberty timing in both Chinese girls and boys, independent of prepubertal body fatness, and the association is particularly pronounced among individuals with a higher urinary equol level.

The objective of this study was to compare the clinical effectiveness of traditional vaginal surgery and transvaginal mesh (TVM) surgery on severe pelvic organ prolapse (POP). We performed a retrospective chart review study of 258 severe POP patients who underwent surgery between November 2010 and September 2016. One hundred forty patients underwent traditional vaginal surgery and 118 TVM surgery. The Pelvic Organ Prolapse Quantitation (POP-Q) staging was used for objective evaluation. The Pelvic Floor Distress Inventory-20 (PFDI-20), Pelvic Floor Disease Life Impact Questionnaire Simplified Version-7 (PFIQ-7), and Pelvic Organ Prolapse/Incontinence Sexual Function Questionnaire (PISQ-12) were used for subjective evaluation. Their complications were also recorded. All the data were collected in the outpatient department through the follow-up at 3 months, 1, 3, and 5 years after the operation. Forty patients in the traditional vaginal surgery group and 25 in the TVM group were lost to follow-up. There was no difference in the POP-Q score between the groups (P = 0.346). The recurrence rate increased with follow-up time, reaching nearly 20% in the two groups by 5 years. The TVM group has higher PFDI-20 and PFIQ-7 scores and lower PISQ-12 scores than the traditional vaginal surgery group at six months, 1, 3, and 5 years, respectively (P < 0.001). Mesh exposure has occurred in the TVM group. Both surgeries showed similar objective satisfaction and recurrence rate. However, traditional vaginal surgery has higher subjective satisfaction than TVM in our study and does not risk exposure to prosthetic material.

Background Intestinal microbiota homeostasis and the gut-brain axis are key players associated with host health and alterations in metabolic, inflammatory, and neurodegenerative disorders. Sepsis-associated encephalopathy (SAE), which is closely associated with bacterial translocation, is a common secondary organ dysfunction and an urgent, unsolved problem affecting patient quality of life. Our study examined the neuroprotective effects of the gut microbiome and short-chain fatty acid (SCFA) metabolites on SAE. Methods Male C57BL/6 mice were administered SCFAs in drinking water, then subjected to cecal ligation and puncture (CLP) surgery to induce SAE. 16S rRNA sequencing was used to investigate gut microbiome changes. The open field test (OFT) and Y-maze were performed to evaluate brain function. The permeability of the blood–brain barrier (BBB) was assessed by Evans blue (EB) staining. Hematoxylin and eosin (HE) staining was used to examine intestinal tissue morphology. The expression levels of tight junction (TJ) proteins and inflammatory cytokines was assessed by western blots and immunohistochemistry. In vitro, bEND.3 cells were incubated with SCFAs and then with lipopolysaccharide (LPS). Immunofluorescence was used to examine the expression of TJ proteins. Results The composition of the gut microbiota was altered in SAE mice; this change may be related to SCFA metabolism. SCFA treatment significantly alleviated behavioral dysfunction and neuroinflammation in SAE mice. SCFAs upregulated occludin and ZO-1 expression in the intestine and brain in SAE mice and LPS-treated cerebromicrovascular cells. Conclusions These findings suggested that disturbances in the gut microbiota and SCFA metabolites play key roles in SAE. SCFA supplementation could exert neuroprotective effects against SAE by preserving BBB integrity.

Female Aedes aegypti mosquitoes impose a severe global public health burden as vectors of multiple viral pathogens. Under optimal environmental conditions, Aedes aegypti females have access to human hosts that provide blood proteins for egg development, conspecific males that provide sperm for fertilization, and freshwater that serves as an egg-laying substrate suitable for offspring survival. As global temperatures rise, Aedes aegypti females are faced with climate challenges like intense droughts and intermittent precipitation, which create unpredictable, suboptimal conditions for egg-laying. Here, we show that under drought-like conditions simulated in the laboratory, females retain mature eggs in their ovaries for extended periods, while maintaining the viability of these eggs until they can be laid in freshwater. Using transcriptomic and proteomic profiling of Aedes aegypti ovaries, we identify two previously uncharacterized genes named tweedledee and tweedledum, each encoding a small, secreted protein that both show ovary-enriched, temporally-restricted expression during egg retention. These genes are mosquito-specific, linked within a syntenic locus, and rapidly evolving under positive selection, raising the possibility that they serve an adaptive function. CRISPR-Cas9 deletion of both tweedledee and tweedledum demonstrates that they are specifically required for extended retention of viable eggs. These results highlight an elegant example of taxon-restricted genes at the heart of an important adaptation that equips Aedes aegypti females with ‘insurance’ to flexibly extend their reproductive schedule without losing reproductive capacity, thus allowing this species to exploit unpredictable habitats in a changing world.

Terahertz (THz) radiation is a valuable imaging and sensing tool which is widely used in industry and medicine. However, it biological effects including genotoxicity and cytotoxicity are lacking of research, particularly on the nervous system. In this study, we investigated how terahertz radiation with 10mW (0.12 THz) and 50 mW (0.157 THz) would affect the morphology, cell growth and function of rat hippocampal neurons in vitro.

Abstract MicroRNAs (miRNAs) are involved in lymphoma progression by regulating the tumor microenvironment. Serum miR130b is overexpressed in diffuse large B-cell lymphoma (DLBCL), inducing Th17 cell alterations. To further illustrate its biological significance and therapeutic rationale, miR130b was detected by quantitative real-time PCR in the serum samples of 532 newly diagnosed DLBCL patients. The mechanism of miR130b on lymphoma progression and the tumor microenvironment was investigated both in vitro and in vivo. Therapeutic targeting miR130b was also evaluated, including OX40 agonistic antibody and lipid nanoparticles (LNPs)-miR130b antagomir. The results showed that serum miR130b significantly correlated with tumor miR130b and serum interleukin-17, indicating lymphoma relapse and inferior survival of DLBCL patients. MiR130b overexpression altered tumor microenvironment signaling pathways and increased Th17 cell activity. As mechanism of action, miR130b downregulated tumor OX40L expression by directly targeting IFNAR1/p-STAT1 axis, recruiting Th17 cells via OX40/OX40L interaction, thereby promoting immunosuppressive function of Th17 cells. In co-culture systems of B-lymphoma cells with immune cells, miR130b inhibited lymphoma cell autophagy, which could be counteracted by OX40 agonistic antibody and LNPs-miR130b antagomir. In murine xenograft model established with subcutaneous injection of A20 cells, both OX40 agonistic antibody and LNPs-miR130b antagomir remarkably inhibited Th17 cells and retarded miR130b-overexpressing tumor growth. In conclusion, as an oncogenic biomarker of DLBCL, miR130b was related to lymphoma progression through modulating OX40/OX40L-mediated lymphoma cell interaction with Th17 cells, attributing to B-cell lymphoma sensitivity towards OX40 agonistic antibody. Targeting miR130b using LNPs-miR130b antagomir could also be a potential immunotherapeutic strategy in treating OX40-altered lymphoid malignancies.