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Objectives: This study aimed to survey the geriatric nursing competencies of clinical nursing staff in Chongqing City, China, and provide suggestions to enhance these competencies. Methods: This study was conducted in 204 hospitals in Southwest China from December 24, 2022 to January 7, 2023. The “Geriatric Nursing Competence of Clinical Nurse Investigation Tool” was used to explore factors that influence geriatric nurses’ competencies via stratified sampling. The survey was conducted by distributing and collecting questionnaires through the online platform Wenjuanxing. Results: A total of 10,692 nurses answered the questionnaires. Of these questionnaires, 9,442 were valid. The total geriatric nursing competence score of the clinical nursing staff was 2.29 ± 0.81, the secondary hospital score was 2.23 ± 0.78, and the tertiary hospital’s overall mean score was 2.33 ± 0.83. The factors that influenced secondary hospitals included the department of medicine, age of nurses and total length of career (P

Abstract Background Total knee arthroplasty (TKA) successfully alleviates pain from knee osteoarthritis, but muscle strength and function are reduced for a long period postoperatively. Postoperative active resistance exercise may play a relevant role. Purpose To systematically evaluate effects of lower-limb active resistance exercise (ARE) on mobility, physical function, muscle strength and pain intensity in patients with TKA. Methods A search was conducted in PubMed, EMBASE, and Cochrane Library databases from inception to September 2023. Only randomized controlled trials (RCTs) that compared the effects of ARE and no intervention or other rehabilitation program without PRE were included. The outcome variables were mobility (Maximal walking speed [MWS]/6-Minute Walk Test[6MWT]), physical function (Stair Climb Test [SCT]/Timed Up and Go [TUG]), knee extension/ flexion power(KEP/KFP), joint range of motion (ROM) and pain. Standardized Mean Differences (SMD) or Mean Differences (MD) and 95% confidence intervals (CI) were calculated and combined in meta-analyses. The Cochrane Collaboration’s Handbook were used for the methodological quality assessments. GRADE was used to assess the quality of evidence. The meta-analysis was performed using the RevMan 5.4 software. Results A total of 14 randomized controlled trials, involving 880 patients, were finally included. The lower-limb ARE exhibited significantly greater improvement in MWS (MD 0.13, 95%CI 0.08–0.18, P

Abstract Adult skeletal muscle stem cells, also known satellite cells (SCs), are quiescent and activate in response to injury. However, the activation mechanisms of quiescent SCs (QSCs) remain largely unknown. Here, we investigated the metabolic regulation of SC activation by identifying regulatory metabolites that promote SC activation. Using targeted metabolomics, we found that spermidine acts as a regulatory metabolite to promote SC activation and muscle regeneration in mice. Mechanistically, spermidine activates SCs via generating hypusinated eIF5A. Using SC-specific eIF5A-knockout (KO) and Myod-KO mice, we further found that eIF5A is required for spermidine-mediated SC activation by controlling MyoD translation. More significantly, depletion of eIF5A in SCs results in impaired muscle regeneration in mice. Together, the findings of our study define a novel mechanism that is essential for SC activation and acts via spermidine-eIF5A-mediated MyoD translation. Our findings suggest that the spermidine-eIF5A axis represents a promising pharmacological target in efforts to activate endogenous SCs for the treatment of muscular disease.

Abstract Background The commercial utilization of genetically modified soybeans has yielded substantial economic advantages. Nevertheless, the genetic drift towards wild soybeans is one of the main ecological risks that needs to be addressed. Previous experiments demonstrated the absence of fitness cost or florescence overlap in hybrid offspring resulting from the crossbreeding of transgenic soybean GTS40-3-2 and Zhengzhou wild soybeans. In this study, hybrid progeny was systematically crossed with wild soybeans to establish a backcross progeny system. This system was employed to evaluate the ecological risk associated with the backcross progeny of transgenic and wild soybeans. Results The findings indicated that the offspring from the backcross exhibited glyphosate tolerance. Furthermore, the expression of foreign proteins in the backcross offspring was notably lower than in the transgenic soybean, and there was no significant difference when compared to the hybrid progeny. Parameters such as germination rate, aboveground biomass, pods per plant, full seeds per plant, and 100-grain weight exhibited no significant differences between the negative and positive lines of the backcross progenies, and no fitness cost was identified in comparison to wild soybeans. These results underscore the potential for foreign genes to propagate within other wild soybeans, which requires continuous attention. Conclusions The widespread adoption of genetically modified soybeans has undeniably led to substantial economic gains. However, the research findings emphasize the critical importance of addressing the ecological risks posed by genetic drift towards wild soybeans. The backcross progeny system established in this study indicates that the potential for foreign gene dissemination to wild soybean populations warrants continued attention and mitigation strategies.

Abstract Molecular imaging holds the potential for noninvasive and accurate grading of liver fibrosis. It is limited by the lack of biomarkers that strongly correlate with liver fibrosis grade. Here, we discover the grading potential of fibroblast activation protein alpha (FAPα) for liver fibrosis through transcriptional analysis and biological assays on clinical liver samples. The protein and mRNA expression of FAPα are linearly correlated with fibrosis grade (R2 = 0.89 and 0.91, respectively). A FAPα-responsive MRI molecular nanoprobe is prepared for quantitatively grading liver fibrosis. The nanoprobe is composed of superparamagnetic amorphous iron nanoparticles (AFeNPs) and paramagnetic gadoteric acid (Gd-DOTA) connected by FAPα-responsive peptide chains (ASGPAGPA). As liver fibrosis worsens, the increased FAPα cut off more ASGPAGPA, restoring a higher T1-MRI signal of Gd-DOTA. Otherwise, the signal remains quenched due to the distance-dependent magnetic resonance tuning (MRET) effect between AFeNPs and Gd-DOTA. The nanoprobe identifies F1, F2, F3, and F4 fibrosis, with area under the curve of 99.8%, 66.7%, 70.4%, and 96.3% in patients’ samples, respectively. This strategy exhibits potential in utilizing molecular imaging for the early detection and grading of liver fibrosis in the clinic.

Abstract Background In China, parents who have lost their only child are referred to as Shidu parents (SDPs). This study aimed to investigate the prevalence and risk factors of post-traumatic stress disorder (PTSD) and investigate the influence of depressive and anxiety symptoms on the development of PTSD. Method Four hundred and thirty-six SDPs completed assessments of PTSD (Structured Clinical Interview for DSM-IV Disorders, SCID-IV; The Clinician-Administered PTSD Scale-IV, CAPS-IV), depression (Hamilton depression scale), and anxiety (Hamilton Anxiety Scale) via in-person interviews. Logistic regression and hierarchical multiple linear regression analyses were used to explore the association of demographic characteristics, depression, and anxiety symptoms with PTSD. Results The prevalence of PTSD in SDPs was 14.45%. The comorbidity of depression and anxiety symptoms was 87.30% in the SDPs with PTSD. The logistic regression model, which included factors of gender, age, education, depression, and anxiety, which contributed to the development of PTSD, was significant [χ² (11) = 122.47, p

Abstract Electroceuticals, through the selective modulation of peripheral nerves near target organs, are promising for treating refractory diseases. However, the small sizes and the delicate nature of these nerves present challenges in simplifying the fixation and stabilizing the electrical-coupling interface for neural electrodes. Herein, we construct a robust neural interface for fine peripheral nerves using an injectable bio-adhesive hydrogel bioelectronics. By incorporating a multifunctional molecular regulator during network formation, we optimize the injectability and conductivity of the hydrogel through fine-tuning reaction kinetics and multi-scale interactions within the conductive network. Meanwhile, the mechanical and electrical stability of the hydrogel is achieved without compromising its injectability. Minimal tissue damage along with low and stable impedance of the injectable neural interface enables chronic vagus neuromodulation for myocardial infarction therapy in the male rat model. Our highly-stable, injectable, conductive hydrogel bioelectronics are readily available to target challenging anatomical locations, paving the way for future precision bioelectronic medicine.

Abstract Currently, cocrystallization is a promising strategy for tailoring the physicochemical properties of active pharmaceutical ingredients. Theophylline, an alkaloid and the most primary metabolite of caffeine, is a readily available compound found in tea and coffee. It functions primarily as a bronchodilator and respiratory stimulant, making it a mainstay treatment for lung diseases like asthma. Theophylline’s additional potential benefits, including anti-inflammatory and anticancer properties, and its possible role in neurological disorders, have garnered significant research interest. Cocrystal formation presents a viable approach to improve the physicochemical properties of theophylline and potentially mitigate its toxic effects. This review comprehensively explores several successful studies that utilized cocrystallization to favorably alter the physicochemical properties of theophylline or its CCF. Notably, cocrystals can not only enhance the solubility and bioavailability of theophylline but also exhibit synergistic effects with other APIs. The review further delves into the hydrogen bonding sites within the theophylline structure and the hydrogen bonding networks observed in cocrystal structures. Graphical Abstract

Abstract Background Narrative nursing is a novel approach according with humanistic care, which has been shown to be effective in improving health outcomes for both patients and nurses. Nevertheless, few studies have investigated the status of narrative nursing practice among nurses, and a comprehensive understanding of factors influencing this practice remains elusive. Design This was an observational, cross-sectional study using convenience sampling method. Methods After obtaining the informed consent, a total of 931 registered nurses from three hospitals in China were investigated. Data were collected using the Social Support Rating Scale, the General Self-efficacy Scale, and the Knowledge-Attitude-Practice Survey of Clinical Nurses on Narrative Nursing. All the scales were validated in the Chinese population. The questionnaire results were verified by an independent investigator. Factors influencing narrative nursing practice were determined through a series of analyses, including independent sample t-tests, one-way ANOVA, and Pearson correlations. Subsequently, path analysis was performed and a structural equation model was established. Results The score of narrative nursing practice in this study was 30.26 ± 5.32. The structural equation model showed a good fit, with a Root Mean Square Error of Approximation (RMSEA) of 0.007 (90%CI: 0.000, 0.047). Both social support and narrative nursing attitude could directly affect narrative nursing practice (βsocial support = 0.08, P

Abstract Phototherapy is a promising antitumor modality, which consists of photothermal therapy (PTT) and photodynamic therapy (PDT). However, the efficacy of phototherapy is dramatically hampered by local hypoxia in tumors, overexpression of indoleamine 2,3-dioxygenase (IDO) and programmed cell death ligand-1 (PD-L1) on tumor cells. To address these issues, self-assembled multifunctional polymeric micelles (RIMNA) were developed to co-deliver photosensitizer indocyanine green (ICG), oxygenator MnO2, IDO inhibitor NLG919, and toll-like receptor 4 agonist monophosphoryl lipid A (MPLA). It is worth noting that RIMNA polymeric micelles had good stability, uniform morphology, superior biocompatibility, and intensified PTT/PDT effect. What’s more, RIMNA-mediated IDO inhibition combined with programmed death receptor-1 (PD-1)/PD-L1 blockade considerably improved immunosuppression and promoted immune activation. RIMNA-based photoimmunotherapy synergized with PD-1 antibody could remarkably inhibit primary tumor proliferation, as well as stimulate the immunity to greatly suppress lung metastasis and distant tumor growth. This study offers an efficient method to reinforce the efficacy of phototherapy and alleviate immunosuppression, thereby bringing clinical benefits to cancer treatment. Graphical Abstract

Objective: To develop a deep learning model to predict lymph node (LN) status in clinical stage IA lung adenocarcinoma patients. Methods: This diagnostic study included 1,009 patients with pathologically confirmed clinical stage T1N0M0 lung adenocarcinoma from two independent datasets (699 from Cancer Hospital of Chinese Academy of Medical Sciences and 310 from PLA General Hospital) between January 2005 and December 2019. The Cancer Hospital dataset was randomly split into a training cohort (559 patients) and a validation cohort (140 patients) to train and tune a deep learning model based on a deep residual network (ResNet). The PLA Hospital dataset was used as a testing cohort to evaluate the generalization ability of the model. Thoracic radiologists manually segmented tumors and interpreted high-resolution computed tomography (HRCT) features for the model. The predictive performance was assessed by area under the curves (AUCs), accuracy, precision, recall, and F1 score. Subgroup analysis was performed to evaluate the potential bias of the study population. Results: A total of 1,009 patients were included in this study; 409 (40.5%) were male and 600 (59.5%) were female. The median age was 57.0 years (inter-quartile range, IQR: 50.0–64.0). The deep learning model achieved AUCs of 0.906 (95% CI: 0.873–0.938) and 0.893 (95% CI: 0.857–0.930) for predicting pN0 disease in the testing cohort and a non-pure ground glass nodule (non-pGGN) testing cohort, respectively. No significant difference was detected between the testing cohort and the non-pGGN testing cohort (P = 0.622). The precisions of this model for predicting pN0 disease were 0.979 (95% CI: 0.963–0.995) and 0.983 (95% CI: 0.967–0.998) in the testing cohort and the non-pGGN testing cohort, respectively. The deep learning model achieved AUCs of 0.848 (95% CI: 0.798–0.898) and 0.831 (95% CI: 0.776–0.887) for predicting pN2 disease in the testing cohort and the non-pGGN testing cohort, respectively. No significant difference was detected between the testing cohort and the non-pGGN testing cohort (P = 0.657). The recalls of this model for predicting pN2 disease were 0.903 (95% CI: 0.870–0.936) and 0.931 (95% CI: 0.901–0.961) in the testing cohort and the non-pGGN testing cohort, respectively. Conclusions: The superior performance of the deep learning model will help to target the extension of lymph node dissection and reduce the ineffective lymph node dissection in early-stage lung adenocarcinoma patients.

Tebufenozide, an efficient insect growth regulator (IGR) against lepidopteran pests, presents a novel mode of action with minimal non-target impact. By competing with ecdysteroids for ecdysone receptor (EcR) binding, it regulates insect growth precisely. This study explores tebufenozide's potential as a multitarget IGR, targeting both EcR and Ostrinia furnacalis chitinase I (OfChtI). The inhibitory activity against OfChtI is comparable to that of substrates (GlcNAc)5, with an IC50 of 45.77 ​μM. Our computational findings indicate that tebufenozide binds at the subsite −1 to +1 of OfChtI through various interactions. Notably, tebufenozide establishes a pi-pi interaction with the flipped sidechain of Trp107, enabling tebufenozide to deeply penetrate into the S1 pocket, thereby obstructing substrate binding to OfChtI. These insights highlight the potency of multitarget strategies, laying the groundwork for innovative IGR designs that offer comprehensive pest management solutions.

Cerebral venous sinus thrombosis (CVST) and hyperlipidemia are severe complications of L-Asparaginase (L-Asp) during the treatment of B-cell acute lymphoblastic leukemia (B-ALL). Herein, we reported a 9-year-old B-ALL boy who underwent abnormal hypertriglyceridemia and CVST presenting as seizures and disturbance of consciousness twice during the induction therapy. Fortunately, he survived treatment with anticoagulant and lipid-lowering therapy. No thrombophilia-related gene mutation was detected, but a heterozygous mutation in lipoprotein lipase (LPL) gene was identified. His neurological symptoms were managed with short-term anticoagulant therapy and long-term lipid-lowering therapy. This case illustrated the manifestation and potential pathogenesis of CVST and highlighted the essentiality of screening baseline lipid profile and dyslipidemia- and thrombophilia-related gene mutation.

Oral administration is the most simple, noninvasive, convenient treatment. With the increasing demands on the targeted drug delivery, the traditional oral treatment now is facing some challenges: 1) biologics how to implement the oral treatment and ensure the bioavailability is not lower than the subcutaneous injections; 2) How to achieve targeted therapy of some drugs in the gastrointestinal tract? Based on these two issues, drug delivery microrobots have shown great application prospect in oral drug delivery due to their characteristics of flexible locomotion or driven ability. Therefore, this paper summarizes various drug delivery microrobots developed in recent years and divides them into four categories according to different driving modes: magnetic-controlled drug delivery microrobots, anchored drug delivery microrobots, self-propelled drug delivery microrobots and biohybrid drug delivery microrobots. As oral drug delivery microrobots involve disciplines such as materials science, mechanical engineering, medicine, and control systems, this paper begins by introducing the gastrointestinal barriers that oral drug delivery must overcome. Subsequently, it provides an overview of typical materials involved in the design process of oral drug delivery microrobots. To enhance readers' understanding of the working principles and design process of oral drug delivery microrobots, we present a guideline for designing such microrobots. Furthermore, the current development status of various types of oral drug delivery microrobots is reviewed, summarizing their respective advantages and limitations. Finally, considering the significant concerns regarding safety and clinical translation, we discuss the challenges and prospections of clinical translation for various oral drug delivery microrobots presented in this paper, providing corresponding suggestions for addressing some existing challenges.

Background: The global prevalence of diabetic heart complication has been on the increase, and some of the drugs that are currently used to treat diabetes mellitus (DM) have not been able to mitigate this complication. Objective: This study determines the effect of Brazil nut (Bertholletia excelsa) and metformin on diabetic cardiomyopathy (DCM) in fructose/streptozotocin (STZ)-induced type 2 diabetic rats and also characterizes using Gas Chromatography Mass Spectrophotometry and Fourier Transform Infrared the bioactive compounds in 50% aqueous ethanol extract of Brazil nut. Design: After inducing type 2 DM, 30 male albino Wistar rats were separated into five groups that comprised of six rats per group, and they were treated as follows: groups 1 (Control) and 2 (Diabetic control) rats received rat pellets and distilled water; group 3 (Diabetic + Brazil nut) received rat pellets and Brazil nut extract (100 mg/kg, orally) dissolved in distilled water, group 4 (Diabetic + metformin) received metformin (100 mg/kg, orally) dissolved in distilled water, while group 5 (Diabetic + Brazil nut + metformin) received oral administrations of Brazil nut (100 mg/kg) and metformin (100 mg/kg) dissolved in distilled water. This study lasted for 6 weeks. The dose of Brazil nut used was selected from our pilot study on the minimum therapeutic dose of different concentrations of Brazil nut extract. Results: STZ administration induced insulin resistance, hyperglycemia, loss of weight, dyslipidemia, oxidative stress, inflammation, apoptosis, alteration of mammalian target of rapamycin, mitogen-activated protein kinase, heart function markers (creatine kinase MB, lactate dehydrogenase, and aspartate amino transaminase), and heart histology of the diabetic control, which was ameliorated after treatment with Brazil nut and metformin, but their combined treatment was better than the single treatments. Conclusion: This study shows that Brazil nut contains several bioactive compounds that support its biological properties as well as its candidature as a complementary therapy to metformin in mitigating cardiac complications arising from DM in rats.

Abstract Numerous studies have shown that the Krüppel-like factors (KLFs) family of transcription factors regulate various eukaryotic physiological processes including the proliferation, differentiation, senescence, death, and carcinogenesis of animal cells. In addition, they are involved in the regulation of key biological processes such as cell cycle, DNA repair, and immune response. Current studies focus on investigating the role of KLFs in normal physiological conditions and the incidence and development of diseases. However002C the significance of KLFs family genes in clear cell renal cell carcinoma (ccRCC) remains partly understood; therefore, an in-depth investigation of their role and clinical value in this cancer is desired. The study aimed to investigate the role of KLF family genes in the incidence, development, and prognosis of ccRCC, and to identify the related potential biomarkers and therapeutic targets. The expression of KLFs in the RNA sequencing data of 613 ccRCCs from the TCGA database was analyzed using R software, and UALCAN and GEPIA assessed the expression of KLF genes in ccRCC. Real-time fluorescence quantitative PCR analysis was performed using 10 pairs of paired ccRCC sample tissues and renal cancer cell lines from the First Affiliated Hospital of Nanchang University. Overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) of Kidney Clear Cell Carcinoma (KIRC) samples at differential expressions of KLFs in the TCGA database were analyzed using the R software, followed by generating a nomogram prediction model. GSCALite assessed the interactions of KLF genes with miRNAs and generated network maps. Protein interaction network maps of 50 neighboring genes associated with KLF mutations were analyzed using STRING with GO and KEGG functional enrichment analyses. The cBioPortal determined the probability of KLF gene mutations and their impact on OS and disease-free survival (DFS) in patients with ccRCC. Immune cell infiltration of KLFs was analyzed using TIMER. Finally, GSCALite was used to analyze the drug sensitivity and associated pathways of action of KLFs. Correlation validation using cellular experiments. KLF3/5/9/15 were significantly downregulated in ccRCC tissues, whereas KLF16/17 were upregulated compared with the adjacent tissues. Patients with high mRNA levels of KLF16/17 showed significantly lower OS, PFI, and DSS, whereas KLF3/5/9 showed a reverse trend. In patients with ccRCC, a significant correlation was observed between KLF mutations and OS and DSS. Furthermore, the correlation of KLF3/5/9 with immune cell infiltration was stronger than that of KLF15/16, while KLF17 was significantly associated with the Epithelial-Mesenchymal Transition (EMT) pathway. Overexpression of KLF5 inhibits the proliferative and migratory capacity of renal cancer cells (786-O and OS-RC-2), as well as their sensitivity to relevant small molecule drugs. Our research revealed the expression levels and biological significance of KLF genes in ccRCC, particularly highlighting the potential of KLF5 as a promising biomarker and therapeutic target for effective prognosis and diagnosis of ccRCC.

Abstract Accurate prediction of the recovery of Disorders of Consciousness (DoC) is of paramount significance for clinicians and families. Serum total bilirubin (TBIL) formed by activation of heme oxygenase 2, is associated with incidence and prognosis of cardiovascular and cerebrovascular diseases. However, studies that based TBIL and DoC are limited. The study attempted to examine the association between serum TBIL levels and prognosis in patients with DoC. One hundred and sixty-eight patients with DoC in the Second hospital of Shandong University from June 2021 to June 2023 were recruited. The clinical characteristics and venous blood samples were collected within 24 h after admission. The diagnosis of DoC was determined by two skilled investigators employing various behavioral evaluations along the coma recovery scale-revised (CRS-R) and the investigators conducted follow-up assessments of diagnosis at 1, 3, and 6 months after admission. For statistical analysis, we categorized patients with an improvement in clinical diagnosis from study entry as having a “good outcome”. In total, 139 individuals enrolled in the study. The median TBIL level was 8.2 μmol/L. Good recovery of DoC at 1, 3, and 6 months occurred in 25 (18.0%), 41 (29.5%), and 56 (40.3%) patients, respectively. After full adjustment, a significant association was found between TBIL levels and the prognosis of DoC at 1, 3, and 6 months. When TBIL levels were analyzed as categorical variables, an increasing trend in the tertiles of TBIL levels demonstrated a significant positive association with the recovery of DoC at 1, 3, and 6 months. Stratified analysis revealed that the association between serum TBIL levels and the recovery of DoC remained consistent across different sub-populations. A high serum TBIL level is associated with an improved likelihood of recovery of DoC. Additional research is required to elucidate the underlying pathophysiological causal association between TBIL levels and DoC.

Abstract Background Nearly three in four U.S. medical students graduate with debt in six-figure dollar amounts which impairs students emotionally and academically and impacts their career choices and lives long after graduation. Schools have yet to develop systems-level solutions to address the impact of debt on students’ well-being. The objectives of this study were to identify students at highest risk for debt-related stress, define the impact on medical students’ well-being, and to identify opportunities for intervention. Methods This was a mixed methods, cross-sectional study that used quantitative survey analysis and human-centered design (HCD). We performed a secondary analysis on a national multi-institutional survey on medical student wellbeing, including univariate and multivariate logistic regression, a comparison of logistic regression models with interaction terms, and analysis of free text responses. We also conducted semi-structured interviews with a sample of medical student respondents and non-student stakeholders to develop insights and design opportunities. Results Independent risk factors for high debt-related stress included pre-clinical year (OR 1.75), underrepresented minority (OR 1.40), debt $20–100 K (OR 4.85), debt >$100K (OR 13.22), private school (OR 1.45), West Coast region (OR 1.57), and consideration of a leave of absence for wellbeing (OR 1.48). Mental health resource utilization (p = 0.968) and counselors (p = 0.640) were not protective factors against debt-related stress. HCD analysis produced 6 key insights providing additional context to the quantitative findings, and associated opportunities for intervention. Conclusions We used an innovative combination of quantitative survey analysis and in-depth HCD exploration to develop a multi-dimensional understanding of debt-related stress among medical students. This approach allowed us to identify significant risk factors impacting medical students experiencing debt-related stress, while providing context through stakeholder voices to identify opportunities for system-level solutions.

Abstract Protein methylation is a functionally important post-translational modification that occurs on diverse amino acid residues. The current proteomics approaches are inefficient to discover the methylation on residues other than Arg and Lys, which hinders the deep understanding of the functional role of rare protein methylation. Herein, we present a methyl-specific metabolic labeling approach for global methylome mapping, which enable the acquisition of methylome dataset covering diverse methylation types. Interestingly, of the identified methylation events, His methylation is found to be preferably occurred in C3H1 zinc fingers (ZFs). These His methylation events are determined to be Nπ specific and catalyzed by CARNMT1. The His methylation is found to stabilize the structure of ZFs. U2AF1 is used as a proof-of-concept to highlight the functional importance of His methylation in ZFs in RNA binding and RNA metabolism. The results of this study enable novel understanding of how protein methylation regulates cellular processes.

Abstract The long-term interaction between the environment and humans has significantly shaped contemporary landscapes worldwide. As a heritage landscape, the polder is essential for understanding the impact of the past human activities on contemporary landscape on low-lying area of land. In this case study, we reconstructed the regional spatial distribution of the polders in the early twentieth century and examined their coherence over the past century using historical maps and other materials in the Jianghan Plain. The results revealed several key findings: (1) In the early twentieth century, there were 1571 polders covering an area of 11,826.1 km2 with a perimeter of 17,035.9 km. (2) These polders exhibited a J-shaped distribution, with few large-scale polders despite their substantial areas. (3) The shape of these polders reflected an ability to balance human needs and the natural environment. (4) Considerable regional differences in these polders were attributed to centuries-old interactions between humans and the environment. (5) The remnants of these early twentieth century polders have had a lasting influence on the contemporary landscape, particularly in rural areas. This case study underscores how taking into account a broader historical perspective can enhance our understanding of present-day landscapes and, more importantly, the role that past human actions have played in shaping them.

Abstract Background Gallbladder cancer (GBC) is characterized by high mortality rate. Our study sought therapeutic candidates for GBC. Results Bioinformatics analysis identified significant upregulation of MST1R in GBC. In vitro experiments demonstrated that the MST1R inhibitor MGCD-265 effectively restrained GBC cell proliferation at lower concentrations. Additionally, it induced cycle arrest and apoptosis in GBC cells in a dose-dependent manner. Mouse models exhibited that MGCD-265 treatment significantly diminished the proliferative capacity of GBC-SD cells. Transcriptomics sequencing revealed significant transcriptome alterations, with 200 transcripts upregulated and 883 downregulated. KEGG and GO analyses highlighted enrichment in processes like cell adhesion and pathways such as protein digestion and absorption. Downstream genes analysis identified JMJD6 upregulation post-MGCD-265 treatment. In vivo experiments confirmed that combining MGCD-265 with the JMJD6 inhibitor SKLB325 enhanced the anticancer effect against GBC. Conclusion Overall, targeting MST1R and its downstream genes, particularly combining MGCD-265 with SKLB325, holds promise as a therapeutic strategy for GBC.

Abstract The sole use of single modality data often fails to capture the complex heterogeneity among patients, including the variability in resistance to anti-HER2 therapy and outcomes of combined treatment regimens, for the treatment of HER2-positive gastric cancer (GC). This modality deficit has not been fully considered in many studies. Furthermore, the application of artificial intelligence in predicting the treatment response, particularly in complex diseases such as GC, is still in its infancy. Therefore, this study aimed to use a comprehensive analytic approach to accurately predict treatment responses to anti-HER2 therapy or anti-HER2 combined immunotherapy in patients with HER2-positive GC. We collected multi-modal data, comprising radiology, pathology, and clinical information from a cohort of 429 patients: 310 treated with anti-HER2 therapy and 119 treated with a combination of anti-HER2 and anti-PD-1/PD-L1 inhibitors immunotherapy. We introduced a deep learning model, called the Multi-Modal model (MuMo), that integrates these data to make precise treatment response predictions. MuMo achieved an area under the curve score of 0.821 for anti-HER2 therapy and 0.914 for combined immunotherapy. Moreover, patients classified as low-risk by MuMo exhibited significantly prolonged progression-free survival and overall survival (log-rank test, P

Abstract Macrophages are multifunctional innate immune cells that play indispensable roles in homeostasis, tissue repair, and immune regulation. However, dysregulated activation of macrophages is implicated in the pathogenesis of various human disorders, making them a potential target for treatment. Through the expression of pattern recognition and scavenger receptors, macrophages exhibit selective uptake of pathogens and apoptotic cells. Consequently, the utilization of drug carriers that mimic pathogenic or apoptotic signals shows potential for targeted delivery to macrophages. In this study, a series of mannosylated or/and phosphatidylserine (PS) -presenting liposomes were developed to target macrophages via the design of experiment (DoE) strategy and the trial-and-error (TaE) approach. The optimal molar ratio for the liposome formulation was DOPC: DSPS: Chol: PEG-PE = 20:60:20:2 based on the results of cellular uptake and cytotoxicity evaluation on RAW 264.7 and THP-1 in vitro. Results from in vivo distribution showed that, in the DSS-induced colitis model and collagen II-induced rheumatoid arthritis model, PS-presenting liposomes (PS-Lipo) showed the highest accumulation in intestine and paws respectively, which holds promising potential for macrophage target therapy since macrophages are abundant at inflammatory sites and contribute to the progression of corresponding diseases. Organs such as the heart, liver, spleen, lung, and kidney did not exhibit histological alterations such as inflammation or necrosis when exposed to PC-presenting liposomes (PC-Lipo) or PS-Lipo. In addition, liposomes demonstrated hemobiocompatibility and no toxicity to liver or kidney for circulation and did not induce metabolic injury in the animals. Thus, the well-designed PS-Lipo demonstrated the most potential for macrophage target therapy.

Abstract Purpose The atherogenic index of plasma (AIP) is a novel comprehensive lipid index. We aimed to investigate a possible relationship between AIP index and kidney stones in US adults. Methods This cross-sectional study was conducted among adults with complete AIP index and questionnaire records on kidney stones from the National Health and Nutrition Examination Survey (NHANES) spanning from 2007 to 2018. The AIP index served as the exposure variable, defined as the logarithm of the ratio between triglycerides (TG, mmol/L) and high-density lipoprotein cholesterol (HDL-c, mmol/L). Self-reported history of kidney stones was utilized as the outcome variable. The independent relationship between AIP index and the risk of kidney stones was fully assessed. Results A total of 14,833 participants were included in this study, with an average AIP index of -0.07 ± 0.01. The proportion of kidney stones progressively increased with higher AIP index tertile intervals (7.33% vs. 9.97% vs. 12.57%, P 0.05). Conclusions The AIP index may be a potential epidemiological tool to quantify the role of dyslipidemia in the risk of kidney stones in US adults.

Malignant pleural mesothelioma (MPM) is a rare, highly aggressive, and lethal tumor with poor prognosis. Its survival period ranges from four months to one year, and the 5-year survival rate is only about 10%. MPM is highly resistant to chemotherapy, and conventional treatments such as cisplatin combined with pemetrexed or raltitrexed only have a certain effect in about 20% of patients. In recent years, with the continuous in-depth understanding of the genetic variation characteristics of MPM, some progress has been made in the molecular mechanism underlying the chemotherapy resistance of MPM. This article will summarize the research progress of the molecular mechanism underlying the chemotherapy resistance of MPM, including BAP1 gene mutation, microRNA, MTA1-mediated DNA damage repair pathway, GITR-GITRL pathway, TGFa pathway, tumor stem cell, EGFR, and PTEN. The aim of this work is to provide a reference for exploring new therapeutic targets and combined treatment options for MPM.

Abstract Research on the severity and prognosis of sepsis with or without progressive delirium is relatively insufficient. We constructed a prediction model of the risk factors for 28-day mortality in patients who developed sepsis or sepsis-associated delirium. The modeling group of patients diagnosed with Sepsis-3 and patients with progressive delirium of related indicators were selected from the MIMIC-IV database. Relevant independent risk factors were determined and integrated into the prediction model. Receiver operating characteristic (ROC) curves and the Hosmer–Lemeshow (HL) test were used to evaluate the prediction accuracy and goodness-of-fit of the model. Relevant indicators of patients with sepsis or progressive delirium admitted to the intensive care unit (ICU) of a 3A hospital in Xinjiang were collected and included in the verification group for comparative analysis and clinical validation of the prediction model. The total length of stay in the ICU, hemoglobin levels, albumin levels, activated partial thrombin time, and total bilirubin level were the five independent risk factors in constructing a prediction model. The area under the ROC curve of the predictive model (0.904) and the HL test result (χ2 = 8.518) indicate a good fit. This model is valuable for clinical diagnosis and treatment and auxiliary clinical decision-making.

Abstract Background Chinese Cymbidium orchids, cherished for their deep-rooted cultural significance and significant economic value in China, have spawned a rich tapestry of cultivars. However, these orchid cultivars are facing challenges from insufficient cultivation practices and antiquated techniques, including cultivar misclassification, complex identification, and the proliferation of counterfeit products. Current commercial techniques and academic research primarily emphasize species identification of orchids, rather than delving into that of orchid cultivars within species. Results To bridge this gap, the authors dedicated over a year to collecting a cultivar image dataset for Chinese Cymbidium orchids named Orchid2024. This dataset contains over 150,000 images spanning 1,275 different categories, involving visits to 20 cities across 12 provincial administrative regions in China to gather pertinent data. Subsequently, we introduced various visual parameter-efficient fine-tuning (PEFT) methods to expedite model development, achieving the highest top-1 accuracy of 86.14% and top-5 accuracy of 95.44%. Conclusion Experimental results demonstrate the complexity of the dataset while highlighting the considerable promise of PEFT methods within flower image classification. We believe that our work not only provides a practical tool for orchid researchers, growers and market participants, but also provides a unique and valuable resource for further exploring fine-grained image classification tasks. The dataset and code are available at https://github.com/pengyingshu/Orchid2024 .

Abstract Dual inhibition of vascular endothelial growth factor and epidermal growth factor receptor (EGFR) signaling pathways offers the prospect of improving the effectiveness of EFGR-targeted therapy. In this phase 3 study (ClinicalTrial.gov: NCT04028778), 315 patients with treatment-naïve, EGFR-mutated, advanced non-small cell lung cancer (NSCLC) were randomized (1:1) to receive anlotinib or placebo plus gefitinib once daily on days 1–14 per a 3-week cycle. At the prespecified final analysis of progression-free survival (PFS), a significant improvement in PFS was observed for the anlotinib arm over the placebo arm (hazards ratio [HR] = 0.64, 95% CI, 0.48–0.80, P = 0.003). Particularly, patients with brain metastasis and those harboring EGFR amplification or high tumor mutation load gained significant more benefits in PFS from gefitinib plus anlotinib. The incidence of grade 3 or higher treatment-emergent adverse events was 49.7% of the patients receiving gefitinib plus anlotinib versus 31.0% of the patients receiving gefitinib plus placebo. Anlotinib plus gefitinib significantly improves PFS in patients with treatment-naïve, EGFR-mutated, advanced NSCLC, with a manageable safety profile.

Abstract Proteasome inhibitors (PIs), such as bortezomib and calfizomib, were backbone agents in the treatment of multiple myeloma (MM). In this study, we investigated bortezomib interactors in MM cells and identified dihydrolipoamide dehydrogenase (DLD) as a molecular target of bortezomib. DLD catalyzes the oxidation of dihydrolipoamide to form lipoamide, a reaction that also generates NADH. Our data showed that bortezomib bound to DLD and inhibited DLD’s enzymatic function in MM cells. DLD knocked down MM cells (DLD-KD) had decreased levels of NADH. Reduced NADH suppressed assembly of proteasome complex in cells. As a result, DLD-KD MM cells had decreased basal-level proteasome activity and were more sensitive to bortezomib. Since PIs were used in many anti-MM regimens in clinics, we found that high expression of DLD correlated with inferior prognosis of MM. Considering the regulatory role of DLD in proteasome assembly, we evaluated DLD targeting therapy in MM cells. DLD inhibitor CPI-613 showed a synergistic anti-MM effect with bortezomib in vitro and in vivo. Overall, our findings elucidated DLD as an alternative molecular target of bortezomib in MM. DLD-targeting might increase MM sensitivity to PIs.

Abstract Background Ischemia reperfusion (IR) causes impaired myocardial function, and autophagy activation ameliorates myocardial IR injury. Isoliquiritigenin (ISO) has been found to protect myocardial tissues via AMPK, with exerting anti-tumor property through autophagy activation. This study aims to investigate ISO capacity to attenuate myocardial IR through autophagy activation mediated by AMPK/mTOR/ULK1 signaling. Methods ISO effects were explored by SD rats and H9c2 cells. IR rats and IR-induced H9c2 cell models were established by ligating left anterior descending (LAD) coronary artery and hypoxia/re-oxygenation, respectively, followed by low, medium and high dosages of ISO intervention (Rats: 10, 20, and 40 mg/kg; H9c2 cells: 1, 10, and 100 μmol/L). Myocardial tissue injury in rats was assessed by myocardial function-related index, HE staining, Masson trichrome staining, TTC staining, and ELISA. Autophagy of H9c2 cells was detected by transmission electron microscopy (TEM) and immunofluorescence. Autophagy-related and AMPK/mTOR/ULK1 pathway-related protein expressions were detected with western blot. Results ISO treatment caused myocardial function improvement, and inhibition of myocardial inflammatory infiltration, fibrosis, infarct area, oxidative stress, CK-MB, cTnI, and cTnT expression in IR rats. In IR-modeled H9c2 cells, ISO treatment lowered apoptosis rate and activated autophagy and LC3 fluorescence expression. In vivo and in vitro, ISO intervention exhibited enhanced Beclin1, LC3II/LC3I, and p-AMPK/AMPK levels, whereas inhibited P62, p-mTOR/mTOR and p-ULK1(S757)/ULK1 protein expression, activating autophagy and protecting myocardial tissues from IR injury. Conclusion ISO treatment may induce autophagy by regulating AMPK/mTOR/ULK1 signaling, thereby improving myocardial IR injury, as a potential candidate for treatment of myocardial IR injury.

Abstract Polymer nanocomposites with tuning functions are exciting candidates for various applications, and most current research has focused on static mechanical reinforcement. Actually, under service conditions of complex dynamic interference, stable dynamic mechanical properties with high energy dissipation become more critical. However, nanocomposites often exhibit a trade-off between static and dynamic mechanics, because of their contradictory underlying physics between chain crosslinking and chain relaxation. Here, we report a general strategy for constructing ultra-stable dynamic mechanical complex fluid nanocomposites with high energy dissipation by infusing complex fluids into the nanoconfined space. The key is to tailor full-scale polymer dynamics across an exceptionally broad timescale by single-chain confinement. These materials exhibit stable storage modulus (100 ~ 102 MPa) with high energy dissipation (loss factor > 0.4) over a broad frequency range (10−1 ~ 107 Hz)/temperature range (−35 ~ 85°C). In the loss factor > 0.4 region, their dynamic mechanical stability (rate of modulus change versus temperature (k)) is 10 times higher than that of conventional polymer nanocomposites.

Abstract Accumulated evidence suggested that gut microbial dysbiosis interplayed with progressive chronic kidney disease (CKD). However, no available therapy is effective in suppressing progressive CKD. Here, using microbiomics in 480 participants including healthy controls and patients with stage 1–5 CKD, we identified an elongation taxonomic chain Bacilli-Lactobacillales-Lactobacillaceae-Lactobacillus-Lactobacillus johnsonii correlated with patients with CKD progression, whose abundance strongly correlated with clinical kidney markers. L. johnsonii abundance reduced with progressive CKD in rats with adenine-induced CKD. L. johnsonii supplementation ameliorated kidney lesion. Serum indole-3-aldehyde (IAld), whose level strongly negatively correlated with creatinine level in CKD rats, decreased in serum of rats induced using unilateral ureteral obstruction (UUO) and 5/6 nephrectomy (NX) as well as late CKD patients. Treatment with IAld dampened kidney lesion through suppressing aryl hydrocarbon receptor (AHR) signal in rats with CKD or UUO, and in cultured 1-hydroxypyrene-induced HK-2 cells. Renoprotective effect of IAld was partially diminished in AHR deficiency mice and HK-2 cells. Our further data showed that treatment with L. johnsonii attenuated kidney lesion by suppressing AHR signal via increasing serum IAld level. Taken together, targeting L. johnsonii might reverse patients with CKD. This study provides a deeper understanding of how microbial-produced tryptophan metabolism affects host disease and discovers potential pathways for prophylactic and therapeutic treatments for CKD patients.

Abstract Background To explore whether nobiletin has a protective effect on high-fat diet (HFD)-induced enteric nerve injury and its underlying mechanism. Methods An obesity model was induced by a HFD. Nobiletin (100 mg/kg and 200 mg/kg) and vehicle were administered by gastric gavage for 4 weeks. Lee’s index, body weight, OGTT and intestinal propulsion assays were performed before sacrifice. After sampling, lipids were detected using Bodipy 493/503; lipid peroxidation was detected using MDA and SOD kits and the expression of PGP 9.5, Trem2, GFAP, β-tubulin 3, Bax, Bcl2, Nestin, P75 NTR, SOX10 and EDU was detected using immunofluorescence. The GDNF, p-AKT, AKT, p-FOXO3a, FOXO3a and P21 proteins were detected using western blotting. The relative mRNA expression levels of NOS2 were detected via qPCR. Primary enteric neural stem cells (ENSCs) were cultured. After ENSCs were treated with palmitic acid (PA) and nobiletin, CCK-8 and caspase-3/7 activity assays were performed to evaluate proliferation and apoptosis. Results HFD consumption caused colon lipid accumulation and peroxidation, induced enteric nerve damage and caused intestinal motor dysfunction. However, nobiletin reduced lipid accumulation and peroxidation in the colon; promoted Trem2, β-tubulin 3, Nestin, P75NTR, SOX10 and Bcl2 expression; inhibited Bax and GFAP expression; reduced NOS2 mRNA transcription; and regulated the GDNF/AKT/FOXO3a/P21 pathway. Nobiletin also promoted PA-induced impairment of ENSCs. Conclusions Nobiletin restored HFD-induced enteric nerve injury, which may be associated with inhibiting enteric nerve apoptosis, promoting enteric nerve survival and regulating the GDNF/AKT/FOXO3a/P21 pathway.

Abstract Background Fall prevention and balance control constitute critical components of rehabilitation for stroke survivors. Kneeling training, characterized by its low center of gravity focus, has been incorporated into rehabilitation regimens to enhance postural control across various pathological conditions. Despite its widespread use, empirical evidence substantiating the efficacy of kneeling training is limited, particularly in the context of mobility and balance improvement for patients who have had a stroke. This study aims to substantiate the safety and effectiveness of kneeling training in individuals recovering from stroke. Methods A randomized controlled trial comparing kneeling training and conventional rehabilitation training was conducted, involving sixty-seven participants allocated to the Kneeling Training Group (KNT) and the Conventional Rehabilitation Group (CVR). The KNT group underwent 30-minute sessions of kneeling training, while the CVR group received conventional treadmill walking training, both administered six times per week over four weeks. Evaluation encompassed the Fugl-Meyer Assessment for Lower Extremity (FMA-LE), the Berg Balance Scale (BBS), and gait analysis was conducted at baseline, as well as at the 2 and 4-week intervals. Results Our study established the safety of a 4-week kneeling training program. Notably, the KNT group exhibited more pronounced improvements in BBS scores at weeks 2 and 4 compared to the CVR group. However, no significant disparities emerged in FMA-LE and gait analysis between the two groups. Our findings suggest that kneeling training may serve as a viable option for enhancing lower limb balance in survivors who have had a stroke. Conclusions We conclude that kneeling training, characterized by its safety, simplicity, and no restrictions on location or equipment, represents a valuable therapeutic approach for enhancing walking balance in individuals recovering from stroke. Trial registration Clinical trials ChiCTR1900028385, December 20, 2019.

In order to explore the diagnostic value of ultrasound combined with shear wave elastography (SWE) for prostate cancer (PCa), 120 patients with suspected prostate cancer were selected for SWE, contrast-enhanced ultrasound (CEUS), SWE and CEUS combined examination. The results showed that among the 120 patients, 57 cases were diagnosed as prostate cancer and 63 cases as benign prostatic lesions by biopsy. Among 58 cases of PCa diagnosed by SWE, 46 cases were confirmed by pathology, with a sensitivity of 80.70% and a specificity of 77.20%. Among 54 cases of PCa diagnosed by CEUS, 41 cases were confirmed by pathology, with a sensitivity of 80.70% and a specificity of 77.20%. 61 patients with PCa were diagnosed by we and CEUS, and 51 patients were diagnosed by pathology. The sensitivity, specificity and accuracy were 89.47%, 84.70% and 85.38%, respectively. Receiver operating characteristic (ROC) curve results showed that the area under the curve (AUC) of swe and CEUS was 0.944, showing the highest diagnostic efficacy. It can be seen that the combined use of SWE and CEUS provides a more superior diagnostic effect for PCa.

This study examines the flood disaster management network within the Guangdong–Hong Kong–Macao Greater Bay Area (GBA) from 2015 to 2021, identifying government department involvement and influence shifts. Key findings indicate a decrease in the centrality of the Public Security Office and Department of Transportation, suggesting a strategic shift toward more specialized, technology-driven disaster management. Conversely, the Science Bureau's increased engagement, from 8.43% to 12.84%, highlights a policy shift toward scientific research and technological innovation in managing flood risks. The analysis reveals underutilized communication between the Central Committee, the Poverty Alleviation Office, and the Publicity Department, highlighting opportunities for improved integration in disaster management and public communication strategies. To address these issues, the study suggests strengthening inter-departmental collaboration to leverage technological advancements in disaster management. It also recommends integrating flood disaster management with poverty alleviation initiatives to support affected populations comprehensively. Increasing the involvement of the Publicity Department is crucial for improving timely and transparent communication of flood-related data to the public. The conclusions advocate for an adaptive, strategically planned network approach to flood disaster management in the GBA, aiming to bolster responsiveness and preparedness for future flood events. HIGHLIGHTS The study reveals a strategic shift in the flood disaster management network within the GBA, with decreased centrality of traditional departments like the Public Security Office and Department of Transportation, and increased engagement of the Science Bureau, highlighting a move toward specialized, technology-driven approaches.; The study identifies underutilized communication between key departments, such as the Central Committee, the Poverty Alleviation Office, and the Publicity Department, suggesting significant opportunities for improved integration and coordination in disaster management strategies.; The study recommends enhancing inter-departmental collaboration, integrating flood management with poverty alleviation, and increasing the Publicity Department's role for better communication, advocating for an adaptive, strategic network approach to improve disaster preparedness and responsiveness in the GBA.;

Objective To understand the clinical characteristics and microecological status of lower genital tract in females with genital herpes in gynecological clinic in order to standardize the treatment of genital herpes. Methods A total of 27 women diagnosed with genital herpes were enrolled from the gynecological clinic of Beijing Obstetrics and Gynecology Hospital, Capital Medical University. The clinical data and vaginal microecology of participants were analyzed. Results All patients presented with various degree of external genital itching, pain, burning pain, sting pain, etc. Gynecological examination showed typical external genital herpes and/or irregular small ulcers. One case presented with cervical herpes-like changes. Abnormal vaginal microecology was observed in 88.89% of the patients (24/27), including 8 cases of decreased function of flora, 2 cases of bacterial vaginosis, 6 cases of vulvovaginal candidiasis, 7 cases of abnormal flora, and 1 case of mixed infections. The pH of vaginal secretions was higher, evidenced by 22 cases (22/27, 81.48%) with pH >4.5. Conclusions The clinical manifestations of female genital herpes vary and are often accompanied by vaginal dysbiosis. In clinic, it is recommended to conduct vaginal microbiota examination and personalize targeted treatment for all women with suspected genital herpes.

Abstract Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Increasing evidence suggests that inflammation played an important role in the pathogenesis of T2DM. Prospective studies on the link between immunoglobulins concentrations and the risk of T2DM in adults are limited. We developed a cohort study including 7,093 adults without T2DM history. The incidence of T2DM was 16.45 per 1,000 person-years. Compared with the lowest quartiles, the hazard ratios (95% confidence intervals) of T2DM for the highest quartiles of IgG, IgE, IgM and IgA were 0.64 (0.48–0.85), 0.94 (0.72–1.23), 0.68 (0.50–0.92) and 1.62 (1.24–2.11) (P for trend was

Abstract Virus‒host protein‒lncRNA interaction (VHPLI) predictions are critical for decoding the molecular mechanisms of viral pathogens and host immune processes. Although VHPLI interactions have been predicted in both plants and animals, they have not been extensively studied in viruses. For the first time, we propose a new deep learning-based approach that consists mainly of a convolutional neural network and bidirectional long and short-term memory network modules in combination with transfer learning named CBIL‒VHPLI to predict viral–host protein‒lncRNA interactions. The models were first trained on large and diverse datasets (including plants, animals, etc.). Protein sequence features were extracted using a k-mer method combined with the one-hot encoding and composition–transition–distribution (CTD) methods, and lncRNA sequence features were extracted using a k-mer method combined with the one-hot encoding and Z curve methods. The results obtained on three independent external validation datasets showed that the pre-trained CBIL‒VHPLI model performed the best with an accuracy of approximately 0.9. Pretraining was followed by conducting transfer learning on a viral protein–human lncRNA dataset, and the fine-tuning results showed that the accuracy of CBIL‒VHPLI was 0.946, which was significantly greater than that of the previous models. The final case study results showed that CBIL‒VHPLI achieved a prediction reproducibility rate of 91.6% for the RIP-Seq experimental screening results. This model was then used to predict the interactions between human lncRNA PIK3CD-AS2 and the nonstructural protein 1 (NS1) of the H5N1 virus, and RNA pull-down experiments were used to prove the prediction readiness of the model in terms of prediction. The source code of CBIL‒VHPLI and the datasets used in this work are available at https://github.com/Liu-Lab-Lnu/CBIL-VHPLI for academic usage.

Abstract The RATIONALE-306 study revealed that patients with advanced or metastatic oesophageal squamous cell carcinoma (OSCC) could benefit from treatment with tislelizumab plus chemotherapy. This study aimed to evaluate the cost-effectiveness of tislelizumab plus chemotherapy for treating OSCC from the perspective of the Chinese healthcare system. Partitioned survival model estimated the cost-effectiveness of tislelizumab plus chemotherapy compared with chemotherapy alone for treating OSCC using RATIONALE-306 data. Costs and utilities were obtained from local databases and published studies. Costs, quality-adjusted life-years (QALYs), life-years, incremental cost-effectiveness ratios (ICER), incremental net health benefits (INHB), and incremental net monetary benefits (INMB) were outcomes. Price simulation were conducted at the willingness-to-pay (WTP) threshold. Sensitivity and subgroup analyses were performed to assess model robustness. Compared with chemotherapy alone, tislelizumab plus chemotherapy yielded an ICER of USD 27,896/QALY, gained an additional 0.414 QALYs and 0.751 life-years, and increased the cost by USD 11,560. Probabilistic sensitivity analysis revealed that tislelizumab plus chemotherapy was cost-effective at the WTP of USD 38,258/QALY with probability of 94.43%. When the price in China was less than USD 3.714 per mg, the price simulation results indicated that tislelizumab plus chemotherapy was cost-effective at a WTP threshold of USD 38,258. Tislelizumab plus chemotherapy yielded an INHB of 0.112 QALYs and an INMB of USD 4,279 compared with chemotherapy alone at a WTP threshold of USD 38,258. Based on the sensitivity analyses, the above results were stable. A general trend was observed for subgroups with better survival benefits related to a higher probability of cost-effectiveness. From the Chinese healthcare perspective, tislelizumab plus chemotherapy is more cost-effective than chemotherapy alone as a first-line therapy for OSCC. These findings can help clinicians make optimal clinical decisions and assist decision-makers in evaluating the cost-effectiveness of tislelizumab in clinical practice.

Abstract To examine the role of inequality in academic achievement, we analyse a cross-national dataset including data from three cycles from 2012 to 2018 from the PISA, an international assessment of 15-year-old students’ math, reading, and science performance. The Gini coefficient and gender inequality index (GII) were used as metrics for a country’s economic inequality and gender inequality, respectively. The results show that gender inequality has a negative association with academic achievement for both boys and girls. Moreover, gender inequality has a stronger association with academic achievement than does economic inequality. We also find that gender inequality in reproductive health may contribute substantially to the association between gender inequality and academic achievement. Despite substantial advances in gender equality worldwide, multisectoral and multilevel approaches from the community to the country level are needed to ensure substantial long-term reductions in economic, gender, and educational inequalities.

Abstract Background The development of ketamine-like rapid antidepressants holds promise for enhancing the therapeutic efficacy of depression, but the underlying cellular and molecular mechanisms remain unclear. Implicated in depression regulation, the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) is investigated here to examine its role in mediating the rapid antidepressant response. Methods The onset of antidepressant response was assessed through depression-related behavioral paradigms. The signaling mechanism of PACAP in the hippocampal dentate gyrus (DG) was evaluated by utilizing site-directed gene knockdown, pharmacological interventions, or optogenetic manipulations. Overall, 446 mice were used for behavioral and molecular signaling testing. Mice were divided into control or experimental groups randomly in each experiment, and the experimental manipulations included: chronic paroxetine treatments (4, 9, 14 d) or a single treatment of ketamine; social defeat or lipopolysaccharides-injection induced depression models; different doses of PACAP (0.4, 2, 4 ng/site; microinjected into the hippocampal DG); pharmacological intra-DG interventions (CALM and PACAP6-38); intra-DG viral-mediated PACAP RNAi; and opotogenetics using channelrhodopsins 2 (ChR2) or endoplasmic natronomonas halorhodopsine 3.0 (eNpHR3.0). Behavioral paradigms included novelty suppressed feeding test, tail suspension test, forced swimming test, and sucrose preference test. Western blotting, ELISA, or quantitative real-time PCR (RT-PCR) analysis were used to detect the expressions of proteins/peptides or genes in the hippocampus. Results Chronic administration of the slow-onset antidepressant paroxetine resulted in an increase in hippocampal PACAP expression, and intra-DG blockade of PACAP attenuated the onset of the antidepressant response. The levels of hippocampal PACAP expression were reduced in both two distinct depression animal models and intra-DG knockdown of PACAP induced depression-like behaviors. Conversely, a single infusion of PACAP into the DG region produced a rapid and sustained antidepressant response in both normal and chronically stressed mice. Optogenetic intra-DG excitation of PACAP-expressing neurons instantly elicited antidepressant responses, while optogenetic inhibition induced depression-like behaviors. The longer optogenetic excitation/inhibition elicited the more sustained antidepressant/depression-like responses. Intra-DG PACAP infusion immediately facilitated the signaling for rapid antidepressant response by inhibiting calcium/calmodulin-dependent protein kinase II (CaMKII)-eukaryotic elongation factor 2 (eEF2) and activating the mammalian target of rapamycin (mTOR). Pre-activation of CaMKII signaling within the DG blunted PACAP-induced rapid antidepressant response as well as eEF2-mTOR-brain-derived neurotrophic factor (BDNF) signaling. Finally, acute ketamine treatment upregulated hippocampal PACAP expression, whereas intra-DG blockade of PACAP signaling attenuated ketamine’s rapid antidepressant response. Conclusions Activation of hippocampal PACAP signaling induces a rapid antidepressant response through the regulation of CaMKII inhibition-governed eEF2-mTOR-BDNF signaling.

Abstract Background Cutaneous squamous cell carcinoma (CSCC) is one of the most common types of skin cancer worldwide. Therefore, the identification of biomarkers associated with CSCC progression could aid in the early detection of high-risk squamous cell carcinoma and the development of novel therapeutic strategies. Objective This study aimed to investigate the expression patterns of silent mating type Information Regulation 2 homolog 6 (SIRT6) in CSCC and its clinical significance. Methods The protein expression level of SIRT6 in tissues was detected by immunohistochemistry, and the correlation between SIRT6 expression and clinicopathological parameters in CSCC patients was analyzed. The relative expression of SIRT6 in CSCC cell lineage and tissue specimens was determined by western blotting and PCR. The effect of SIRT6 silencing on cell proliferation was evaluated using cell counting kit 8. Wound healing, transwell method, and flow cytometry were used to investigate the migration, invasion, and cell cycle distribution/apoptosis of CSCC cells after SIRT6 silencing, respectively. Western blot was used to detect the expression of EMT (Epithelial-Mesenchymal Transition), cycle, apoptosis, and other related proteins. Results The high expression of SIRT6 was correlated with the location of cancer tissue and Broder staging in CSCC patients. Knockdown of SIRT6 inhibited the proliferation, migration, invasion and EMT of CSCC cells, and promoted their apoptosis, with cells blocked in G1 phase. Study limitations No animal experiments were conducted to further verify the results. Conclusion Decreased expression of SIRT6 can inhibit the occurrence and development of CSCC.

AlCoCrFeMo0.05Ni2 high-entropy alloy (HEA) has great potential for high-temperature applications. However, its FCC matrix will decompose during annealing, which seriously limits its high-temperature applications. Here, the lattice distortion, Gibbs free energy change, phonon spectra, density of states, and bond length distribution of the FCC matrix were calculated by first-principles calculations. The findings indicate that the primary barrier to the formation of a single homogeneous solid solution in the alloy is more closely associated with Gibbs free energy rather than the degree of lattice distortion. The vibration frequency of Al is not in sync with the overall structure, making it prone to desolvation at elevated temperatures. Furthermore, an analysis of bond lengths reveals that the Al–Ni bond length is significantly shorter than the theoretical value, facilitating the formation of a (Ni, Al)-rich phase. In contrast, the longer bond lengths of Al–Cr and Al–Mo facilitate the detachment of Cr and Mo from the (Ni, Al)-rich phase, resulting in the formation of (Cr, Mo)-rich phase. This in-depth investigation sheds light on the phase decomposition mechanism of high-entropy alloys, offering valuable insights for future research in this field.

Abstract Background Acute coronary syndrome (ACS) is one of the common causes of cardiovascular death. The related lncRNAs were novel approaches for early diagnosis and intervention. This paper focused on the clinical function of SNHG7 for patients after PCI. Methods The expression of SNHG7 was assessed in ACS patients. The predictive roles of SNHG7 were unveiled by the ROC curve. The relationship between SNHG7 and Gensini scores was judged by Pearson analysis. One-year follow-up was conducted and all patients were catalogued into different groups based on the prognosis. The qRT-PCR, K-M curve, and Cox regression analysis were performed to document the prognostic significance of SNHG7. Results SNHG7 was highly expressed in ACS and its three subtypes. SNHG7 showed a certain value in predicting ACS, UA, NSTEMI, and STEMI. Gensini is a closely correlated indicator of SNHG7. The declined expression of SNHG7 was observed in the non-MACE and survival groups. The risk of MACE and death was increased in the group with high expression of SNHG7. SNHG7 was an independent biomarker in patients with ACS after PCI. Conclusions SNHG7 might be a diagnostic and prognostic tool for ACS patients.

Abstract With the gradual liberalization of the three-child policy and the development of assisted reproductive technology in China, the number of women with high-risk pregnancies is gradually increasing. In this study, 4211 fetuses who underwent chromosomal microarray analysis (CMA) with high-risk prenatal indications were analysed. The results showed that the overall prenatal detection rate of CMA was 11.4% (480/4211), with detection rates of 5.82% (245/4211) for abnormal chromosome numbers and 5.58% (235/4211) for copy number variants. Additionally, the detection rates of clinically significant copy number variants were 3.78% (159/4211) and 1.8% (76/4211) for variants of uncertain significance. The detection rates of fetal chromosomal abnormalities were 6.42% (30/467) for pregnant women with advanced maternal age (AMA), 6.01% (50/832) for high-risk maternal serum screening (MSS) results, 39.09% (224/573) with abnormal non-invasive prenatal testing (NIPT) results, 9.21% (127/1379) with abnormal ultrasound results, and 5.1% (49/960) for other indications. Follow-up results were available for 4211 patients, including 3677 (3677/4211, 87.32%) whose infants were normal after birth, 462 (462/4211, 10.97%) who terminated their pregnancy, 51 (51/4211, 1.21%) whose infants were abnormal after birth, and 21 (21/4211, 0.50%) who refused follow-up. The results of this study demonstrate significant variation in the diagnostic rate of chromosomal microarray analysis across different indications, providing valuable guidance for clinicians to assess the applicability of CMA technology in prenatal diagnosis.

Abstract Background Enhanced glycolysis is a crucial metabolic event that drives the development of liver fibrosis, but the molecular mechanisms have not been fully understood. Lactate is the endproduct of glycolysis, which has recently been identified as a bioactive metabolite binding to G-protein-coupled receptor 81 (GPR81). We then questioned whether GPR81 is implicated in the development of liver fibrosis. Methods The level of GPR81 was determined in mice with carbon tetrachloride (CCl4)-induced liver fibrosis and in transforming growth factor beta 1 (TGF-β1)-activated hepatic stellate cells (HSCs) LX-2. To investigate the significance of GPR81 in liver fibrosis, wild-type (WT) and GPR81 knockout (KO) mice were exposed to CCl4, and then the degree of liver fibrosis was determined. In addition, the GPR81 agonist 3,5-dihydroxybenzoic acid (DHBA) was supplemented in CCl4-challenged mice and TGF-β1-activated LX-2 cells to further investigate the pathological roles of GPR81 on HSCs activation. Results CCl4 exposure or TGF-β1 stimulation significantly upregulated the expression of GPR81, while deletion of GPR81 alleviated CCl4-induced elevation of aminotransferase, production of pro-inflammatory cytokines, and deposition of collagen. Consistently, the production of TGF-β1, the expression of alpha-smooth muscle actin (α-SMA) and collagen I (COL1A1), as well as the elevation of hydroxyproline were suppressed in GPR81 deficient mice. Supplementation with DHBA enhanced CCl4-induced liver fibrogenesis in WT mice but not in GPR81 KO mice. DHBA also promoted TGF-β1-induced LX-2 activation. Mechanistically, GPR81 suppressed cAMP/CREB and then inhibited the expression of Smad7, a negative regulator of Smad3, which resulted in increased phosphorylation of Smad3 and enhanced activation of HSCs. Conclusion GPR81 might be a detrimental factor that promotes the development of liver fibrosis by regulating CREB/Smad7 pathway.

Abstract Background Bow Hunter’s syndrome (BHS), also known as rotational vertebral artery occlusion (RVAO), is a rare condition characterized by dynamic vertebrobasilar insufficiency due to position-dependent occlusion of the vertebral artery (VA). In the existing literature, most cases of BHS are attributed to osteophytic compression originating from the occipital condyle or within the transverse foramen, often accompanied by anatomical abnormalities of the VA. However, cases presenting solely with VA anomalies in the absence of any cervical vertebral structural abnormality are rare. This case report presents a unique instance of BHS in a 56-year-old male, attributed to the anomalous origin of the right VA and the absence of the left VA, without cervical structural abnormalities. Case presentation The patient exhibited symptoms like episodic dizziness and vertigo, which were exacerbated by rightward head rotation and alleviated upon returning to a neutral position. Diagnostic evaluation, including digital subtraction angiography, revealed that the right VA originated from the right common carotid artery and compression-induced stenosis of the right VA during head rotation. Conservative management, including avoidance of certain head movements and anti-arteriosclerosis medication, led to symptom resolution over a two-year follow-up period. Conclusions This report contributes to the understanding of BHS by highlighting a rare vascular anomaly presentation and incorporates a review of 14 similar case reports in the literature describing that an anatomical abnormality of the VA is mainly responsible for the pathology of BHS in the absence of cervical vertebral anomalies, thus emphasizing the need for careful diagnostic and management strategies.

Abstract Background At present, shoulder arthroscopy is usually used for treatment of rotator cuff injuries. There is still debate over the precise technique of using shoulder arthroscopy to treat partial articular-sided supraspinatus tendon injuries. Objective To compare the clinical efficacy of the arthroscopic transtendon repair method and the arthroscopic full-thickness repair method in the treatment of patients with Ellman III partial articular-sided supraspinatus tendon tears and to analyze the influencing factors of postoperative efficacy. Study design Cohort study; level of evidence,4. Methods A total of 84 partial-thickness rotator cuff tear (PTRCT) patients with Ellman III injuries who underwent surgical treatment in our hospital between January 2017 and January 2020 were selected and divided into the arthroscopic trans-tenon repair group (32 cases) and the arthroscopic full-thickness repair group (52 cases). Shoulder joint pain and functional status were assessed by the Constant score, ASES score and VAS score; shoulder mobility was assessed by measuring shoulder ROM. The clinical outcomes of the two groups of patients were compared, and the factors affecting the postoperative efficacy of the patients were investigated. Results All patients were followed up for at least 2 years. The Constant score, ASES score, and VAS score of the two groups of patients were all improved compared with those before surgery, and the differences were statistically significant (P 0.05). The results of binary logistic regression analysis showed that the preoperative ASES score and whether biceps tenotomy was performed were independent risk factors for satisfactory postoperative efficacy (P