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Abstract Background Receptor-interacting protein kinase 3 (RIPK3) has been implicated in the pathogenesis of diverse human cancers. However, the role of RIPK3 in acute myeloid leukemia (AML) is not fully understood, which needs further research and clarification. Methods We first identified the expression and clinical prognostic value of RIPK3 in AML through a public database and further validated in our research cohort. In addition, the biological function of RIPK3 in leukemic development was further verified through in vitro experiments. Results Based on the GEPIA database, we screened that RIPK3 overexpression among RIPK family was associated with poor prognosis in AML. Afterwards, another independent cohort from our research center further confirmed the expression pattern of RIPK3 in AML patients. Clinically, increased RIPK3 expression was closely related to specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation. The significant association of RIPK3 overexpression with FAB-M4/M5 was further validated in AML cell lines. Notably, AML patients with RIPK3 overexpression received transplantation presented a markedly longer survival than those just receiving chemotherapy, whereas those with RIPK3 underexpression showed similar survival between transplantation and chemotherapy group. Bioinformatics analysis showed the significant association of RIPK3 expression with diverse oncogenes/tumor suppressor genes and tumor-related biological processes in AML. Subsequently, we further performed functional experiments in vitro confirmed the potential oncogenic role of RIPK3 in AML. Conclusions Overexpression of RIPK3 was associated with specific subtypes of AML, such as FAB-M4/M5, normal karyotype and NPM1 mutation, and may facilitate the leukemic development. Moreover, RIPK3 overexpression was associated poor prognosis, and may guide treatment choice in AML.

Abstract Background The homeobox (HOX) genes especially for HOXA cluster play crucial roles in leukemogenesis. HOXA overexpression caused by genetic alterations, such as KMT2A rearrangements, NUP98- fusions and FLT3-ITD mutations, is frequently identified in AML. However, very few studies determined the DNA methylation-mediated epigenetic regulation of the HOXA cluster genes in AML. Methods We systematically first screened the prognostic value of HOXA cluster genes methylation in AML from The Cancer Genome Atlas (TCGA) datasets. Afterwards, the candidate prognosis-related gene HOXA9 were selected for clinical relevance analysis and were further validated in another independent cohort from our research center. Results The methylation of HOXA9, among HOXA cluster genes, negatively correlated with adverse prognosis and expression were screened and identified in AML among TCGA datasets. Clinically, HOXA9 hypomethylation was positively correlated with specific subtypes of AML, such as French-American-British (FAB)-M5/M7, normal karyotype and FLT3, NPM1 and DNMT3A mutation, whereas negatively associated with FAB-M3, t(15;17), t(8;21) and t(16;16). Importantly, AML patients with HOXA9 hypomethylation may profit from transplantation, whereas AML patients with HOXA9 hypermethylation could not, suggesting that HOXA9 methylation may be used to guide therapeutic selection between transplantation and chemotherapy. Bioinformatics analysis demonstrated the association of HOXA9 expression with diverse leukemia-related genes (HOXAs, SOSTDC1, MEG3, miR-10a, miR-381 and miR-193b) and signaling pathways (PI3K-Akt signaling) in AML. Subsequently, we further validate the hypomethylation pattern of HOXA9 in AML patients and the epigenetic regulation of HOXA9 methylation in AML cell-lines. Conclusions HOXA9 methylation linked to HOXA9 expression correlates with diverse genetic abnormalities of AML, such as normal karyotype, t(15;17), t(8;21), t(16;16) and FLT3, NPM1 and DNMT3A mutations. Moreover, HOXA9 hypomethylation may be associated with adverse prognosis, and may guide treatment choice in AML.

The aim of the study was to investigate the inhibitory effect and mechanism of ε-poly-L-lysine on Botrytis cinerea causing gray mold in apples. The effects of different concentrations of ε-PL on colony diameter, spore germination, mycelial growth of B. cinerea, and its effect on controlling gray mold in apples were studied. The changes in cell permeability, antioxidant enzyme activities, cellular soluble protein and nucleic acid leakage, malonaldehyde content, and reactive oxygen species of B. cinerea were also investigated. The results showed that the minimum inhibitory concentration of ε-PL against B. cinerea was 400 mg/L, and the concentration of ε-PL could effectively control gray mold in apples. ε-PL concentration above 100 mg/L could significantly inhibit the spore germination and mycelium growth of B. cinerea (P

Abstract Background Pre-harvest sprouting (PHS) is one of the most important problems associated with the severe decrease of yield and quality under disaster weather of continuous rain in wheat harvesting stage. At present, the functions and mechanisms related to the involvement of post-transcriptional regulation has not been studied very clearly in PHS resistance. Results This study compared the differences of germinated seeds in miRNAome between the PHS-tolerant and PHS-susceptible white wheat varieties. A total of 1879 miRNAs were identified from three different stages during seed germination. In order to further obtain candidate miRNAs, the different datasets of differentially expressed miRNAs were excavated by using differential-expression and time-series analysis. Combined with degradome data, the miRNA-mRNA networks analysis was performed after genome-wide screening of target genes, and then KEGG enrichment highlighted that the starch and sucrose metabolism pathway related to PHS was specifically enriched in an especial target-gene dataset derived from R12R18-HE miRNAs. Based on transcriptome data, a network associated with starch metabolism was systematically and completely reconstructed in wheat. Then, the starch degradation pathway controlled by seven miRNA-RNA pairs were supposed to be the essential regulation center for seed germination in wheat, which also could play a critical role on the PHS resistance. Conclusion Our findings revealed the complex impact of the miRNA-mediated mechanism for forming intrinsic and inherent differences, which resulting in significant difference on PHS performance between white wheat varieties.

Abstract Background The continuum management of diabetes remains under-evaluated in China. This study aimed to estimate the proportions of diabetes adults at each stage of the cascade of care framework in Shandong, China. Methods We conducted a secondary analysis using the 2018 China Adult Chronic Disease and Nutrition Surveillance (CACDNS) data in Shandong. This nationwide cross-sectional survey was conducted between September and November 2018, investigating the major chronic diseases among Chinese adults through interviews, physical examinations, and laboratory tests. We employed the cascade model to examine the proportion of diabetes adults, including both type 1 and type 2, from diabetes screening, diagnosis, pharmaceutical and non-pharmaceutical treatments, to single and comprehensive management targets, and quantified the attrition between each stage. Diabetes screening was defined as participants reported to have ever received a blood glucose test. Diabetes diagnosis was defined as: 1) fasting plasma glucose (FPG) ≥ 126 mg/dL, or 2) 2-h oral glucose tolerance test (2 h-OGTT) ≥ 200 mg/dL, or 3) hemoglobin A1c (HbA1c) ≥ 6.5%, or 4) self-reported diabetes. Diabetes management targets included: 1) single glycemic target of personalized HbA1c level, 2) comprehensive ABC targets of personalized HbA1c level, blood pressure (BP)

Abstract Inevitable gefitinib resistance is the biggest bottleneck in current treatment and the mechanisms are not fully understood. Here, we observe that PFTK1 (also named CDK14) is significantly enhanced in NSCLC with gefitinib resistance. And the upregulation of PFTK1 is negatively associated with progression-free survival (PFS) in NSCLC patients who receive gefitinib treatment. Further study suggests that gefitinib can critically accelerate PFTK1 through suppressing its promoter methylation in a DNMT3B-dependent manner. Gain and loss of function assays demonstrate that desregulation of PFTK1 significantly enhances gefitinib resistance in NSCLC. PFTK1 interacts with LRP6 and activates Wnt/β-catenin signaling to attenuate gefitinib-induced cellular apoptosis. Moreover, FMF-04-159-2, a specific covalent inhibitor of PFTK1, can reverse the effect of PFTK1 on gefitinib resistance in vitro and in vivo. Consequently, these findings shed new light on the mechanism underlying gefitinib resistance, and suggest PFTK1 as a target for gefitinib treatment in NSCLC.

Abstract Assessing the eco-health of regional reservoirs is essential for sustainable water resource utilization and water security, particularly in water-scarce areas. This study constructed a Benthic Index of Biotic Integrity (B-IBI) based on the community characteristics of macrobenthos in ten large and medium-sized reservoirs across four major river basins in Henan Province, China. A total of 90 taxa were identified, representing 3 phyla, 6 classes, 17 orders, 45 families and 81 genera. The B-IBI was derived from five key metrics: the number of crustacean and mollusca taxa, Intolerant %, the BI index, the BMWP index, and the Shannon–Wiener index. The B-IBI scores across 44 sites in the ten reservoirs ranged from 0.35 to 3.99. The assessment classified two reservoirs (QTH and HKC in the Yellow River basin) as poor, whereas one reservoir (QP in the Huai River sbasin) was classified as excellent. The B-IBI index effectively distinguished impaired sites from reference sites, supporting its suitability for eco-health assessments of reservoirs in Henan Province.

Abstract Acute ischemic stroke (AIS) triggers immune responses and neuroinflammation, contributing to brain injury. Histone lactylation, a metabolic stress-related histone modification, plays a critical role in various diseases, but its involvement in cerebral ischemia remains unclear. This study utilized a transient middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen–glucose deprivation/reoxygenation (OGD/R) model to investigate the role of microglial histone lactylation in ischemia–reperfusion injury. Lactate overload post-AIS increased histone lactylation, while reduced SMEK1 expression in microglia correlated with elevated lactate and neuroinflammation. Microglia-specific SMEK1 deficiency enhanced lactate production by inhibiting the pyruvate dehydrogenase kinase 3-pyruvate dehydrogenase (PDK3-PDH) pathway, increasing H3 lysine 9 lactylation (H3K9la), activating Ldha and Hif-1α transcription, and promoting glycolysis. SMEK1 overexpression improved neurological recovery in ischemic mice. This study highlights SMEK1 as a novel regulator of histone lactylation and a potential therapeutic target for mitigating neuroinflammation and enhancing recovery after AIS.

Abstract Mitochondrial DNA (mtDNA) variants in patients with myelodysplastic neoplasms (MDS) are shown to be prognostic of outcomes after allogeneic hematopoietic cell transplantation (allo-HCT). However, the prognostic impact of donor mtDNA variants is unknown. Here, we performed whole-genome sequencing on 494 donors who were matched to MDS patients enrolled in the Center for International Blood and Marrow Transplant Research (CIBMTR). We evaluated the impact of donor mtDNA variants on recipients’ transplantation outcomes, including overall survival, relapse, relapse-free survival, and transplant-related mortality. The optimism-adjusted bootstrap method was employed to evaluate the prognostic performance of models that include donor mtDNA variants alone and combined with MDS- and HCT-related clinical factors. In the entire donor cohort, we identified 1,825 mtDNA variants, including 67 potential pathogenic variants. Genetic variants on MT-CYB and MT-ND5 genes were identified as independent predictors of posttransplant outcomes. Integration of donor mtDNA variants into the models based on the International Prognostic Scoring System-Revised (IPSS-R) could capture more prognostic information for MDS patients. Sensitivity analysis in 397 unrelated donors obtained similar results. More importantly, we found that incorporating donor mtDNA variants with donor age and the degree of HLA-matching could help to identify “suboptimal” younger HLA-well-matched unrelated donors and “optimal” older HLA-partially/mismatched unrelated donors. Our study shows that mtDNA variants in donors, including those from unrelated donors, hold prognostic value for MDS patients undergoing allo-HCT and augment the prognostic stratification of current scoring systems. These findings present an opportunity to refine donor selection strategies and improve posttransplant outcomes for MDS patients.

Abstract Purpose This study aimed to report a newly developed, high‐fidelity synthetic simulator to simulate excision and primary anastomotic (EPA) bulbar urethroplasty and its clinical use for new practitioners in shortening the learning curve. Material and Methods The bulbar urethral anastomosis simulator consists of several standardized components created according to the actual size of the male patient. Interns, novice residents, and fellows inexperienced with urethral reconstruction (n = 10, 5, 5) from different medical centres were invited to participate in the training programme. Two reconstructive urology experts monitored each practice. Following the training, three kinds of validity testing were used to assess the simulator: face, content, and construct. In the intern group, the task performance in the first five training sessions and the last five training ones were compared using a self‐control approach. In the resident and fellow group, the real surgical data, including estimated blood loss, operative duration, and 6‐month post‐operative success rate of trainees after training, are plotted, which are compared with that of reconstructive urology experts (n = 5) included retrospectively to study the effectiveness of the simulator in shortening the learning curve. Results The overall mean satisfaction rate for the simulators was inspiring and evaluated by experts. In the intern group, significant improvement can be achieved through 10 training sessions (p

Abstract Four new isoquinoline alkaloids, hypecotumines A-D (1–4), were isolated and identified from the whole herbs of Hypecoum erectum L. Their structures were determined by a combination of HRESIMS, NMR, and X-ray diffraction analysis methods. Compounds 1–4 were characterized by a terminal double bond at C-9 and their plausible biosynthetic pathway was hypothesized. Since PCSK9 plays a key role in the development of cardiovascular disease (CVD), exploration of PCSK inhibitors from natural products are beneficial for drug discovery of CVD treatment. SPR and Western blot assays showed compound 4 had PCSK9 inhibition activity with KD value of 59.9 µM and thus elevated the LDLR level. Further molecular docking studies demonstrated that 4 and PCSK9 could form stable interactions via key hydrogen bonds. Graphical Abstract

Abstract Aging has made stroke a top killer and disabler, with post-stroke sarcopenia worsening disability and quality of life. While resistance training benefits the elderly, its impact on stroke patients is understudied. This study evaluates the potential of a 4-week unilateral resistance training (URT) program to prevent sarcopenia in stroke patients. It assesses the impact of URT on hand grip strength (HG), muscle thickness (MT), upper limb functionality, and the psychological status of the patients. The study aims to quantitatively analyze these indicators to inform evidence-based post-stroke rehabilitation practices. This study employed a randomized controlled trial (RCT) involving 77 eligible stroke survivors, equally allocated into a control group (n = 39) and an intervention group (n = 38). The control group received standard rehabilitation, while the intervention group additionally underwent a 4-week URT program. The primary outcomes were unaffected side HG and MT, measuring muscle mass and function. Secondary outcomes included the Fugl-Meyer Assessment of the Upper Extremity (FMA-UE) for upper limb functionality and the Hamilton Depression Rating Scale (HAMD) for psychological well-being changes. Statistical analysis showed significant differences (p

This study puts forward a machine vision-based prediction method to solve the problem regarding the measurement of traits in shiitake mushroom caps during the shiitake mushroom breeding process. It enables precise phenotyping through accurate image acquisition and analysis. In practical applications, this method improves the breeding process by rapidly and non-invasively assessing key traits such as the size and color of shiitake mushroom caps, which helps in efficiently screening strains and reducing human errors. Firstly, an edge detection model was established. This model is called KL-Dexined. It achieved an per-image best threshold (OIS) rate of 93.5%. Also, it reached an Optimal Dynamic Stabilization (ODS) rate of 96.3%. Moreover, its Average Precision (AP) was 97.1%. Secondly, the edge information detected by KL-Dexined was mapped onto the original image of shiitake mushroom caps, and using the OpenCV model,11 phenotypic key features including shiitake mushroom caps area, perimeter, and external rectangular length were obtained. Experimental results demonstrated that the R² between predicted values and true values was 0.97 with an RMSE as low as 0.049. After conducting correlation analysis between phenotypic features and shiitake mushroom caps weight, four most correlated phenotypic features were identified: Area, Perimeter, External rectangular width, and Long axis; they were divided into four groups based on their correlation rankings. Finally,M3 group using GWO_SVM algorithm achieved optimal performance among six mainstream machine learning models tested with an R²value of 0.97 and RMSE only at 0.038 when comparing predicted values with true values. Hence, this study provided guidance for predicting key traits in shiitake mushroom caps.

Allogeneic hematopoietic stem-cell transplantation (allo-HCT), an early developed methodology for precision medicine, remains the only curative therapy for myelodysplastic syndromes (MDS). However, allo-HCT carries significant risks of morbidity and mortality due to relapse and transplant-related complications. Recurrent mutations in mitochondrial DNA (mtDNA) have been identified as significant prognostic indicators for MDS outcomes following allo-HCT. However, the biological mechanisms of mtDNA mutations remain unclear. Thus, here we performed deep variant phenotyping by integrating computational biophysics and structural genomics approaches to reveal the molecular mechanisms underlying mtDNA variant dysfunction. This emerging genomics discipline employs structural models, molecular mechanic calculations, and accelerated molecular dynamic simulations to analyze gene products, focusing on their structures and motions that determine their function. We applied this methodology on the variants in the mitochondria-encoded complex I genes that are associated with MDS pathobiology and prognosis after allo-HCT. Our results demonstrate that this approach significantly outperforms conventional analytical methods, providing enhanced and more accurate information to support the potential pathogenicity of these variants and better infer their dysfunctional mechanisms. We conclude that the adoption and further expansion of computational structural genomics approaches, as applied to the mitochondrial genome, have the potential to significantly increase our understanding of molecular mechanisms underlying the disease. Our study lays a foundation for translating mitochondrial biology into clinical applications, which will advance the integration of precision medicine with allo-HCT.

IntroductionCoastal wetlands play an important role in the global ecosystem, yet they are increasingly facing ecological degradation due to pollution and the spread of invasive Spartina alterniflora (S. alterniflora). Among the environmental challenges, microplastics (MPs) contamination in S. alterniflora-invaded coastal wetlands is of growing concern. However, the effects of MPs pollution in S. alterniflora-invaded coastal wetlands are not clear.MethodsThis study investigated the effects of S. altemiflora invasion on the distribution of MPs and the effects of MPs pollution on the physicochemical properties of sediments and the structure of microbial communities in the Tiaozini wetland of Jiangsu Province, China.Results and discussionThe total MPs abundance of the S. altemiflora single-plant area was the highest (16.338 x103 items/kg d.w.). Polyurethane and Chlorinated polyisoprene are typical MPs types in the study area. Polyurethane exhibits high abundance at all sampling sites, while Chlorinated polyisoprene is one of the dominant MPs types in the single-plant and sub-mature area of S. alterniflora. The results showed that the invasion of S. alterniflora promoted the accumulation of MPs in the sediments of the coastal wetland. This accumulation increased the total organic carbon (TOC), available phosphorus (AP) and total nitrogen (TN) contents. Moreover, MPs pollution increased the ALP and SUC enzyme activities of sediment. In addition, MPs contamination increased the abundance of Proteobacteria and Bacteroidota in the sediments. This study highlights the complex interactions between MPs pollution and S. alterniflora invasion, providing the foundation for understanding the synergistic impacts of these stressors on coastal wetland ecosystems.

BackgroundBladder cancer (BC) is a common tumor worldwide. Screening for BC currently lacks a highly efficient, non-invasive, and inexpensive method. Serum microRNA (miRNA), which is stable and commonly present, has the potential to serve as a novel marker for BC diagnosis.Materials & methodsBased on a study involving 112 BC patients and 112 healthy subjects, we conducted this research in three phases to identify applicable microRNAs (miRNAs) in serum for BC diagnosis using quantitative reverse transcription polymerase chain reaction (qRT-PCR). A panel with optimal diagnostic value was developed. Additionally, we used bioinformatic analysis to explore the potential biological functions of the crucial miRNAs.ResultsThe diagnostic panel consisted of miR-212-3p, miR-30c-5p, and miR-206, with an area under the curve (AUC) of 0.838, sensitivity of 83.33%, and specificity of 73.81%. Furthermore, ATF3, GJA1, JPH2, MVB12B, RUNX1T1, SLC8A1, SPATA6, and TPM3 may be potential target genes of these three miRNAs.ConclusionWe developed a three-miRNA panel that could serve as a highly efficient and inexpensive biomarker for BC diagnosis and screening.

Polychlorinated biphenyls (PCBs) were continuously receiving attention after their ban for use and production, owing to significant persistence, transport, and toxicity at trace level. Due to the field data gap of all 209 PCB congeners in previous studies, the source and environmental migration of lacustrine PCBs were not comprehensively understood. In this study, 209 PCB congeners in 277 water and 155 sediment samples collected from China's 23 large lakes across a longitudinal transect (18–45 °N) were analyzed. Results showed that the concentrations of Σ209PCBs were 0.03–41.04 ng/L and 0.26–163.82 ng/g dry weight in lake water and sediment, respectively. In lake water, the dominant PCB congeners, detected in over 50 % of all samples, were PCB 11, PCB 28+31, PCB 41+64+68, PCB 47+48+75, and PCB 51, with contributions to Σ209PCBs as 39.8 %, 6.6 %, 3.5 %, 18.4 %, and 6.4 %, respectively. Source apportionment revealed that major contributions of PCB 11, 41+64+68, 47+48+75, 51, and 209, were mainly from unintentionally produced PCBs (UP-PCBs) while PCB 28+31 and the other congeners from historical PCB commercials. Therefore, the selective congener analysis (excluding UP-PCBs) common in previous lake studies was an omission. Simultaneously, the longitudinal fractionation of PCBs was also found in lake waters, likely caused by the East Asian monsoon. Moreover, fugacity fractions of PCBs between water and sediment indicated their overall equilibrium or net sorption. Overall, PCB 28+31 can be well indicative of PCB migration. This study provides basic information for the migration and transformation of trace toxic persistent organic pollutants.

Objective: Activating brown adipose tissue (BAT) thermogenesis is a promising approach to combat obesity and metabolic disorders. The post-transcriptional regulation of BAT thermogenesis mediated by RNA-binding proteins (RBPs) is still not fully understood. This study explores the physiological role of novel RBPs in BAT differentiation and thermogenesis. Methods: We used multiple public datasets to screen out novel RBPs responsible for BAT differentiation and thermogenesis. In vitro loss- and gain-of-function experiments were performed in both C3H10T1/2 preadipocytes and mature brown adipocytes to determine the role of Y-box binding protein 3 (YBX3) in brown adipocyte differentiation and thermogenesis. Adeno-associated virus (AAV)-mediated BAT-specific knockdown or overexpression of Ybx3 was applied to investigate the function of YBX3 in vivo. Results: YBX3 is a brown adipocyte-enriched RBP induced by cold stimulation and β-adrenergic signaling. Both in vitro loss- and gain-of-function experiments demonstrate that YBX3 is essential for brown adipocyte differentiation and thermogenesis. BAT-specific loss of Ybx3 dampens thermogenesis and exacerbates diet-induced obesity in mice, while overexpression of Ybx3 promotes thermogenesis and confers protection against diet-induced metabolic dysfunction. Transcriptome analysis and mitochondrial stress test indicate that Ybx3 deficiency compromises the mitochondrial oxidative phosphorylation, leading to thermogenic failure. Mechanistically, YBX3 stabilizes the mRNA of Slc3a2 and Pparg, which facilitates branched-chain amino acid (BCAA) influx and catabolism and fuels brown adipocyte differentiation and thermogenesis. Conclusions: YBX3 facilitates BAT fueling BCAA to boost thermogenesis and energy expenditure, which protects against obesity and metabolic dysfunction. Thus, YBX3 could be a promising therapeutic target for obesity.

Abstract Background Thyroid hormone is the key endocrine regulator of growth, development, metabolism, and other bodily functions. α-Klotho has been involved in the aging process and acts as an endocrine factor involved in the regulation of various metabolic processes in humans. However, the relationship between α-Klotho and thyroid profile has not been uniformly recognize. Objective To determine the relationship between α-Klotho and thyroid profile in adult individuals. Methods Population data of 4614 adult individuals were obtained from the NHANES database during the period of 2007–2012. Weighted multivariable regression analysis was performed using a general linear model with serum α-Klotho as the independent variable and thyroid profile as the dependent variables, respectively. The generalized additive model was used for smoothing curve fitting and threshold effect analysis. Results α-Klotho was associated with a slightly higher FT3, TT3 and TT4 level in unadjusted and adjusted regression models. However, a higher α-Klotho level was associated with a lower TSH level. After α-Klotho was grouped as quantiles with reference (Q1), α-Klotho still showed a statistically significant positive correlation with FT3 and TT3 levels in Q2, Q3 and Q4. In addition, α-Klotho was positively corrected with TT4, but negatively associated with TSH in Q4. Conclusions Serum soluble α-Klotho was positively associated with FT3, TT3 and TT4, but negatively correlated with TSH. The significant effect of α-Klotho on thyroid profile suggests its potential as a predictive marker of thyroid functions, indicating its possible involvement in the regulation of thyroid hormone secretion.

Abstract Small extracellular vesicles (sEVs) are important mediators of intercellular communication between tumor cells and their surrounding environment. Furthermore, the mechanisms by which miRNAs carried in tumor sEVs regulate macrophage polarization remain largely unknown. To concentrate sEVs, we used the traditional ultracentrifugation method. Western blot, NanoSight, and transmission electron microscopy were used to identify sEVs. To determine the function of sEVs-miR-487a, we conducted in vivo and in vitro investigations. The intercellular communication mechanism between osteosarcoma cells and M2 macrophages, mediated by sEVs carrying miR-487a, was validated using luciferase reporter assays, transwell assays, and Western blot analysis. In vitro, sEVs enriched in miR-487a and delivered miR-487a to macrophages, promoting macrophage polarization toward an M2-like type, which promotes proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT) of osteosarcoma cells. In vivo, sEVs enriched in miR-487a facilitate lung metastasis of osteosarcoma. Moreover, plasma miR-487a in sEVs was shown to be a potential biomarker applicable for osteosarcoma diagnosis. In summary, miR-487a derived from osteosarcoma cells can be transferred to macrophages via sEVs, then promote macrophage polarization towards an M2-like type by targeting Notch2 and activating the GATA3 pathway. In a feedback loop, the activation of macrophages accelerates epithelial-mesenchymal transition (EMT), which in turn promotes the migration, invasion, and lung metastasis of osteosarcoma cells. This reciprocal interaction between activated macrophages and osteosarcoma cells contributes to the progression of the disease. Our data demonstrate a new mechanism that osteosarcoma tumor cells derived exosomal-miR-487a which is involved in osteosarcoma development by regulating macrophage polarization in tumor microenvironment (TME).

In this paper, we established two results concerning non-surjective $ (\varepsilon, s) $-isometries of uniformly convex Banach spaces, which extended some known results of Dolinar and Jung.

Abstract Background Social alienation refers to the state of feeling isolated, helpless, and unsatisfied due to maintaining distance from others or avoiding social interaction and activities. This phenomenon is caused by a lack of social skills, social anxiety, physical health problems, and other reasons. Older maintenance hemodialysis patients are exposed to a higher risk of social alienation. However, previous studies have been performed using the total score of the scale, which does not allow the identification of the characteristics of various patient groups with different levels of social alienation. In contrast, latent profile analysis can classify individuals into different categories based on continuous observational indicators, which improves accuracy and provides a more objective assessment by accounting for the uncertainty of variables. Given the concealed nature of social alienation and the differences in characteristics and treatment measures between different profiles, developing a predictive model for social alienation in older maintenance hemodialysis patients holds significance. Objective To explore the latent profile analysis of social alienation in older maintenance hemodialysis patients and to develop and validate a predictive model for social alienation in this population. Methods A total of 350 older maintenance hemodialysis patients were selected as the study subjects using convenience sampling. A cross-sectional survey was conducted using a general information questionnaire, the Generalized Alienation Scale, and the Self-Perceived Burden Scale. Based on the results of the Generalized Alienation Scale, a latent profile analysis was performed, followed by univariate analysis and multinomial logistic regression to develop a predictive model. The effectiveness of the predictive model was evaluated in terms of its authenticity, reliability, and predictive ability. Results Three hundred nineteen valid questionnaires were collected. The social alienation of older maintenance hemodialysis patients based on latent profile analysis were divided into three profiles, which were named the low/medium/high-symptom groups, comprising 21%, 38.9%, and 40.1% of participants, respectively. Based on male, monthly social activity hours, Age-Adjusted Charlson Comorbidity Index, dialysis age, and Self-Perceived Burden Scale, a predictive model of social alienation for older maintenance hemodialysis patients was developed, and the Hosmer–Lemeshow tests showed no statistical significance (P > 0.05). The model has high predictive efficiency in authenticity, reliability and predictability. Conclusion Older maintenance hemodialysis patients exhibited moderate to high levels of social alienation. The latent profile analysis based method was used to divide patients into low/medium/high-symptom profiles, and the predictive model demonstrates excellent authenticity, reliability, and predictability.