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Abstract Accumulating evidence suggests that caspase-3 plays critical roles beyond apoptosis, serving pro-survival functions in malignant transformation and tumorigenesis. However, the mechanism of non-apoptotic action of caspase-3 in oncogenic transformation remains unclear. In the present study, we show that caspase-3 is consistently activated in malignant transformation induced by exogenous expression of oncogenic cocktail (c-Myc, p53DD, Oct-4, and H-Ras) in vitro as well as in the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse model of breast cancer. Genetic ablation of caspase-3 significantly attenuated oncogene-induced transformation of mammalian cells and delayed breast cancer progression in MMTV-PyMT transgenic mice. Mechanistically, active caspase-3 triggers the translocation of endonuclease G (EndoG) from mitochondria, which migrates to the nucleus, thereby induces phosphorylation of Src-STAT3 signaling pathway to facilitate oncogenic transformation. Taken together, our data suggest that caspase-3 plays pivotal role in facilitating rather than suppressing oncogene-induced malignant transformation of mammalian cells.

Shale oil and gas resources mainly exist in the pore and fracture system. Quantitative characterization of pore development characteristics and gas-bearing properties is crucial for shale reservoir evaluation. The pore development of shale reservoir exhibits strong complexity and heterogeneity, and research on pore development characteristics of coal measure shale lags behind that of marine shale reservoir. Hence, it is urgent to investigate the pore heterogeneity characteristics of coal-bearing shale and its influence on gas bearing properties. Therefore, the coal-bearing Cretaceous Nenjiang shales from the Songyuan area of the Songliao Basin were selected as the research object in this study. Through total organic carbon (TOC) analysis, X-ray diffraction experiments, porosity analysis, nitrogen adsorption–desorption experiments, and methane isothermal adsorption experiments, the characteristics of pore structure, heterogeneity, and gas bearing properties of coal-bearing shale were analyzed. The influence of rock and mineral components on pore structure and heterogeneity characteristics, the relationship between pore structure characteristics and fractal characteristics, and the effects of pore structure and heterogeneity on gas bearing properties were also discussed. The results show that: (1) The organic matter abundance of the shale in the Nenjiang Formation does not change significantly (the average TOC content is 2.38%). Ink bottle-shaped pores are mostly developed, and the Nenjiang shale is rich in clay minerals (average content 55.6%), with slit-shaped pores mostly developed. The pore surface of shale exhibits obvious fractal characteristics, with average fractal dimensions D1 and D2 of 2.54 and 2.74, respectively, indicating that the internal structure is more complex than the surface structure. (2) The enrichment of organic carbon increases the specific surface area by affecting the development of micropores and pores, consequently increasing the fractal dimension of pores. Similarly, the development of clay minerals increases the number of mesopores and macropores, thereby increasing the fractal dimension of pores. (3) Small pores develop larger specific surface areas, which increases the complexity and heterogeneity of the pore structure. This promotes remarkable fractal characteristics, expands the adsorption sites, and improves the adsorption capacity. This work will provide a scientific theoretical basis for the comprehensive evaluation of coal-bearing shale reservoirs and research on shale gas reservoir formation theory.

Abstract Numerous clinical studies speculated the association between multiple myeloma (MM) and inflammatory diseases; however, there is limited validation of these claims via establishing a causal relationship and revealing the underlying mechanism. This exploratory study employed bidirectional Mendelian randomization (MR) analysis to investigate the causal relationships between MM and inflammatory diseases, including atherosclerosis, asthma, ankylosing spondylitis, Alzheimer's disease (AD), Parkinson's disease (PD), sarcoidosis, inflammatory bowel disease, nonalcoholic fatty liver disease, type II diabetes, and schizophrenia (SZ). Transcriptomic and genome‐wide Bayesian colocalization analyses were further applied to reveal the underlying mechanism. A significant and previously unrecognized positive association was identified between genetic predisposition to MM and the risk of SZ. Two independent case reports showed that treatment‐resistant psychosis is due to underlying MM and is resolved by treating MM. From our MR analyses, various statistical methods confirmed this association without detecting heterogeneity or pleiotropy effects. Transcriptomic analysis revealed shared inflammation‐relevant pathways in MM and SZ patients, suggesting inflammation as a potential pathophysiological mediator of MM's causal effect on SZ. Bayesian colocalization analysis identified rs9273086, which maps to the protein‐coding region of HLA‐DRB1, as a common risk variant for both MM and SZ. Polymorphism of the HLA‐DRB1 allele has been implicated in AD and PD, further highlighting the impact of our results. Additionally, we confirmed that interleukin‐6 (IL‐6) is a risk factor for SZ through secondary MR, reinforcing the role of neuroinflammation in SZ etiology. Overall, our findings showed that genetic predisposition to MM, HLA‐DRB1 polymorphism, and enhanced IL‐6 signaling are associated with the increased risk of SZ, providing evidence for a causal role for neuroinflammation in SZ etiology.

Objectives There is still controversy over the choice of treatment for end‐stage spinal metastases. With the continuous development of microwave technology in spinal tumors, related studies have reported that microwave combined with techniques such as pedicle screw fixation and percutaneous vertebroplasty can achieve the purpose of tumor ablation, relieving spinal cord compression, enhancing spinal stability, effectively relieving pain, and reducing recurrence rates. This study aimed to analyze the effectiveness of microwave ablation combined with decompression and pedicle screw fixation in the palliative management of spinal metastases with pathological fractures. Methods This retrospective study enrolled 82 patients with spinal metastases and pathological fractures treated between January 2016 and July 2020, with 44 patients undergoing pedicle screw fixation along with laminectomy (fixation group) and the remaining 38 receiving microwave ablation in addition to the treatment provided to group fixation (MWA group). Before surgery, all patients underwent pain assessment using the visual analogue scale (VAS) and evaluation of spinal cord injury using the Frankel classification. After surgery, the patients' prognoses were assessed using the Tomita score, modified Tokuhashi score system, and progression‐free survival. Additionally, we compared operative time and blood loss between the two groups. Survival analysis utilized the Kaplan–Meier method with a log‐rank test for group comparisons. Paired t‐tests and the Mann–Whitney U test were applied to metric and non‐normally distributed data, respectively. Neurological function improvement across groups was evaluated using the χ2 test. Results All patients were followed up for a median duration of 18 and 20 months in the fixation and MWA groups, respectively, with follow‐up periods ranging from 6 to 36 months. Statistically significant reductions in postoperative VAS scores were observed in all patients compared with their preoperative scores. The MWA group exhibited reduced blood loss (t = 2.74, p = 0.01), lower VAS scores at the 1‐ and 3‐month follow‐ups (t = 2.34, P = 0.02; t = 2.83, p = 0.006), and longer progression‐free survival than the fixation group (p = 0.03). Although the operation times in the MWA group were longer than those in the fixation group, this difference was not statistically significant (t = 6.06, p = 0.12). No statistically significant differences were found regarding improvements in spinal cord function between the two groups (p = 0.77). Conclusion Compared with decompression and pedicle screw fixation for treating spinal metastases with pathological fractures, microwave ablation combined with decompression and pedicle screw fixation showed better outcomes in terms of pain control, longer progression‐free survival, and lower blood loss without increasing operative time, which has favorable implications for clinical practice.

Abstract Background The genetic diversity of yak, a key domestic animal on the Qinghai-Tibetan Plateau (QTP), is a vital resource for domestication and breeding efforts. This study presents the first yak pangenome obtained through the de novo assembly of 16 yak genomes. Results We discovered 290 Mb of nonreference sequences and 504 new genes. Our pangenome-wide presence and absence variation (PAV) analysis revealed 5,120 PAV-related genes, highlighting a wide range of variety-specific genes and genes with varying frequencies across yak populations. Principal component analysis (PCA) based on binary gene PAV data classified yaks into three new groups: wild, domestic, and Jinchuan. Moreover, we proposed a ‘two-haplotype genomic hybridization model’ for understanding the hybridization patterns among breeds by integrating gene frequency, heterozygosity, and gene PAV data. A gene PAV-GWAS identified a novel gene (BosGru3G009179) that may be associated with the multirib trait in Jinchuan yaks. Furthermore, an integrated transcriptome and pangenome analysis highlighted the significant differences in the expression of core genes and the mutational burden of differentially expressed genes between yaks from high and low altitudes. Transcriptome analysis across multiple species revealed that yaks have the most unique differentially expressed mRNAs and lncRNAs (between high- and low-altitude regions), especially in the heart and lungs, when comparing high- and low-altitude adaptations. Conclusions The yak pangenome offers a comprehensive resource and new insights for functional genomic studies, supporting future biological research and breeding strategies.

The presence of high-density defects is rarely observed in bulk 3 mol% yttria-stabilized tetragonal zirconia polycrystal (3Y-TZP) ceramics obtained through conventional pressureless sintering. In the present work, fine-grained dense 147 nm 3Y-TZP ceramics were prepared by pressureless sintering of commercial 0.25 wt% alumina-doped zirconia powders at 1300 ℃. A novel discovery was reported in which large amounts of defects were present in the grain interiors of the sample. The phenomenon was further examined using three types of powder samples, and the reasons for defect formation were investigated by microstructural characterization using high-resolution transmission electron microscopy (HRTEM) analysis and Rietveld refinement. The results confirmed the essential dependence of the defect formation on the alumina addition. The authors attributed the defect formation to the significant difference in ionic radii of the solvent and solute during the dissolution of alumina into the zirconia lattice. The sintering kinetics were proposed to be enhanced by the presence of substantial defects, which consequently favored the low-temperature sintering of the alumina-doped zirconia ceramics.

Abstract Background Patients with metastatic gastric cancer (mGC) have poor prognosis. This real-world study aimed to describe treatment regimens and survival of mGC patients. Methods A retrospective analysis was conducted using anonymized German claims data (AOK PLUS) covering a period from 2010 to 2021. The study population included newly diagnosed mGC cases identified from 2011 to 2020. The index date was defined as the first diagnosis of metastasis on or after gastric cancer diagnosis. Therapy regimens were identified based on inpatient and outpatient data, and subsequently stratified by line of treatment. Survival analyses were conducted using the Kaplan–Meier method. Results The cohort consisted of 5,278 mGC incident cases (mean age: 72.7 years; male: 61.9%). Nearly half of the incident cases received mGC-related treatment (49.8%). Treated patients were more often male, younger, and had fewer comorbidities compared to untreated patients. Of the 2,629 mGC patients who started the first line of treatment (1LOT), 32.8% switched to 2LOT, and 10.2% reached 3LOT. Longer survival time was observed among disease-specific treated cases compared with untreated cases (median real-world overall survival (rwOS): 12.7 months [95%CI 12.1 – 13.3 months] vs. 3.7 months [95%CI 3.4 – 4.0 months]). Conclusion Systemic therapy was not received in almost half of the mGC patients. In those patients, a very short median rwOS was observed. Treatment patterns were generally in line with the guideline recommendations, however, therapy switching rates and poor prognosis indicate high unmet needs also in the treated population.

Abstract Background Non-coding RNA is a key epigenetic regulation factor during skeletal muscle development and postnatal growth, and miR-542-3p was reported to be conserved and highly expressed in the skeletal muscle among different species. However, its exact functions in the proliferation of muscle stem cells and myogenesis remain to be determined. Methods Transfection of proliferative and differentiated C2C12 cells used miR-542-3p mimic and inhibitor. RT-qPCR, EdU staining, immunofluorescence staining, cell counting kit 8 (CCK-8), and Western blot were used to evaluate the proliferation and myogenic differentiation caused by miR-542-3p. The dual luciferase reporter analysis and rescued experiment of the target gene were used to reveal the molecular mechanism. Results The data shows overexpression of miR-542-3p downregulation of mRNA and protein levels of proliferation marker genes, reduction of EdU+ cells, and cellular vitality. Additionally, knocking it down promoted the aforementioned phenotypes. For differentiation, the miR-542-3p gain-of-function reduced both mRNA and protein levels of myogenic genes, including MYOG, MYOD1, et al. Furthermore, immunofluorescence staining immunized by MYHC antibody showed that the myotube number, fluorescence intensity, differentiation index, and myotube fusion index all decreased in the miR-542-3p mimic group, compared with the control group. Conversely, these phenotypes exhibited an increased trend in the miR-542-3p inhibitor group. Mechanistically, phosphatase and tensin homolog (Pten) was identified as the bona fide target gene of miR-542-3p by dual luciferase reporter gene assay, si-Pten combined with miR-542-3p inhibitor treatments totally rescued the promotion of proliferation by loss-function of miR-542-3p. Conclusions This study indicates that miR-542-3p inhibits the proliferation and differentiation of myoblast and Pten is a dependent target gene of miR-542-3p in myoblast proliferation, but not in differentiation.

Background The causal relationship between childhood adiposity and adult risk of heart diseases has not been clearly demonstrated. This study aims to ascertain whether genetically predicted childhood body mass index (BMI) and childhood obesity are causally associated with adult coronary heart disease, myocardial infarction, heart failure, atrial fibrillation, hypertrophic cardiomyopathy, and pulmonary heart disease. Methods and Results To investigate the causative relationships and underlying mechanisms between childhood adiposity and adult heart diseases, 3 main methods of Mendelian randomization were used: 2‐sample Mendelian randomization, multivariable Mendelian randomization with controlling for several cardiometabolic risk variables, and mediation analysis. Every 1‐SD rise in genetically predicted childhood body mass index was associated with 24% (odds ratio [OR], 1.24 [95% CI, 1.12–1.37]), 28% (OR, 1.28 [95% CI, 1.14–1.42]), 28% (OR, 1.28 [95% CI, 1.14–1.42]), and 27% (OR, 1.27 [95% CI, 1.04–1.49]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. Every 1‐unit increase in log‐odds in childhood obesity was associated with 11% (OR, 1.11 [95% CI, 1.06–1.16]), 14% (OR, 1.14 [95% CI, 1.04–1.23]), 10% (OR, 1.10 [95% CI, 1.03–1.18]), and 20% (OR, 1.20 [95% CI, 1.08–1.32]) higher risk of coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, respectively. The link between childhood adiposity and adult heart diseases was found to be mediated by high‐density lipoprotein cholesterol, triglyceride, hypertension, and type 2 diabetes. Conclusions Our findings support the causal relationships between childhood adiposity and risk of adult coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation. Blood lipids, hypertension, and type 2 diabetes are factors that mediate the aforementioned associations.

Granuloma formation is generally correlated with infection. Pulmonary granulomas caused by foreign bodies aspiration are uncommon. The clinical and radiologic features of such cases often lack specificity, which makes it difficult to distinguish from malignancy. Aspiration is usually not considered in the differential diagnosis of patients presenting with mass-like abnormalities on chest imaging. Occult aspiration history, diverse clinical manifestations, atypical imaging findings, and limited availability of pathogen detection techniques make the precise diagnosis a substantial challenge. Herein, we describe an older patient presenting with chest pain and worrisome lung masses/nodules that proved to be pulmonary granulomas caused by foreign matters aspiration. In addition, the patient developed Mendelson syndrome due to acute macroaspiration. Lung tissue metagenomics next-generation sequencing (mNGS) revealed Streptococcus intermedius, a normal flora of the oropharynx. The aim of this case was to underscore the importance of considering aspiration as a potential differential diagnosis of patients presenting with pulmonary granulomas, especially in patients with recurrent pneumonia or predisposing factors. In addition, mNGS act as a potential, rapid, and effective technique for diagnosing aspiration-related syndrome, showing satisfactory performance in identifying pathogens.

Objective Artificial hip arthroplasty (AHA) is widely accepted in elderly patients with femoral neck fractures, but it is associated with high risk of death and various postoperative complications due to old age and accompanying chronic diseases. Therefore, this study aimed to explore the risk factors for death in elderly patients with femoral neck fractures after AHA and to establish a nomogram risk prediction model, which is expected to reveal high‐risk patients and improve the postoperative quality of life and survival rate of patients. Methods Elderly patients who underwent AHA for femoral neck fractures in our hospital from September 2014 to May 2021were retrospectively analyzed. These patients were divided into a survival group and a death group according to their clinical outcomes. The following clinical data were recorded for the patients in the two groups: sex, age, underlying diseases, smoking and drinking history, preoperative nutritional risk score (NRS) and American Society of Anesthesiologists (ASA) score, as well as relevant indicators about the operation. These data were subject to univariate analysis and then logistic analysis to determine the risk factors of death. Subsequently, a nomogram risk prediction model was established and further validated with the receiver operating characteristic curve (ROC) and the Hosmer–Lemeshow test. Finally, the effects of predictive risk factors were analyzed using the Kaplan–Meier survival curve. Results Follow‐up was completed by 260 patients, including 206 patients in the survival group and 54 patients in the death group; the overall death rate was 20.77%, and the follow‐up time, age, postoperative 1, 3 and 5‐year death rates were 3.47 ± 1.93 years, 75.32 ± 9.12 years, 5.77%, 12.51%, and 25.61%, respectively. The top three causes of death in 54 patients were respiratory disease, cerebrocardiovascular disease, and digestive disease, respectively. The logistic analysis indicated that elderly patients with femoral neck fractures, the risk factors for death after AHA were age ≥ 80 years, preoperative NRS ≥ 4, HB ≤ 90 g/L, CR ≥ 110 umol/L, and ASA score ≥ 3, as well as postoperative albumin ≤ 35 g/L, the nomogram was established, and then its predictive performance was successfully validated using the ROC curve (AUC = 0.814, 95% confidence interval = 0.749–0.879) and the Hosmer–Lemeshow test (p = 0.840). Furthermore, Kaplan–Meier survival curve analysis revealed that the abovementioned six indicators were correlated with the post‐AHA survival time of elderly patients with femoral neck fractures (pLog Rank

Objective There has been long‐standing debate about whether a medial opening wedge high tibial osteotomy (MOWHTO) gap should be filled with autologous bone graft or any other filler to expedite the healing process. The main purpose of this study was to compare the clinical and radiological outcomes of MOWHTO with an opening gap ≥10 mm, utilizing autograft, allograft, or no graft at 1 year postoperatively. Methods A total of 68 patients were included in this retrospective study and divided into three treatment groups: Group A (no bone graft), Group B (autologous iliac crest graft), and Group C (allogenous tibia plateau graft). At postoperative 1‐year follow‐up, the area of callus filling in the most medial side of the knee was measured using anteroposterior radiographs, and a modified van Hemert scoring system was used to evaluate bone union outcomes in five mediolaterally divided zones. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores and relevant complications were assessed. The correlations between the gap width and bone union scores were evaluated. Results Patients in the autograft group demonstrated better bone union progression (p = 0.031) and higher bone union scores (p

E-commerce with the immersive scene of live streaming gives users a new interaction and consumption experience, extending a new path for traditional marketing. Live barrage, being the primary means of users’ social engagement in live e-commerce, encapsulates their inclination to purchase products, commonly referred to as consumption intention. The mining of live barrage enables the exploration of latent user behavior and consumption intention. The current methods employed for mining consumption intention in e-commerce live barrage encounter challenges including insufficient corpus, excessively brief text, and significant semantic deficiencies. Therefore, this study proposes a paradigm of consumption intention recognition by combining the text features of barrage: by constructing a dataset of Live barrage, cleaning the original dataset, and then using a fused BERT’s feature network model BERT-BiLSTM to identify the consumption intention in live e-commerce Live barrage. The experimental results demonstrate the efficacy of the proposed method for recognizing consumption intention. Finally, this study conducted text mining on live barrage containing consumption intent, including word cloud visualization, topic extraction, and co-occurrence analysis, further investigating consumers’ purchasing needs and intentions.

Knee arthroscopy is the replacement choice for patients with symptomatic degenerative arthropathy who have failed conservative treatment, such as intra-articular loose bodies and meniscal pathology. Postoperative joint pain and swelling are the main problems affecting enhanced recovery after surgery, which is thought to be a disorder of the joint environment caused by the trauma of surgery (1, 2, 3). Arthroscopic surgery involves irrigating the joint with a high-pressure flushing solution, which results in the loss of synovial fluid secreted by the joint itself. Synovial fluid has been shown to lubricate and protect the articular cartilage, and it needs to be re-secreted several days after surgery (3). In addition, studies have shown that the lavage fluid could cause damage to articular cartilage, which could also lead to early postoperative joint discomfort (4, 5). Therefore, some scholars have proposed that early postoperative synovial fluid analog supplementation to restore the internal environment may reduce early postoperative joint discomfort and accelerate the rehabilitation process (6, 7, 8, 9).

Objective Intertrochanteric fracture is a very common but serious type of hip fracture in nonagenarians. The surgical treatment remains a significant challenge for orthopedists. The objective of this study was to investigate postoperative complications and survival outcomes compared between bipolar hemiarthroplasty (HA) and proximal femoral nail anti‐rotation (PFNA) in nonagenarians with intertrochanteric fractures, and to evaluate the efficacy and safety of the two surgical procedures in this patient population. Methods A total of 113 consecutive nonagenarians who underwent bipolar HA or PFNA for the treatment of intertrochanteric fractures from January 2006 to August 2021 were retrospectively studied in the current paper. There were 34 males and 79 females, with a mean age of 92.2 years (range 90–101 years) at the time of operation. The average duration of follow‐up was 29.7 months (range 1–120 months). The full cohort was divided into bipolar HA (77 cases) and PFNA (36 cases) groups. Damage control orthopedics was used to determine the optimal surgery time and assist in perioperative management. A restrictive blood transfusion strategy was employed, along with appropriate adjustments under multidisciplinary assessment, throughout the perioperative period. Perioperative clinical information and prognostic data were analyzed. Kaplan–Meier survival curves were used for survival analysis, and landmark analysis divided the entire follow‐up period into 1–12 months (short‐term), 13–42 months (medium‐term) and 43–120 months (long‐term) according to the configurations of Kaplan–Meier survival curves. Results Both groups had similar general variables except for the proportion of high adjusted Charlson comorbidity index (aCCI) (≥6 points) (6.5% in bipolar HA group and 22.2% in PFNA group, p = 0.024). Intraoperative blood loss and transfusion requirements were greater, and the intraoperative transfusion rates were higher in the bipolar HA group compared to the PFNA group (all p 0.05). Both groups had similar overall survival curves (p = 0.37). However, landmark analysis revealed that bipolar HA group exhibited higher survival rates in medium‐term (p = 0.01), while similar survival rates were observed in the short‐ and long‐term post‐operation periods (both p > 0.05). Cox regression with survival‐time‐dependent covariate calculated the hazard ratio (HR) of bipolar HA was 0.41 in medium‐term (p = 0.039). Conclusion Bipolar HA is equally effective and reliable as PFNA for treating intertrochanteric fractures in nonagenarians. Despite resulting in more intraoperative blood loss and transfusions, bipolar HA therapy is associated with a higher medium‐term survival rate compared to PFNA treatment. The application of damage control orthopedics and precise perioperative patient blood management could contribute to the positive clinical outcomes observed in this patient population.

Apoptosis-inducing factor mitochondrion-associated 2 (AIFM2) has been identified as a gene with anti-ferroptosis properties. To explore whether AIFM2 exerts anti-ferroptosis role in yaks (Bos grunniens), we cloned yak AIFM2 gene and analyzed its biological characteristics. The coding region of AIFM2 had 1122 bp and encoded 373 amino acids, which was conserved in mammals. Next, RT-qPCR results showed an extensive expression of AIMF2 in yak tissues. Furthermore, we isolated yak skin fibroblasts (YSFs) and established a bisphenol A (BPA)-induced ferroptosis model to further investigate the role of AIFM2. BPA elevated oxidative stress (reactive oxygen species, ROS) and lipid peroxidation (malondialdehyde, MDA and BODIPY), and reduced cell viability and antioxidant capacity (glutathione, GSH), with the severity depending on the dosage. Of note, a supplement of Ferrostatin-1 (Fer), an inhibitor of ferroptosis, restored the previously mentioned indicators. Subsequently, we constructed an AIFM2 overexpression vector and designed AIFM2 specific interfering siRNAs, which were transfected into YSFs. The results showed that overexpressing AIFM2 alleviated ferroptosis, characterizing by significant changes of cell viability, ROS, BODIPY, MDA and GSH. Meanwhile, interfering AIFM2 aggravated ferroptosis, demonstrating the critical anti-ferroptosis role of the yak AIFM2 gene. This study shed light on further exploring the molecular mechanism of AIFM2 in plateau adaptability.

Aim: This study aimed to improve comparative effectiveness estimates and discuss challenges encountered through the application of Bayesian borrowing (BB) methods to augment an external control arm (ECA) constructed from real-world data (RWD) using historical clinical trial data in first-line non-small cell lung cancer (NSCLC). Materials & methods: An ECA for a randomized controlled trial (RCT) in first-line NSCLC was constructed using Concert AI Patient360™ to assess chemotherapy with or without cetuximab, in the bevacizumab-inappropriate subpopulation. Cardinality matching was used to match patient characteristics between the treatment arm (cetuximab + chemotherapy) and ECA. Overall survival (OS) was assessed as the primary outcome using Cox proportional hazards (PH). BB was conducted using a static power prior under a Weibull PH parameterization with borrowing weights from 0.0 to 1.0 and augmentation of the ECA from a historical control trial. Results: The constructed ECA yielded a higher overall survival (OS) hazard ratio (HR) (HR = 1.53; 95% CI: 1.21–1.93) than observed in the matched population of the RCT (HR = 0.91; 95% CI: 0.73–1.13). The OS HR decreased through the incorporation of BB (HR = 1.30; 95% CI: 1.08–1.54, borrowing weight = 1.0). BB was applied to augment the RCT control arm via a historical control which improved the precision of the observed HR estimate (1.03; 95% CI: 0.86–1.22, borrowing weight = 1.0), in comparison to the matched population of the RCT alone. Conclusion: In this study, the RWD ECA was unable to successfully replicate the OS estimates from the matched population of the selected RCT. The inability to replicate could be due to unmeasured confounding and variations in time-periods, follow-up and subsequent therapy. Despite these findings, we demonstrate how BB can improve precision of comparative effectiveness estimates, potentially aid as a bias assessment tool and mitigate challenges of traditional methods when appropriate external data sources are available.

Background Accurate prediction and assessment of myocardial fibrosis (MF) and adverse cardiovascular events (MACEs) are crucial in patients with dilated cardiomyopathy (DCM). Several studies indicate that galectin-3 (gal-3) as a promising prognostic predictor in patients with DCM. Methods A comprehensive search was conducted in PubMed, EMBASE, the Cochrane Library, and Web of Science for relevant studies up to August 2023. The hazard ratios (HRs) of gal-3 for MACEs in DCM patients, and for MACEs in LGE(+) versus LGE(-) groups, were evaluated. Statistical analysis was performed using STATA SE 14.0 software. Results Seven studies, encompassing 945 patients, met the eligibility criteria. In DCM patients, abnormally elevated gal-3 levels were indicative of an increased MACEs risk (HR = 1.10, 95% CI [1.00–1.21], I2 = 65.7%, p = 0.008). Compared with the LGE(-) group, the level of gal-3 in LGE(+) group was higher (HR = 1.12, 95% CI [1.05–1.19], I2 = 31.4%, p = 0.233), and the combination of gal-3 and LGE significantly improved the prediction of MACEs. Sensitivity analysis confirmed the robustness of all results. Conclusions This study’s findings suggest that elevated gal-3 levels significantly correlate with increased MACE risk in DCM, highlighting its potential as a biomarker. However, significant heterogeneity among studies necessitates further research to ascertain gal-3’s predictive and diagnostic value in DCM prognosis, particularly in conjunction with LGE. PROSPERO ID CRD42023471199.

The Corona Virus Disease (COVID-19), caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), has quickly spread worldwide and resulted in significant morbidity and mortality. Although most infections are mild, some patients can also develop severe and fatal myocarditis. In eukaryotic RNAs, 5-methylcytosine (m5C) is a common kind of post-transcriptional modification, which is involved in regulating various biological processes (such as RNA export, translation, and stability maintenance). With the rapid development of m5C modification detection technology, studies related to viral m5C modification are ever-increasing. These studies have revealed that m5C modification plays an important role in various stages of viral replication, including transcription and translation. According to recent studies, m5C methylation modification can regulate SARS-CoV-2 infection by modulating innate immune signaling pathways. However, the specific role of m5C modification in SARS-CoV-2-induced myocarditis remains unclear. Therefore, this review aims to provide insights into the molecular mechanisms of m5C methylation in SARS-CoV-2 infection. Moreover, the regulatory role of NSUN2 in viral infection and host innate immune response was also highlighted. This review may provide new directions for developing therapeutic strategies for SARS-CoV-2-associated myocarditis.

Purpose: Different arch structures may cause different foot function injuries. In the past, the arch structure and flexibility of the foot were often defined by the height of the arch, and there was no three-dimensional (3D) structure classification method. In order to form a more complete 3D description, we propose a new classification system of arch volume flexibility (AVF), and then use this new classification system to investigate the relationship between the AVF and arch index (AI), and the arch height flexibility (AHF) and AI, respectively. Methods: It is proposed to recruit 180 young male adults for the test. We obtained arch volume and AI through 3D scanning and obtained the navicular height through manual measurement. Based on these data, we calculated the AHF and the AVF. Using the quintile method, these arches are divided into very stiff, stiff, neutral, flexible, and very flexible. According to AI value, all arches were divided into cavus, rectus, and planus. The distribution of AVF was compared using χ2 goodness of fit test. The spearman correlation test was used to compare the AHF and AVF. A p

Abstract Interferon-gamma (IFN-γ) signaling is necessary for the proinflammatory activation of macrophages but IFN-γ-independent pathways, for which the initiating stimuli and downstream mechanisms are lesser known, also contribute. Here we identify, by high-content screening, SEPTIN2 (SEPT2) as a negative regulation of IFN-γ-independent macrophage autoactivation. Mechanistically, endoplasmic reticulum (ER) stress induces the expression of SEPT2, which balances the competition between acetylation and ubiquitination of heat shock protein 5 at position Lysine 327, thereby alleviating ER stress and constraining M1-like polarization and proinflammatory cytokine release. Disruption of this negative feedback regulation leads to the accumulation of unfolded proteins, resulting in accelerated M1-like polarization, excessive inflammation and tissue damage. Our study thus uncovers an IFN-γ-independent macrophage proinflammatory autoactivation pathway and suggests that SEPT2 may play a role in the prevention or resolution of inflammation during infection.

This is an eassay in the field of process mineralogy. Using optical microscope, chemical multi-element analysis, chemical phase analysis, X-ray diffraction, scanning electron microscopy-energy spectrometer and other comprehensive methods, the process mineralogical characteristics of a pegmatite lithium beryllium ore were studied. The mineral composition, chemical properties, symbiosis relationship of minerals, particle size distribution of main minerals and connection growth characteristics in the ore were ascertained. On this basis, the occurrence state of valuable elements such as lithium and beryllium in the ore and the mineralogical factors affecting the recovery of valuable elements such as lithium and beryllium in the ore are described, which provides a basis for the beneficiation work of the mine.

Abstract Background Wearable sensors have become a complementary means for evaluation of body function and gait in lower limb osteoarthritis. This study aimed to review the applications of wearable sensors for gait analysis after total knee arthroplasty (TKA). Methods Five databases, including Web of Science Core Collection, Embase, Cochrane, Medline, and PubMed, were searched for articles published between January 2010 and March 2023, using predetermined search terms that focused on wearable sensors, TKA, and gait analysis as broad areas of interest. Results A total of 25 articles were identified, involving 823 TKA patients. Methodologies varied widely across the articles, with inconsistencies found in reported patient characteristics, sensor data and experimental protocols. Patient-reported outcome measures (PROMs) and gait variables showed various recovery times from 1 week postoperatively to 5 years postoperatively. Gait analysis using wearable sensors and PROMs showed differences in controlled environments, daily life, and when comparing different surgeries. Conclusion Wearable sensors offered the potential to remotely monitor the gait function post-TKA in both controlled environments and patients’ daily life, and covered more aspects than PROMs. More cohort longitudinal studies are warranted to further confirm the benefits of this remote technology in clinical practice.

Abstract Macrophages are heterogenic phagocytic cells that play distinct roles in physiological and pathological processes. Targeting different types of macrophages has shown potent therapeutic effects in many diseases. Although many approaches are developed to target anti‐inflammatory macrophages, there are few researches on targeting pro‐inflammatory macrophages, which is partially attributed to their non‐s pecificity phagocytosis of extracellular substances. In this study, a novel recombinant protein is constructed that can be anchored on an exosome membrane with the purpose of targeting pro‐inflammatory macrophages via antigen recognition, which is named AnCar‐ExoLaIMTS. The data indicate that the phagocytosis efficiencies of pro‐inflammatory macrophages for different AnCar‐ExoLaIMTS show obvious differences. The AnCar‐ExoLaIMTS3 has the best targeting ability for pro‐inflammatory macrophages in vitro and in vivo. Mechanically, AnCar‐ExoLaIMTS3 can specifically recognize the leucine‐rich repeat domain of the TLR4 receptor, and then enter into pro‐inflammatory macrophages via the TLR4‐mediated receptor endocytosis pathway. Moreover, AnCar‐ExoLaIMTS3 can efficiently deliver therapeutic cargo to pro‐inflammatory macrophages and inhibit the synovial inflammatory response via downregulation of HIF‐1α level, thus ameliorating the severity of arthritis in vivo. Collectively, the work established a novel gene/drug delivery system that can specifically target pro‐inflammatory macrophages, which may be beneficial for the treatments of arthritis and other inflammatory diseases.

ObjectiveGATA binding protein 3 (GATA3) and forkhead box A1 (FOXA1) have been individually implicated in the progression of upper tract urothelial carcinoma (UTUC). This study aims to evaluate the prognostic value of GATA3/FOXA1 co-expression in UTUC patients.MethodsWe collected 108 UTUC pathological tissue samples with complete follow-up data and 24 normal control urothelial tissues. We created a 132-site microarray and performed immunohistochemistry (IHC) to measure GATA3 and FOXA1 expression levels. Kaplan-Meier survival and Cox regression analyses were conducted to assess UTUC prognosis.ResultsGATA3 expression was positively correlated with FOXA1 (P=0.031). Absence of GATA3/FOXA1 co-expression (GATA3-/FOXA1-) was associated with tumor extensive necrosis (P=0.001) after Bonferroni correction for multiple comparisons. GATA3-/FOXA1- was associated with shorter Disease-Free Survival (DFS) (P=0.001) and Cancer-Specific Survival (CSS) (P

Background: The efficacy of Kinesio tape (KT) in lateral elbow tendinopathy (LET) has been widely discussed, but controversy remains. Objectives: To perform a meta-analysis of randomized controlled trials (RCTs) in the literature to ascertain the efficacy of KT in LET. Design: Systematic review and meta-analysis. Method: Two independent reviewers carried out a literature search in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Any discrepancies were addressed by a third author. Included in the study were RCTs comparing KT to a control group in the context of LET. The quality of evidence was assessed with the 2.0 version of Cochrane Collaboration risk of bias tool. Evaluation centered on clinical outcomes, such as function scores and pain, with comparison made using the risk ratio for dichotomous variables and the mean difference for continuous variables. Statistical significance was considered for P values

Listeria monocytogenes (Lm), a foodborne bacterium, can infect people and has a high fatality rate in immunocompromised individuals. Listeriolysin O (LLO), the primary virulence factor of Lm, is critical in regulating the pathogenicity of Lm. This review concludes that LLO may either directly or indirectly activate a number of host cell viral pathophysiology processes, such as apoptosis, pyroptosis, autophagy, necrosis and necroptosis. We describe the invasion of host cells by Lm and the subsequent removal of Lm by CD8 T cells and CD4 T cells upon receipt of the LLO epitopes from major histocompatibility complex class I (MHC-I) and major histocompatibility complex class II (MHC-II). The development of several LLO-based vaccines that make use of the pore-forming capabilities of LLO and the immune response of the host cells is then described. Finally, we conclude by outlining the several natural substances that have been shown to alter the three-dimensional conformation of LLO by binding to particular amino acid residues of LLO, which reduces LLO pathogenicity and may be a possible pharmacological treatment for Lm.

AbstractJiangxi has superior natural environmental conditions, but tourism development is insufficient. This study analysed the distribution characteristics of natural tourism resources in Jiangxi Province, evaluated the potential of ecotourism, spatialized the coupling and coordination relationship between tourism resources and tourism potential and proposed the direction of tourism development and study travel planning. Results: (1) Natural tourist attractions in Jiangxi are relatively dense in the north and northeast, while relatively sparse in the south. (2) Natural tourism potential is generally high in the surrounding and low in the middle and high in the south and low in the north, and are distributed in a strip like manner. (3) Jiangxi is basically in a coordinated state, with the overall coupling index is relatively high, while the spatial differences in coordination index are significant, indicating that natural tourism resources and natural tourism potential have a strong mutual influence but their distribution characteristics do not match. (4) Future optimized development zone of natural tourism will be in the north and northeast, and the expanded development zone will be in the northwest and southeast. Both thematic and comprehensive study travel routes can be launched in regions with relatively concentrated natural tourist attractions. This article provides a research perspective on the interaction between tourism resource endowment and development practices, and the results can provide reference for relevant fields, natural tourism development, and study travel practices.

Carbon supported Ru-Sn bimetallic catalyst shows excellent performance in room-temperature hydrogenation of acetone, 100% acetone conversion with 100% product selectivity to isopropyl alcohol can be achieved within a short reaction time. Catalyst structure-function relationship reveals a synergetic behavior between Ru and Sn sites, demonstrating the essential correlation between Sn/Ru atomic ratio and the resultant variation in catalytic performance. Room temperature hydrogenation of 4-heptanone was also studied, verifying the consistency of the established structure-function relationship in ketones hydrogenation reactions.

Statins are highly prevalent in patients with coronary artery disease. Statins exert their anti-inflammatory effects on the vascular wall and circulating levels of pro-inflammatory cytokines. However, increasing attention revealed the exacerbation of macrophage inflammation induced by statins, and a clear mechanistic explanation of whether the detrimental effects of statins on macrophage inflammatory phenotypes outweigh the beneficial effects is has not yet been established. Here, RNA-sequencing and RT-qPCR analyses demonstrated that statins significantly upregulated EphA2, Nlrp3, IL-1β and TNF-α expression in macrophages. Mechanistically, we found that atorvastatin reduced KLF4 binding to the EphA2 promoter using KLF4-chromatin immunoprecipitation, suppressed HDAC11-mediated deacetylation and subsequently led to enhanced EphA2 transcription. The 4D-label-free proteomics analysis further confirmed the upregulated EphA2 and inflammatory signals. Furthermore, the proinflammatory effect of atorvastatin was neutralized by an addition of recombinant Fc-ephrinA1, a selective Eph receptor tyrosine kinase inhibitor (ALW-II-41–27) or EphA2-silencing adenovirus (siEphA2). In vivo, EphA2 was identified a proatherogenic factor and apoE-/- mice placed on a high-fat diet following gastric gavage with atorvastatin exhibited a consistent elevation in EphA2 expression. We further observed that the transfection with siEphA2 in atorvastatin-treated mice significantly attenuated atherosclerotic plaque formation and abrogated statin-orchestrated macrophages proinflammatory genes expression as compared to that in atorvastatin alone. Increased plaque stability index was also observed following the addition of siEphA2, as evidenced by increased collagen and smooth muscle content and diminished lipid accumulation and macrophage infiltration. The data suggest that blockage of EphA2 provides an additional therapeutic benefit for further improving the anti-atherogenic effects of statins.

Abstract Background The diagnosis of periprosthetic joint infection (PJI) remains a challenge in clinical practice. Many novel serum and joint fluid biomarkers have important implications for the diagnosis of PJI. The presented study evaluated the value of joint fluid interleukin-6 (IL-6) combined with the neutral polymorphonuclear leukocyte (PMN%) ratio for chronic PJI diagnosis after arthroplasty. Materials and methods Sixty patients with chronic PJI or aseptic failure who underwent hip or knee revision from January 2018 to January 2020 in our department were included in this retrospective study. According to the 2013 MSIS diagnostic criteria, the 60 patients were divided into a PJI group and a non-PJI group (30 patients per group). We collected the joint fluid before surgery and determined the level of IL-6 and the PMN% by ELISA, and the differences between the two groups were compared. The diagnostic efficacy of joint fluid IL-6 combined with PMN% in chronic PJI was analyzed using a receiver operating characteristic curve (ROC curve). Results The diagnosis of PJI using joint fluid IL-6 combined with PMN% presented an area under the curve of 0.983, which was more accurate than the areas under the curve for diagnosis using IL-6 and PMN% individually (0.901 and 0.914, respectively). The optimal threshold values for IL-6 and PMN% were 662.50 pg/ml and 51.09%, respectively. Their sensitivity and specificity were 96.67% and 93.33%, respectively. The accuracy of the diagnosis of PJI was 95.00%. Conclusions Joint fluid IL-6 combined with PMN% can be used as an auxiliary method to detect chronic infection around the prosthesis after hip/knee arthroplasty. Level of evidence Patients who underwent hip/knee revision at the First Hospital of Chongqing Medical University for periprosthetic infection or aseptic failure of the prosthesis after hip/knee arthroplasty from January 2018 to January 2020 were included. Trial registration This study was approved by the ethics committee of the First Hospital of Chongqing Medical University on September 26, 2018 (local ethics committee number: 20187101) and registered with the China Clinical Trials Registry (registration number: ChiCTR1800020440) with an approval date of December 29, 2018.

Abstract Cuckoo search algorithm is an efficient random search method for numerical optimization. However, it is very sensitive to the setting of the step size factor. To address this issue, a new cuckoo search algorithm based on cloud model is developed to dynamically configure the step size factor. More specifically, the idea of giving consideration to both fuzziness and randomness of cloud model is innovatively introduced into cuckoo search algorithm, and the appropriate step size factor can be determined according to the membership degree and an exponential function, so as to realize the adaptive adjustment of the control parameter. After that, simulation experiments are conducted on 25 benchmark functions with different dimensions and two chaotic time series prediction problems to comprehensively evaluate the superiority of the proposed algorithm. Numerical results demonstrate that the developed method is more competitive than the other five CS and several non-CS algorithms.

Abstract Phosphodiesterase 4D interacting protein (PDE4DIP) is a centrosome/Golgi protein associated with cyclic nucleotide phosphodiesterases. PDE4DIP is commonly mutated in human cancers, and its alteration in mice leads to a predisposition to intestinal cancer. However, the biological function of PDE4DIP in human cancer remains obscure. Here, we report for the first time the oncogenic role of PDE4DIP in colorectal cancer (CRC) growth and adaptive MEK inhibitor (MEKi) resistance. We show that the expression of PDE4DIP is upregulated in CRC tissues and associated with the clinical characteristics and poor prognosis of CRC patients. Knockdown of PDE4DIP impairs the growth of KRAS-mutant CRC cells by inhibiting the core RAS signaling pathway. PDE4DIP plays an essential role in the full activation of oncogenic RAS/ERK signaling by suppressing the expression of the RAS GTPase-activating protein (RasGAP) neurofibromin (NF1). Mechanistically, PDE4DIP promotes the recruitment of PLCγ/PKCε to the Golgi apparatus, leading to constitutive activation of PKCε, which triggers the degradation of NF1. Upregulation of PDE4DIP results in adaptive MEKi resistance in KRAS-mutant CRC by reactivating the RAS/ERK pathway. Our work reveals a novel functional link between PDE4DIP and NF1/RAS signal transduction and suggests that targeting PDE4DIP is a promising therapeutic strategy for KRAS-mutant CRC.

Abstract Background Acute fibrinous and organizing pneumonia (AFOP) is a rare histological interstitial pneumonia pattern characterized by patches of “fibrin balls” distributed within the alveoli and organizing pneumonia. Currently, there is no consensus on the diagnosis and treatment of this disease. Methods We present the case of a 44‐year‐old male with AFOP secondary to Mycobacterium tuberculosis. We have further reviewed organizing pneumonia (OP) and AFOP caused by tuberculosis. Conclusion Tuberculosis secondary to OP or AFOP is rare and challenging to diagnose. We need to constantly adjust the treatment plan based on the patient's symptoms, test results, and response to treatment in order to arrive at an accurate diagnosis and maximize treatment efficacy.

Objective Patellar dislocation is a common injury in sports medicine. While surgical treatment is an important option, pain is severe after surgery. This study compared the analgesic effect and early rehabilitation quality between adductor canal block combined with general analgesia (ACB + GA) and single general analgesia (SGA) after recurrent patellar dislocation (RPD) for “3‐in‐1” procedure surgery. Methods From July 2018 to January 2020, a prospective randomized controlled trial was conducted in analgesia management after RPD for “3‐in‐1” procedure surgery. The 40 patients in the experimental group received ACB (0.3% ropivacaine 30 mL) + GA, while the 38 patients in the control group received SGA. Patients in both groups received “3‐in‐1” procedure surgery, standardized anesthesia, and analgesia during hospitalization. The outcomes included the visual analog scale (VAS), quadriceps strength, Inpatient Satisfaction Questionnaire (IPSQ), Lysholm scores, and Kujala scores. Total rescue analgesic consumption and adverse events were also recorded. One‐way analysis of variance (ANOVA) was used to compare continuous variables between groups and chi‐square or Fisher's exact tests were used to compare count data. Nonparametric Kruskal–Wallis H tests evaluated ranked data. Results No significant differences in resting VAS scores were observed at 8, 12, and 24 h postoperatively. However, the flexion and moving VAS scores of the ACB + GA group were significantly lower than those of the SGA group (p

As one of the five major engineering plastics, polyamide brings many benefits to humans in the fields of transportation, clothing, entertainment, health, and more. However, as the production of polyamide increases year by year, the pollution problems it causes are becoming increasingly severe. This article reviews the current recycling and treatment processes of polyamide, such as chemical, mechanical, and energy recovery, and degradation methods such as thermal oxidation, photooxidation, enzyme degradation, etc. Starting from the synthesis mechanism of polyamide, it discusses the advantages and disadvantages of different treatment methods of polyamide to obtain more environmentally friendly and economical treatment schemes. Finding enzymes that can degrade high-molecular-weight polyamides, exploring the recovery of polyamides under mild conditions, synthesizing environmentally degradable polyamides through copolymerization or molecular design, and finally preparing degradable bio-based polyamides may be the destination of polyamide.

Abstract Aim To explore the mechanism of the healing of tendon tissue and anti-adhesion, and to discuss the role of the transforming growth factor-β3 (TGF-β3)/cAMP response element binding protein-1 (CREB-1) signaling pathway in the healing process of tendons. Method All mice were divided into four groups of 1, 2, 4, and 8 weeks respectively. Each time group was divided into four treatment groups: the amplification group, the inhibition group, the negative group, and the control group. When the tendon injury model was established, the CREB-1 virus was injected into the tendon injury parts. A series of methods such as gait behaviourism, anatomy, histological examination, immunohistochemical examination and collagen staining were employed to assess the tendon healing and the protein expression of TGF-β3, CREB-1, Smad3/7 and type I/III collagen (COL-I/III). CREB-1 virus was sent to tendon stem cells to assess the protein expression of TGF-β1, TGF-β3, CREB-1, COL-I/III by methods such as immunohistochemistry and Western blot. Results The amplification group showed better gait behaviourism than the inhibition group in the healing process. The amplification group also had less adhesion than the negative group. Hematoxylin–eosin (HE) staining of tendon tissue sections showed that the number of fibroblasts in the amplification group was less than the inhibition group, and the immunohistochemical results indicated that the expression of TGF-β3, CREB-1, and Smad7 at each time point was higher than the inhibition group. The expression of COL-I/III and Smad3 in the amplification group was lower than the inhibition group at all time points. The collagen staining indicated that the ratio of type I/III collagen in the amplification group was higher than the negative group at 2,4,8 week. The CREB-1 amplification virus could promote the protein expression of TGF-β3, CREB-1 and inhibit the protein expression of TGF-β1 and COL-I/III in the tendon stem cells. Conclusion In the process of tendon injury healing, CREB-1 could promote the secretion of TGF-β3, so as to promote the tendon healing and have the effect of anti-adhesion in tendons. It might provide new intervention targets for anti-adhesion treatment of tendon injuries.

Abstract Iron metabolism dysregulation is tightly associated with cancer development. But the underlying mechanisms remain poorly understood. Increasing evidence has shown that long noncoding RNAs (lncRNAs) participate in various metabolic processes via integrating signaling pathway. In this study, we revealed one iron-triggered lncRNA, one target of YAP, LncRIM (LncRNA Related to Iron Metabolism, also named ZBED5-AS1 and Loc729013), which effectively links the Hippo pathway to iron metabolism and is largely independent on IRP2. Mechanically, LncRIM directly binds NF2 to inhibit NF2-LATS1 interaction, which causes YAP activation and increases intracellular iron level via DMT1 and TFR1. Additionally, LncRIM-NF2 axis mediates cellular iron metabolism dependent on the Hippo pathway. Clinically, high expression of LncRIM correlates with poor patient survival, suggesting its potential use as a biomarker and therapeutic target. Taken together, our study demonstrated a novel mechanism in which LncRIM-NF2 axis facilitates iron-mediated feedback loop to hyperactivate YAP and promote breast cancer development.

Abstract Background Knee arthroscopic arthrolysis serves as an effective treatment for knee arthrofibrosis. However, hemarthrosis is the most common complication in arthroscopic surgery, which has potential adverse effects on postoperative rehabilitation. The purpose of this study was to evaluate the effects of topical tranexamic acid (TXA) in knee arthroscopic arthrolysis. Methods A total of 87 patients with knee arthrofibrosis who underwent arthroscopic arthrolysis from September 2019 to June 2021 were eligible for this retrospective review. Patients in the TXA group (n = 47) received topical administration of TXA (50 mL, 10 mg/mL) at the end of the surgery, and patients in the control group (n = 40) received no TXA. The postoperative drainage volumes, hematologic levels, inflammatory marker levels, knee range of motion (ROM), visual analog scale (VAS) pain scores, Lysholm knee scores and complications were compared between the two groups. The curative effect of each group was calculated according to Judet’s criteria. Results The mean drainage volumes on postoperative day (POD) 1 and POD 2, and total drainage volume were significantly lower in the TXA group than in the control group (P

Abstract Purpose To explore valuable predictors for mediastinal lymph node metastasis in non-small cell lung cancer (NSCLC) patients, we analyzed the potential roles of standardized uptake value (SUV)-derived parameters from preoperative 18F-FDG PET/CT combined with clinical characteristics. Methods Data from 224 NSCLC patients who underwent preoperative 18F-FDG PET/CT scans in our hospital were collected. Then, a series of clinical parameters including SUV-derived features [SUVmax of mediastinal lymph node and primary-tumor SUVmax, SUVpeak, SUVmean, metabolic tumor volume (MTV) and total lesion glycolysis (TLG)] were evaluated. The best possible cutoff points for all measuring parameters were calculated using receiver operating characteristic curve (ROC) analysis. Predictive analyses were performed using a Logistic regression model to determine the predictive factors for mediastinal lymph node metastasis in NSCLC and lung adenocarcinoma patients. After multivariate model construction, data of another 100 NSCLC patients were recorded. Then, 224 patients and 100 patients were enrolled to validate the predictive model by the area under the receiver operating characteristic curve (AUC). Results The mediastinal lymph node metastasis rates in 224 patients for model construction and 100 patients for model validation were 24.1% (54/224) and 25% (25/100), respectively. It was found that SUVmax of mediastinal lymph node ≥ 2.49, primary-tumor SUVmax ≥ 4.11, primary-tumor SUVpeak ≥ 2.92, primary-tumor SUVmean ≥ 2.39, primary-tumor MTV ≥ 30.88 cm3, and primary-tumor TLG ≥ 83.53 were more prone to mediastinal lymph node metastasis through univariate logistic regression analyses. The multivariate logistic regression analyses showed that the SUVmax of mediastinal lymph nodes (≥ 2.49: OR 7.215, 95% CI 3.326–15.649), primary-tumor SUVpeak (≥ 2.92: OR 5.717, 95% CI 2.094–15.605), CEA (≥ 3.94 ng/ml: OR 2.467, 95% CI 1.182–5.149), and SCC (

Abstract Calpains are a class of non-lysosomal cysteine proteases that exert their regulatory functions via limited proteolysis of their substrates. Similar to the lysosomal and proteasomal systems, calpain dysregulation is implicated in the pathogenesis of neurodegenerative disease and cancer. Despite intensive efforts placed on the identification of mechanisms that regulate calpains, however, calpain protein modifications that regulate calpain activity are incompletely understood. Here we show that calpains are regulated by KCTD7, a cytosolic protein of previously uncharacterized function whose pathogenic mutations result in epilepsy, progressive ataxia, and severe neurocognitive deterioration. We show that KCTD7 works in complex with Cullin-3 and Rbx1 to execute atypical, non-degradative ubiquitination of calpains at specific sites (K398 of calpain 1, and K280 and K674 of calpain 2). Experiments based on single-lysine mutants of ubiquitin determined that KCTD7 mediates ubiquitination of calpain 1 via K6-, K27-, K29-, and K63-linked chains, whereas it uses K6-mediated ubiquitination to modify calpain 2. Loss of KCTD7-mediated ubiquitination of calpains led to calpain hyperactivation, aberrant cleavage of downstream targets, and caspase-3 activation. CRISPR/Cas9-mediated knockout of Kctd7 in mice phenotypically recapitulated human KCTD7 deficiency and resulted in calpain hyperactivation, behavioral impairments, and neurodegeneration. These phenotypes were largely prevented by pharmacological inhibition of calpains, thus demonstrating a major role of calpain dysregulation in KCTD7-associated disease. Finally, we determined that Cullin-3–KCTD7 mediates ubiquitination of all ubiquitous calpains. These results unveil a novel mechanism and potential target to restrain calpain activity in human disease and shed light on the molecular pathogenesis of KCTD7-associated disease.

Abstract Copper is a vital mineral, and an optimal amount of copper is required to support normal physiologic processes in various systems, including the cardiovascular system. Over the past few decades, copper-induced cell death, named cuproptosis, has become increasingly recognized as an important process mediating the pathogenesis and progression of cardiovascular disease (CVD), including atherosclerosis, stroke, ischemia-reperfusion injury, and heart failure. Therefore, an in-depth understanding of the regulatory mechanisms of cuproptosis in CVD may be useful for improving CVD management. Here, we review the relationship between copper homeostasis and cuproptosis-related pathways in CVD, as well as therapeutic strategies addressing copper-induced cell death in CVD.

The domestic yak was regarded as a valuable model to explore the molecular mechanism of high-altitude animal adaptation, including the extreme tolerance of starvation and cold stress, which is closely associated with specifically seasonal deposition and metabolism of subcutaneous adipose tissue. However, the key regulators for these processes remain largely unknown. Here, the yak adipogenesis model in vitro was established and liver kinase b1 (LKB1) was regarded as a key negative regulator involved in yak adipocytes lipid accumulation. First, the mRNA level of LKB1 in adipose tissue of yaks from the cold season is significantly higher than that of yaks from the warm season. Interestingly, overexpression of LKB1 significantly inhibited adipocytes lipid accumulation. Consistently, LKB1 overexpression dramatically suppressed mRNA levels of adipogenic transcriptional factors, including C/EBPα, C/EBPβ and PPARγ, and subsequently significantly decreased levels of lipid accumulation related genes (FABP4 and FAS) compared with those of control. In contrast, overexpression of LKB1 promoted thermogenic and lipolysis related genes in yak adipocyte, including PGC1α, PPARα, UCP1, ATGL, HSL and LPL. Therefore, these results would provide new insights to decipher the network for domestic yak adipose deposition, and LKB1 might be as a new molecular target for animal environmental-resistant breeding.

Biological fish exhibit remarkable adaptability and exceptional swimming performance through their powerful and flexible bodies. Therefore, designing a continuum flexible body is significantly important for the development of a robotic fish. However, it is still challenging to replicate these functions of a biological body due to the limitations of actuation and material. In this paper, based on a tensegrity structure, we propose a bionic design scheme for a continuum robotic fish body with a property of stiffness variation. Its detailed structures and actuation principles are also presented. A mathematical model was established to analyze the bending characteristics of the tensegrity structure, which demonstrates the feasibility of mimicking the fish-like oscillation propulsion. Additionally, the stiffness variation mechanism is also exhibited experimentally to validate the effectiveness of the designed tensegrity fish body. Finally, a novel bionic robotic fish design scheme is proposed, integrating an electronic module-equipped fish head, a tensegrity body, and a flexible tail with a caudal fin. Subsequently, a prototype was developed. Extensive experiments were conducted to explore how control parameters and stiffness variation influence swimming velocity and turning performance. The obtained results reveal that the oscillation amplitude, frequency, and stiffness variation of the tensegrity robotic fish play crucial roles in swimming motions. With the stiffness variation, the developed tensegrity robotic fish achieves a maximum swimming velocity of 295 mm/s (0.84 body length per second, BL/s). Moreover, the bionic tensegrity robotic fish also performs a steering motion with a minimum turning radius of 230 mm (0.68 BL) and an angular velocity of 46.6°/s. The conducted studies will shed light on the novel design of a continuum robotic fish equipped with stiffness variation mechanisms.

Dihydroorotate dehydrogenase (DHODH) is a rate-limiting enzyme of de novo biosynthesis of pyrimidine. Although the involvement of DHODH in resisting ferroptosis has been successively reported in recent years, which greatly advanced the understanding of the mechanism of programmed cell death (PCD), the genetic sequence of the yak DHODH gene and its roles in ferroptosis are still unknown. For this purpose, we firstly cloned the coding region sequence of DHODH (1188 bp) from yak liver and conducted a characterization analysis of its predictive protein that consists of 395 amino acids. We found that the coding region of the yak DHODH gene presented high conservation among species. Second, the expression profile of the DHODH gene in various yak tissues was investigated using RT-qPCR. The results demonstrated that DHODH was widely expressed in different yak tissues, with particularly high levels in the spleen, heart, and liver. Third, to investigate the involvement of DHODH in regulating ferroptosis in cells, yak skin fibroblasts (YSFs) were isolated from fetuses. And then, bisphenol S (BPS) was used to induce the in vitro ferroptosis model of YSFs. We observed that BPS decreased the cell viability (CCK8) and membrane potential (JC-1) of YSFs in a dose-dependent manner and induced oxidative stress by elevating reactive oxygen species (ROS). Simultaneously, it was evident that BPS effectively augmented the indicators associated with ferroptosis (MDA and BODIPY staining) and reduced GSH levels. Importantly, the co-administration of Ferrostatin-1 (Fer), a potent inhibitor of ferroptosis, significantly alleviated the aforementioned markers, thereby confirming the successful induction of ferroptosis in YSFs by BPS. Finally, overexpression plasmids and siRNAs of the yak DHODH gene were designed and transfected respectively into BPS-cultured YSFs to modulate DHODH expression. The findings revealed that DHODH overexpression alleviated the occurrence of BPS-induced ferroptosis, while interference of DHODH intensified the ferroptosis process in YSFs. In summary, we successfully cloned the coding region of the yak DHODH gene, demonstrating its remarkable conservation across species. Moreover, using BPS-induced ferroptosis in YSFs as the model, the study confirmed the role of the DHODH gene in resisting ferroptosis in yaks. These results offer valuable theoretical foundations for future investigations into the functionality of the yak DHODH gene and the underlying mechanisms of ferroptosis in this species.

The quality of lamb meat is positively correlated with intramuscular fat content. In recent years, a large number of studies have shown that miRNAs play an important role in the proliferation and differentiation of adipocytes. In this study, we aimed to explore the effect of miR-92a-3p on the differentiation of goat intramuscular preadipocytes. The results showed that the expression level of miR-92a-3p was low in the early stage of differentiation, reached the highest level on the third day of differentiation, and then decreased. And miR-92a-3p can inhibit the accumulation of lipid droplets and down-regulate the determinants of adipogenic differentiation. Mechanistically, by predicting target genes, we found that miR-92a-3p affects the differentiation of goat intramuscular preadipocytes and the accumulation of lipid droplets by regulating the expression of goat gene APOL6. This study provides important new information to better understand the relationship between miRNAs and the differentiation of goat intramuscular preadipocytes, thus providing a new reference for goat intramuscular adipogenesis.

BackgroundPancreatic ductal adenocarcinoma (PDAC) is an extremely deadly neoplasm, with only a 5-year survival rate of around 9%. The tumor and its microenvironment are highly heterogeneous, and it is still unknown which cell types influence patient outcomes.MethodsWe used single-cell RNA sequencing (scRNA-seq) and spatial transcriptome (ST) to identify differences in cell types. We then applied the scRNA-seq data to decompose the cell types in bulk RNA sequencing (bulk RNA-seq) data from the Cancer Genome Atlas (TCGA) cohort. We employed unbiased machine learning integration algorithms to develop a prognosis signature based on cell type makers. Lastly, we verified the differential expression of the key gene LY6D using immunohistochemistry and qRT-PCR.ResultsIn this study, we identified a novel cell type with high proliferative capacity, Prol, enriched with cell cycle and mitosis genes. We observed that the proportion of Prol cells was significantly increased in PDAC, and Prol cells were associated with reduced overall survival (OS) and progression-free survival (PFS). Additionally, the marker genes of Prol cell type, identified from scRNA-seq data, were upregulated and associated with poor prognosis in the bulk RNA-seq data. We further confirmed that mutant KRAS and TP53 were associated with an increased abundance of Prol cells and that these cells were associated with an immunosuppressive and cold tumor microenvironment in PDAC. ST determined the spatial location of Prol cells. Additionally, patients with a lower proportion of Prol cells in PDAC may benefit more from immunotherapy and gemcitabine treatment. Furthermore, we employed unbiased machine learning integration algorithms to develop a Prol signature that can precisely quantify the abundance of Prol cells and accurately predict prognosis. Finally, we confirmed that the LY6D protein and mRNA expression were markedly higher in pancreatic cancer than in normal pancreatic tissue.ConclusionsIn summary, by integrating bulk RNA-seq and scRNA-seq, we identified a novel proliferative cell type, Prol, which influences the OS and PFS of PDAC patients.

Objective Soft tissue sarcomas (STSs) arising from the popliteal fossa pose surgical challenges due to their proximity to critical neurovascular structures. This study aimed to investigate whether a novel 3D imaging technique highlighting these key anatomical structures could facilitate preoperative planning and improve surgical outcomes in STS. Methods This was a prospective, observational, pilot study. Between November 2019 and December 2020, 27 patients with STS of the popliteal fossa undergoing limb‐sparing procedures were enrolled and assigned to either a control or intervention group. Control patients underwent traditional preoperative planning with separate computed tomography angiography, magnetic resonance imaging, and magnetic resonance hydrography. In the intervention group, 3D images were generated from these images, the tumor and skeletomuscular and neurovascular structures were revealed in three dimensions, and this was visualized on the surgeon's smartphone or computer. Primary endpoints were surgical margins and complications. Secondary endpoints included operative time, blood loss, serum C‐reactive protein and interleukin‐6, length of in‐hospital stay, and limb function. Comparisons between groups were made using independent‐sample t‐tests for continuous data and the Mann–Whitney U and Fisher's exact tests for categorical data. Results There was a lower but not significantly different inadvertent positive margin rate (1/15 vs. 3/12, P = 0.294), significantly shorter hospital stay (P = 0.049), and less numbers ≥75th percentile of operative time (P = 0.037) and blood loss (P = 0.024) in the intervention group. Differences in surgical complications, operative time, blood loss, C‐reactive protein and interleukin‐6 levels on the second postoperative day, and limb functional scores were statistically insignificant. Conclusions The novel 3D imaging technique facilitates complex preoperative planning and limb‐salvage surgical procedures for patients with STS of the popliteal fossa, and this may affect how surgical planning is performed in the future.