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Abstract Ovarian cancer (OV) poses a significant challenge in clinical settings due to its difficulty in early diagnosis and treatment resistance. FOXP4, belonging to the FOXP subfamily, plays a pivotal role in various biological processes including cancer, cell cycle regulation, and embryonic development. However, the specific role and importance of FOXP4 in OV have remained unclear. Our research showed that FOXP4 is highly expressed in OV tissues, with its elevated levels correlating with poor prognosis. We further explored FOXP4’s function through RNA sequencing and functional analysis in FOXP4-deficient cells, revealing its critical role in activating the Wnt signaling pathway. This activation exacerbates the malignant phenotype in OV. Mechanistically, FOXP4 directly induces the expression of protein tyrosine kinase 7 (PTK7), a Wnt-binding receptor tyrosine pseudokinase, which causes abnormal activation of the Wnt signaling pathway. Disrupting the FOXP4-Wnt feedback loop by inactivating the Wnt signaling pathway or reducing FOXP4 expression resulted in the reduction of the malignant phenotype of OV cells, while restoring PTK7 expression reversed this effect. In conclusion, our findings underscore the significance of the FOXP4-induced Wnt pathway activation in OV, suggesting the therapeutic potential of targeting this pathway in OV treatment.

Abstract Background and aims Chronic enteropathy associated with SLCO2A1 gene is a rare intestinal disease caused by loss-of-function SLCO2A1 mutations, with clinical and genetic characteristics remaining largely unknown, especially in Chinese patients. This study aims to reveal clinical and genetic features of Chinese CEAS patients, highlighting the previously unreported or unemphasized characteristics. Methods We enrolled 12 Chinese patients with chronic enteropathy associated with SLCO2A1 gene admitted to Peking Union Medical College Hospital from January 2018 to December 2022. Clinical and genetic data of these patients were collected and analyzed. Results 58.3% of patients were male, who also had primary hypertrophic osteoarthropathy, whereas female patients did not have primary hypertrophic osteoarthropathy. Apart from common symptoms associated with anemia and hypoalbuminemia, abdominal pain, ileus, diarrhea, and hematochezia were present. 4 of the 5 female patients had early-onset amenorrhea, though the causal relationship remained to be clarified. Endoscopy and computed tomography enterography revealed that lesions can occur in any part of the digestive tract, most commonly in the ileum. Pathology showed multiple superficial ulcers with adjacent vascular dilatation, and loss of SLCO2A1 expression, particularly in gastrointestinal vascular endothelial cells. Genetic analysis confirmed SLCO2A1 mutations in all patients and identified 11 new SLCO2A1 variants for CEAS. Conclusions This study reports new clinical, pathological, and genetic findings in 12 Chinese patients with chronic enteropathy associated with SLCO2A1 gene. This study provides insights into the pathogenesis of this disease. However, studies with larger sample sizes and more in-depth mechanism research are still required.

Abstract Background & aims Complications after laparoscopic liver resection (LLR) are important factors affecting the prognosis of patients, especially for complex hepatobiliary diseases. The present study aimed to evaluate the value of a three-dimensional (3D) printed dry-laboratory model in the precise planning of LLR for complex hepatobiliary diseases. Methods Patients with complex hepatobiliary diseases who underwent LLR were preoperatively enrolled, and divided into two groups according to whether using a 3D-printed dry-laboratory model (3D vs. control group). Clinical variables were assessed and complications were graded by the Clavien-Dindo classification. The Comprehensive Complication Index (CCI) scores were calculated and compared for each patient. Multivariable analysis was performed to determine the risk factors of postoperative complications. Results Sixty-two patients with complex hepatobiliary diseases underwent the precise planning of LLR. Among them, thirty-one patients acquired the guidance of a 3D-printed dry-laboratory model, and others were only guided by traditional enhanced CT or MRI. The results showed no significant differences between the two groups in baseline characters. However, compared to the control group, the 3D group had a lower incidence of intraoperative blood loss, as well as postoperative 30-day and major complications, especially bile leakage (all P

Abstract Background Ureteropelvic junction obstruction (UPJO) is the most common cause of pediatric congenital hydronephrosis, and continuous kidney function monitoring plays a role in guiding the treatment of UPJO. In this study, we aimed to explore the differentially expressed proteins (DEPs) in the urinary extracellular vesicles(uEVs) of children with UPJO and determine potential biomarkers of uEVs proteins that reflect kidney function changes. Methods Preoperative urine samples from 6 unilateral UPJO patients were collected and divided into two groups: differential renal function (DRF) ≥ 40% and DRF

Abstract Digital transformation involves fundamental changes in business models, organizational structure, corporate culture, and even the way in which customers interact. Chinese new energy vehicle companies hope to achieve faster response speeds, greater operational efficiency, and better user experiences through digital transformation. Therefore, exploring how to successfully carry out digital transformation and its true impact on enterprise performance is of profound significance. The digital transformation of enterprises requires the embedding and absorption of network relationships to acquire and transform external resources and technologies, which further affects the innovation performance of these enterprises. This article introduces absorptive capacity as a mediating variable and network embeddedness as a moderating variable to construct a theoretical model, attempting to elucidate the mechanism of the impact of digital transformation on enterprise innovation performance. By combining theoretical and empirical analysis, the research hypotheses are tested, and the results show that 1. digital transformation (digital technology, digital products, and digital platforms) has a positive impact on enterprise innovation performance, 2. absorptive capacity plays a significant mediating role in the relationship between digital transformation and enterprise innovation performance, and 3. the embeddedness of network relationships has a significant positive moderating effect on the digital transformation of enterprises and their innovation performance. This article delves into an effective approach involving digital transformation, absorptive capacity, and enterprise innovation performance; analyses the moderating effect of network embeddedness; and concludes that the research findings have implications for the development of related research on digital transformation and enterprise innovation. The timely activities of enterprises to effectively carry out digital transformation, as well as the formulation of relevant policies, have positive significance.

Abstract Because of the water scarcity in many regions, different methods have been implemented to address this problem. The desalination technique is known as a practical solution among them. However, brine from the desalination process, which contains high concentrations of salts, minerals, and chemicals, will cause environmental harm to the sea, soil, and groundwater if it is not properly treated. Therefore, recovering critical resources from brine is essential for reducing brine disposal. This study aims to apply two hydrometallurgy systems, namely ion exchange and ionic liquid extraction, to circulate rubidium resources from brine. Dowex G26 resin was employed in the ion exchange system, and the adsorption isotherm model and saturated adsorption capacity were explored initially. The optimal parameters such as pH value, L/S ratio (liquid/solid), adsorption period, and adsorption temperature will then be investigated. In the ionic liquid extraction process, the t-BAMBP/C2mimNTf2 system (4-tert-Butyl-2-(α-methylbenzyl) phenol/1-ethyl-3-methylimidazolium bis(trifluoromethyls​ulfonyl)​imide) was used, and the parameters including pH value, concentrations of t-BAMBP, (O + I)/A ratio (organic + ionic liquid/aqueous), extraction time, and extraction temperature will be optimized as well. The results reveal that adsorption capacity and extraction efficiencies were 14.3 mg g− 1 and 86%, respectively. Furthermore, suitable reagents, including HCl and HNO3, were applied to desorb and strip rubidium from the Dowex G26 and t-BAMBP/C2mimNTf2 systems. To sum up, environmental hazards of desalination brine and rubidium resources can be reduced and recovered through the two different extraction systems.

Abstract Background Few studies have examined the otologic symptoms of Coronavirus disease 2019 (COVID-19). The objective of this study was to identify the effect of COVID-19 on the characteristics and outcomes of patients who have otitis media with effusion (OME). Methods This case-control study compared the characteristics and outcomes of OME patients who did or did not have COVID-19. A total of 65 patients with previous COVID-19 and 40 patients who did not have COVID-19 (controls) were enrolled from October 1, 2022 to January 31, 2023 at a single institution in China. Demographics, medical histories, morbidities, hearing test results, treatments, and outcomes of the two groups were compared. Results The COVID-19 group had significantly better outcomes from OME than the control group, with higher rates of complete resolution (64.6% vs. 30%) and improvement (30.8% vs. 17.5%), and a lower rate of persistent OME (4.6% vs. 52.5%). Previous COVID-19 was independently associated with a more favorable OME outcome in three multivariate logistic regression models. The COVID-19 group also had a greater improvement in hearing threshold based on air-bone gap measurements. Conclusion The outcomes of OME patients who had previous COVID-19 were generally good, in that most patients responded well to treatment and achieved complete resolution or improvement within one month.

Abstract Biomolecular coacervates are emerging models to understand biological systems and important building blocks for designer applications. DNA can be used to build up programmable coacervates, but often the processes and building blocks to make those are only available to specialists. Here, we report a simple approach for the formation of dynamic, multivalency-driven coacervates using long single-stranded DNA homopolymer in combination with a series of palindromic binders to serve as a synthetic coacervate droplet. We reveal details on how the length and sequence of the multivalent binders influence coacervate formation, how to introduce switching and autonomous behavior in reaction circuits, as well as how to engineer wetting, engulfment and fusion in multi-coacervate system. Our simple-to-use model DNA coacervates enhance the understanding of coacervate dynamics, fusion, phase transition mechanisms, and wetting behavior between coacervates, forming a solid foundation for the development of innovative synthetic and programmable coacervates for fundamental studies and applications.

Abstract Multi-stage reverse electrodialysis (MSRED) offers a promising way for efficient salinity gradient energy harvesting. Here, an improved model of the MSRED system under serial control strategy is proposed. The technical–economic analysis is conducted with considering discount, depreciation and different regional tax and electricity price levels under the maximum net power output conditions. Results reveal that net power output and energy efficiency both increase first with increasing stage numbers, reach their maximum values, and then decrease. For 5 M/0.05 M solutions, the optimal net power output of 4.98 kW is obtained at the stage number n = 12. The optimal stage number corresponding to the maximum net power increases with increasing feed solution concentrations. Due to the compromise between net power generation and capital cost, there exist optimal stage numbers leading to the lowest LCOE and largest NPV, respectively. Higher feed solution concentration can significantly decrease the system LCOE and increase the NPV. The optimal stage number corresponding to the maximum NPV increases with increasing feed solution concentrations. In Germany, for 5 M/0.05 M solutions, the lowest LCOE of 0.061 €·kWh−1 is achieved at n = 3 while the highest NPV over the system lifecycle of 52,005 € is obtained at n = 8. Lower tax, higher electricity price, appropriate membrane price and stage numbers, and high salinity gradient sources can significantly accelerate the commercial completeness of the MSRED systems.

In this work, the blueberry candied syrup was separated and purified by microfiltration combined with macroporous resin technology to recover anthocyanins. Firstly, the macroporous resin was screened through static test. On the basis of single factor and Box-Behnken response surface tests, the flow rate, ethanol concentration and elution flow rate were optimized with anthocyanin recovery rate and total sugar removal rate as indexes in the dynamic test. The result showed that the anthocyanin content and the total sugar content were 6.84 mg/100 mL and 31.76 mg/mL respectively. Among AB-8, D101 and HPD 600 resins, AB-8 was optimized for the purification of anthocyanins from blueberry candied syrup, and the best technological conditions for the purification of anthocyanins by macroporous resin were as follows: The flow rate was 2.0 mL/min, the ethanol concentration was 83%, and the elution flow rate was 2.0 mL/min. Under these conditions, the anthocyanin recovery rate was 86.68%, and the total sugar removal rate was 84.13%. After the anthocyanin desorbing solution was concentrated by rotation evaporation, the concentration of anthocyanin was 5.56 mg/100 mL, and the total sugar concentration was 5.24 mg/mL. The color value of anthocyanins was 31.43, which was about 5 times of the color value of anthocyanins in raw materials. Microfiltration combined with macroporous resin purification of blueberry candied syrup anthocyanin was effective, and this study provides some technical reference for the isolation and purification of blueberry anthocyanin.

To improve the thermal barrier properties of epoxy resin coatings, a composite waterborne aerogel multifunctional coating that possesses both mechanical properties and controllable barrier ability was prepared in this study. This coating incorporates granular silica aerogel, organic montmorillonite, and two flame retardants: aluminum hydroxide (ATH) and magnesium hydroxide (MH). The results showed that montmorillonite, modified with stearyl trimethyl ammonium bromide (STAB), exhibited antisymmetric and symmetric stretching vibrational infrared spectral absorption peaks of –CH3, –CH2, characteristic of the long-chain alkane quaternary ammonium salt. This indicated that the quaternary ammonium salt was intercalated into the montmorillonite interlayer, enhancing the surface lamellae. The coating effectively absorbed energy when stressed, resulting in a strength increase of 146.3%. Incorporating high porosity silica aerogel significantly improved the barrier behavior of the composite coating, enabling controlled thermal insulation and excellent corrosion resistance. The coating reduced heat transfer paths and effectively impeded heat transfer, maintaining a high corrosion inhibition efficiency (99.9%) in a 3.5% NaCl solution. Additionally, the individual actions of the two flame retardants led to highly effective flame retardant properties, with the total heat release rate (THR) reduced by about 43.5% and the total smoke production (TSP) by 40.1%.

Abstract Robot joints are the main structure for controlling the motion of the machine body, where the motion state of them directly affects the performance of the industrial robot. Due to the difficulty of obtaining the joint torque information of industrial robots, it is very hard to monitor the motion state of them. Based on the velocity and force driven by current of motors, we propose a novel Bayesian optimization framework to predict the joint motion state of industrial robot in this paper. Based on the temporal correlation of joint current and the correlation between the current and motion state of joint, we use the LSTM and BiLSTM to regressing prediction of the current and state of joint motor first. Then, the Bayesian optimization method is used to adjust the hyperparameters of our network, which realize the analysis of the joint motor current under different motion states and improve the accuracy of the prediction of joint motion states. Finally, we design the joint current acquisition platform of industrial robot based on Hall current sensors, which can collect joint currents without contact and generate experimental dataset. Comparing with the popular intelligent methods, the results show that our Bayesian optimization framework realizes a more accurate prediction of motion state for the four-axis industrial robot on the basis of contact-less current acquisition.

Here, we successfully synthesized Sr-doped perovskite-type oxides of La1−xSrxCo1−λO3−δ, “LSX” (x = 0, 0.1, 0.3, 0.5, 0.7), using the glycine-assisted solution combustion method. The effect of strontium doping on the catalyst structure, NO to NO2 conversion, NOx adsorption and storage, and NOx reduction performance were investigated. The physicochemical properties of the catalysts were studied by XRD, SEM-EDS, N2 adsorption–desorption, FTIR, H2-TPR, O2-TPD, and XPS techniques. The NSR performance of LaCoO3 perovskite was improved after Sr doping. Specifically, the perovskite with 50% of Sr doping (LS5 sample) exhibited excellent NOx storage capacity within a wide temperature range (200–400 °C), and excellent stability after hydrothermal and sulfur poisoning. It also displayed the highest NOx adsorption–storage capacity (NAC: 1889 μmol/g; NSC: 1048 μmol/g) at 300 °C. This superior performance of the LS5 catalyst can be attributed to its superior reducibility, better NO oxidation capacity, increased surface Co2+ concentration, and, in particular, its generation of more oxygen vacancies. FTIR results further revealed that the LSX catalysts primarily store NOx through the “nitrate route”. During the lean–rich cycle tests, we observed an average NOx conversion rate of over 50% in the temperature range of 200–300 °C, with a maximum conversion rate of 61% achieved at 250 °C.

In the process of deep mining, the temperature of mine water is significantly higher than that of shallow coal seams. The erosion of high-temperature hydrothermal fluids affects the physical and chemical characteristics of coal, which in turn affects its spontaneous combustion process. To study the spontaneous combustion characteristics and influencing mechanisms of coal under the influence of hydrothermal erosion in deep mining, through low-field nuclear magnetic resonance, molecular dynamics simulation, mechanical test and C600 trace heat experiment, the influence of hydrothermal erosion on coal porosity, pore size distribution, mechanical strength and oxidation heat characteristic parameters was analyzed. Combined with correlation analysis, the correlation between various parameters was quantitatively described. The study results show that under the dual influence of thermal stress and swelling, the internal pore structure of hydrothermal eroded coal changes significantly. There is a significant positive correlation between hydrothermal temperature and total porosity of coal, and the correlation coefficient is 0.97. With the increase of hydrothermal temperature, the total porosity of coal increases from 0.24% to 1.35%, the proportion of micropores decreases from more than 69% to less than 60%, and the proportion of mesopores and macropores increases. Coal body pore size significantly affects the oxygen diffusion coefficient, which increases exponentially with a linear increase in coal body pore size. Under the influence of hydrothermal erosion, the development of coal pores and the dissolution of some organic matter significantly reduce the mechanical strength of coal. From raw coal to 80 ℃ hydrothermal eroded coal, the average compressive strength decreases from 23 MPa to 11.6 MPa, which is reduced by 50%. Compared with raw coal, the heat release intensity of hydrothermal erosion coal is higher and the heat release is greater. The heat release of TH40, TH50, TH60, TH70 and TH80 increase by 12.61%, 16.63%, 17.32%, 19.36% and 25.02%, respectively. The correlation coefficient between hydrothermal temperature and coal oxidation heat release is 0.92. Hydrothermal erosion significantly affects the porosity and oxidation process of coal. As the hydrothermal temperature increases, the porosity of the coal body increases, the mechanical strength weakens, the oxygen consumption and oxidation rate of the oxidation process accelerate, and the heat release increases. Hydrothermal erosion coal has a higher risk of spontaneous combustion, and the higher the hydrothermal temperature is, the greater the risk is.

Abstract Background Despite the success of tyrosine kinase inhibitors in chronic myeloid leukemia (CML) therapy, CML still faces the challenges of drug resistance and progression to blast crisis. Twenty‐five percent of patients have imatinib resistance and treatment difficulties due to heterogeneity after progression, but little is known about the mechanism. A key transcription factor in hematopoiesis, MYB, has been reported to increase abnormally in several types of aggressive blood disorders including CML. Methods This study used a zebrafish model to explore the relationship between BCR/ABL1 and c‐myb in CML progression. A CML zebrafish model was crossed with a c‐myb hyperactivity transgenic line. Results It was found that both exogenous BCR/ABL1 and c‐myb could up‐regulate the expression of neutrophil‐related genes. More seriously, neutrophil accumulation was observed when BCR/ABL1 was combined with c‐myb overexpression. Further studies showed that c‐myb may be one of the downstream targets of BCR/ABL1 and the effect of BCR/ABL1 on neutrophils was c‐myb dependent. Taking advantage of this inheritable in vivo model, it was shown that a combination of imatinib and flavopiridol, a cyclin‐dependent kinase inhibitor targeting MYB, could more effectively alleviate the aggressive phenotype of the double transgene line. Conclusion In summary, this study suggests that c‐myb acts downstream of BCR/ABL1 and is involved in CML progression and is therefore a risk factor and a valuable target for the treatment of CML progression. The model used in the study could be helpful in high‐throughput drug screening in CML transformation.

This study compared two different methods, the satellite altimetry-based and DEM (digital elevation model)-based, for estimating lake water volume changes. We focused on 34 lakes in China as the testing sites to compare the two methods for lake water volume changes from 2005 to 2020. The satellite altimetry-based method used water levels provided by the DAHITI (Database for Hydrological Time Series of Inland Waters) data and surface areas derived from Landsat imagery. The DEM-based method used the SRTM DEM data in combination with Landsat-derived lake extents. Our results showed a high degree of consistency in lake water volume changes estimated between the two methods (R2 > 0.90), but each method has its limitations. In terms of temporal coverage, the satellite altimetry-based method with the DAHITI data is limited by missing water level data in certain periods. The performance of the DEM-based method in extracting lake shore boundaries in regions with flat terrains (slope

Antibiotics have been recognized as emerging pollutants due to their ecological and human health risks. This paper aims to enhance the ecological risk assessment (ERA) framework for antibiotics, to illustrate the distribution of these risks across different locations and seasons, and to identify the antibiotics that pose high ecological risk. This paper focuses on 52 antibiotics in seven major basins of China. Relying on the optimized approach of ERA and antibiotic monitoring data published from 2017 to 2021, the results of ERA are presented in multilevel. Across the study area, there are marked variations in the spatial distribution of antibiotics' ecological risks. The Huaihe River Basin, the Haihe River Basin, and the Liaohe River Basin are the top three in the ranking of present ecological risks. The research results also reveal significant differences in temporal variation, underscoring the need for increased attention during certain seasons. Ten antibiotics with high contribution rates to ecological risk are identified, which is an important reference to formulate an antibiotic control list. The multilevel results provided both risk values and their ubiquities across a broad study region, which is a powerful support for developing ecological risk management of antibiotics. HIGHLIGHTS Optimized the calculation method of multilevel ecological risks.; Provided ecological risk spatiotemporal distribution of antibiotics for the seven major river basins of China (2017–2021).; Provided the control priority for the seven major river basins.; Provided the top concerned antibiotics with high contribution to ecological risks of the seven major river basins.;

Abstract Pancreatic cancer is one of the most fatal cancers in the world. A growing number of studies have begun to demonstrate that mitochondria play a key role in tumorigenesis. Our previous study reveals that NDUFS2 (NADH: ubiquinone oxidoreductase core subunit S2), a core subunit of the mitochondrial respiratory chain complex I, is upregulated in Pancreatic adenocarcinoma (PAAD). However, its role in the development of PAAD remains unknown. Here, we showed that NDUFS2 played a critical role in the survival, proliferation and migration of pancreatic cancer cells by inhibiting mitochondrial cell death. Additionally, protein mass spectrometry indicated that the NDUFS2 was interacted with a deubiquitinase, OTUB1. Overexpression of OTUB1 increased NDUFS2 expression at the protein level, while knockdown of OTUB1 restored the effects in vitro. Accordingly, overexpression and knockdown of OTUB1 phenocopied those of NDUFS2 in pancreatic cancer cells, respectively. Mechanically, NDUFS2 was deubiquitinated by OTUB1 via K48-linked polyubiquitin chains, resulted in an elevated protein stability of NDUFS2. Moreover, the growth of OTUB1-overexpressed pancreatic cancer xenograft tumor was promoted in vivo, while the OTUB1-silenced pancreatic cancer xenograft tumor was inhibited in vivo. In conclusion, we revealed that OTUB1 increased the stability of NDUFS2 in PAAD by deubiquitylation and this axis plays a pivotal role in pancreatic cancer tumorigenesis and development.

Abstract Background Vaccination is effective in preventing viral respiratory infectious diseases through protective antibodies and the gut microbiome has been proven to regulate human immunity. This study explores the causal correlations between gut microbial features and serum-specific antiviral immunoglobulin G (IgG) levels. Methods We conduct a two-sample bidirectional Mendelian randomization (MR) analysis using genome-wide association study (GWAS) summary data to explore the causal relationships between 412 gut microbial features and four antiviral IgG (for influenza A, measles, rubella, and mumps) levels. To make the results more reliable, we used four robust methods and performed comprehensive sensitivity analyses. Results The MR analyses revealed 26, 13, 20, and 18 causal associations of the gut microbial features influencing four IgG levels separately. ​Interestingly, ten microbial features, like genus Collinsella, species Bifidobacterium longum, and the biosynthesis of L-alanine have shown the capacity to regulate multiple IgG levels with consistent direction (rise or fall). The ​reverse MR analysis suggested several potential causal associations of IgG levels affecting microbial features. Conclusions The human immune response against viral respiratory infectious diseases could be modulated by changing the abundance of gut microbes, which provided new approaches for the intervention of viral respiratory infections.

Abstract Background Studies have shown that chemotherapy and radiotherapy can cause premature ovarian failure and loss of fertility in female cancer patients. Ovarian cortex cryopreservation is a good choice to preserve female fertility before cancer treatment. Following the remission of the disease, the thawed ovarian tissue can be transplanted back and restore fertility of the patient. However, there is a risk to reintroduce cancer cells in the body and leads to the recurrence of cancer. Given the low success rate of current in vitro culture techniques for obtaining mature oocytes from primordial follicles, an artificial ovary with primordial follicles may be a good way to solve this problem. Methods In the study, we established an artificial ovary model based on the participation of mesenchymal stem cells (MSCs) to evaluate the effect of MSCs on follicular development and oocyte maturation. P2.5 mouse ovaries were digested into single cell suspensions and mixed with bone marrow derived mesenchymal stem cells (BM-MSCs) at a 1:1 ratio. The reconstituted ovarian model was then generated by using phytohemagglutinin. The phenotype and mechanism studies were explored by follicle counting, immunohistochemistry, immunofluorescence, in vitro maturation (IVM), in vitro fertilization (IVF), real-time quantitative polymerase chain reaction (RT-PCR), and Terminal-deoxynucleotidyl transferase mediated nick end labeling(TUNEL) assay. Results Our study found that the addition of BM-MSCs to the reconstituted ovary can enhance the survival of oocytes and promote the growth and development of follicles. After transplanting the reconstituted ovaries under kidney capsules of the recipient mice, we observed normal folliculogenesis and oocyte maturation. Interestingly, we found that BM-MSCs did not contribute to the formation of follicles in ovarian aggregation, nor did they undergo proliferation during follicle growth. Instead, the cells were found to be located around growing follicles in the reconstituted ovary. When theca cells were labeled with CYP17a1, we found some overlapped staining with green fluorescent protein(GFP)-labeled BM-MSCs. The results suggest that BM-MSCs may participate in directing the differentiation of theca layer in the reconstituted ovary. Conclusions The presence of BM-MSCs in the artificial ovary was found to promote the survival of ovarian cells, as well as facilitate follicle formation and development. Since the cells didn’t proliferate in the reconstituted ovary, this discovery suggests a potential new and safe method for the application of MSCs in clinical fertility preservation by enhancing the success rate of cryo-thawed ovarian tissues after transplantation.

Abstract Background Poor nurse-patient relationship poses an obstacle to care delivery, jeopardizing patient experience and patient care outcomes. Measuring nurse-patient relationship is challenging given its multi-dimensional nature and a lack of well-established scales. Purpose This study aimed to develop a multi-dimensional scale measuring nurse-patient relationship in China. Methods A preliminary scale was constructed based on the existing literature and Delphi consultations with 12 nursing experts. The face validity of the scale was tested through a survey of 45 clinical nurses. This was followed by a validation study on 620 clinical nurses. Cronbach’s α, content validity and known-group validity of the scale were assessed. The study sample was further divided into two for Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA), respectively, to assess the construct validity of the scale. Results The Nurse-Patient Relationship Scale (NPRS) containing 23 items was developed and validated, measuring five dimensions: nursing behavior, nurse understanding and respect for patient, patient misunderstanding and mistrust in nurse, communication with patient, and interaction with patient. The Cronbach’s α of the NPRS ranged from 0.725 to 0.932, indicating high internal consistency. The CFA showed excellent fitness of data into the five-factor structure: χ2/df = 2.431, GFI = 0.933, TLI = 0.923, CFI = 0.939, IFI = 0.923, RMSEA = 0.070. Good content and construct validity are demonstrated through expert consensus and psychometric tests. Conclusion The NPRS is a valid tool measuring nurse-patient relationship in China.

Abstract While electrochemical N2 reduction presents a sustainable approach to NH3 synthesis, addressing the emission- and energy-intensive limitations of the Haber-Bosch process, it grapples with challenges in N2 activation and competing with pronounced hydrogen evolution reaction. Here we present a tandem air-NOx-NOx −-NH3 system that combines non-thermal plasma-enabled N2 oxidation with Ni(OH)x/Cu-catalyzed electrochemical NOx − reduction. It delivers a high NH3 yield rate of 3 mmol h−1 cm−2 and a corresponding Faradaic efficiency of 92% at −0.25 V versus reversible hydrogen electrode in batch experiments, outperforming previously reported ones. Furthermore, in a flow mode concurrently operating the non-thermal plasma and the NOx − electrolyzer, a stable NH3 yield rate of approximately 1.25 mmol h−1 cm−2 is sustained over 100 h using pure air as the intake. Mechanistic studies indicate that amorphous Ni(OH)x on Cu interacts with hydrated K+ in the double layer through noncovalent interactions and accelerates the activation of water, enriching adsorbed hydrogen species that can readily react with N-containing intermediates. In situ spectroscopies and density functional theory (DFT) results reveal that NOx − adsorption and their hydrogenation process are optimized over the Ni(OH)x/Cu surface. This work provides new insights into electricity-driven distributed NH3 production using natural air at ambient conditions.

Abstract Background Bone marrow mesenchymal stem cells (BMSCs) can undergo inadequate osteogenesis or excessive adipogenesis as they age due to changes in the bone microenvironment, ultimately resulting in decreased bone density and elevated risk of fractures in senile osteoporosis. This study aims to investigate the effects of osteocyte senescence on the bone microenvironment and its influence on BMSCs during aging. Results Primary osteocytes were isolated from 2-month-old and 16-month-old mice to obtain young osteocyte-derived extracellular vesicles (YO-EVs) and senescent osteocyte-derived EVs (SO-EVs), respectively. YO-EVs were found to significantly increase alkaline phosphatase activity, mineralization deposition, and the expression of osteogenesis-related genes in BMSCs, while SO-EVs promoted BMSC adipogenesis. Neither YO-EVs nor SO-EVs exerted an effect on the osteoclastogenesis of primary macrophages/monocytes. Our constructed transgenic mice, designed to trace osteocyte-derived EV distribution, revealed abundant osteocyte-derived EVs embedded in the bone matrix. Moreover, mature osteoclasts were found to release osteocyte-derived EVs from bone slices, playing a pivotal role in regulating the functions of the surrounding culture medium. Following intravenous injection into young and elderly mouse models, YO-EVs demonstrated a significant enhancement of bone mass and biomechanical strength compared to SO-EVs. Immunostaining of bone sections revealed that YO-EV treatment augmented the number of osteoblasts on the bone surface, while SO-EV treatment promoted adipocyte formation in the bone marrow. Proteomics analysis of YO-EVs and SO-EVs showed that tropomyosin-1 (TPM1) was enriched in YO-EVs, which increased the matrix stiffness of BMSCs, consequently promoting osteogenesis. Specifically, the siRNA-mediated depletion of Tpm1 eliminated pro-osteogenic activity of YO-EVs both in vitro and in vivo. Conclusions Our findings suggested that YO-EVs played a crucial role in maintaining the balance between bone resorption and formation, and their pro-osteogenic activity declining with aging. Therefore, YO-EVs and the delivered TPM1 hold potential as therapeutic targets for senile osteoporosis. Graphical abstract

Abstract Patients with refractory immune thrombocytopenia (ITP) frequently encounter substantial bleeding risks and demonstrate limited responsiveness to existing therapies. Umbilical cord-derived mesenchymal stem cells (UC-MSCs) present a promising alternative, capitalizing on their low immunogenicity and potent immunomodulatory effects for treating diverse autoimmune disorders. This prospective phase I trial enrolled eighteen eligible patients to explore the safety and efficacy of UC-MSCs in treating refractory ITP. The research design included administering UC-MSCs at escalating doses of 0.5 × 106 cells/kg, 1.0 × 106 cells/kg, and 2.0 × 106 cells/kg weekly for four consecutive weeks across three cohorts during the dose-escalation phase, followed by a dose of 2.0 × 106 cells/kg weekly for the dose-expansion phase. Adverse events, platelet counts, and changes in peripheral blood immunity were monitored and recorded throughout the administration and follow-up period. Ultimately, 12 (with an addition of three patients in the 2.0 × 106 cells/kg group due to dose-limiting toxicity) and six patients were enrolled in the dose-escalation and dose-expansion phase, respectively. Thirteen patients (13/18, 72.2%) experienced one or more treatment emergent adverse events. Serious adverse events occurred in four patients (4/18, 22.2%), including gastrointestinal hemorrhage (2/4), profuse menstruation (1/4), and acute myocardial infarction (1/4). The response rates were 41.7% in the dose-escalation phase (5/12, two received 1.0 × 106 cells/kg per week, and three received 2.0 × 106 cells/kg per week) and 50.0% (3/6) in the dose-expansion phase. The overall response rate was 44.4% (8/18) among all enrolled patients. To sum up, UC-MSCs are effective and well tolerated in treating refractory ITP (ClinicalTrials.gov ID: NCT04014166).

By collecting focal mechanism solutions of earthquakes at different depths from Northeast Japan to Northeast China during 1957 to 2022, the joint iterative stress inversion method is used to calculate the tectonic stress field in the subduction zone and the tectonic stress field state in Northeast China. The results show that the shallow area of the Japan trench is not only affected by the subduction and extrusion of the Pacific plate, but also related to the extrusion of the North American plate. The deep source earthquakes in Northeast China are closely related to the long-term action of the trench subduction zone. The formation of the Changbaishan volcanic area has a great relationship with the thrust of the subduction zone. The seismicity of the subduction zone indirectly controls the formation and activity of the volcanic area in Northeast Asia. The principal compressive stress axis distributes in the NEE-SWW direction in the Yingkou area of Liaoning, while the principal tensile stress axis distributes in the NNW-SSE direction. Based on the results of the focal mechanism of shallow earthquakes in the volcanic area and its surrounding areas, it is believed that the current tectonic stress field in the northeastern volcanic area continues the overall structure of stress in the northeastern region, with the principal compressive stress axis in the NEE-SWW direction and the principal tensile stress axis in the NNW-SSE direction.

Objective The data of various monitoring points regarding rail potential as monitoring object is correlated in time and space, and the direct manifestation of changes in rail-to-rebar structural resistance is reflected in rail potential variation. It is aimed to explore a method for monitoring the rail-to-ground insulation state and diagnosing defects based on rail potential spatiotemporal correlation. Method The stray current monitoring system with rail potential as the monitoring object is elaborated. The characteristics of rail potential data under insulation defects are analyzed and a feature matrix for the data is established. Based on the anomaly detection principle of Minkowski distance, the detection steps for abnormal sections of rail-to-ground insulation and for insulation defect locationing are explained. A project in Qingdao Rail Transit is taken as study case for modeling and simulation to evaluate the effectiveness and accuracy of the proposed method. Result & Conclusion The proposed method can effectively monitor the rail insulation state and accurately locate insulation defects.

Shouchenglu is the first monograph on urban defense in ancient China. Based on Shouchenglu, combined with relevant historical documents and image data, this paper sorts out its content, and chooses to explore the internal logic of the evolution of urban defense in the Song Dynasty from three new perspectives: urban defense structure, city walls and their ancillary facilities, and coping strategies for siege weapons. We have carried out graphic translation of the miscellaneous contents of it, and through drawing analysis charts, we can more intuitively show the evolution of the urban defense system in the Song Dynasty and put forward analysis and conjecture. Through the study of Shouchenglu, we found that the evolution of the urban defense system in the Song Dynasty had a clear evolutionary logic. The evolution of the urban defense system in the Song Dynasty was not only the progress of architectural technology, but also the improvement of adaptability in the face of various complex situations. We believe that our research results have certain reference significance for the future urban excavation and the protection and restoration of historical heritage in the Song Dynasty.

Abstract During the development of the vertebrate nervous system, 50% of the nerve cells undergo apoptosis shortly after formation. This process is important for sculpting tissue during morphogenesis and removing transiently functional cells that are no longer needed, ensuring the appropriate number of neurons in each region. Dysregulation of neuronal apoptosis can lead to neurodegenerative diseases. However, the molecular events involved in activating and regulating the neuronal apoptosis program are not fully understood. In this study, we identified several RB1 mutations in patients with neurodegenerative diseases. Then, we used a zebrafish model to investigate the role of Rb1 in neuronal apoptosis. We showed that Rb1-deficient mutants exhibit a significant hindbrain neuronal apoptosis, resulting in increased microglia infiltration. We further revealed that the apoptotic neurons in Rb1-deficient zebrafish were post-mitotic neurons, and Rb1 inhibits the apoptosis of these neurons by regulating bcl2/caspase through binding to Kmt5b. Moreover, using this zebrafish mutant, we verified the pathogenicity of the R621S and L819V mutations of human RB1 in neuronal apoptosis. Collectively, our data indicate that the Rb1-Kmt5b-caspase/bcl2 axis is crucial for protecting post-mitotic neurons from apoptosis and provides an explanation for the pathogenesis of clinically relevant mutations.

Abstract Objective This study aims to analyze the molecular characteristics of the novel coronavirus (SARS-CoV-2) Omicron variant BA.2.76 in Jining City, China. Methods Whole-genome sequencing was performed on 87 cases of SARS-CoV-2 infection. Evolutionary trees were constructed using bioinformatics software to analyze sequence homology, variant sites, N-glycosylation sites, and phosphorylation sites. Results All 87 SARS-CoV-2 whole-genome sequences were classified under the evolutionary branch of the Omicron variant BA.2.76. Their similarity to the reference strain Wuhan-Hu-1 ranged from 99.72 to 99.74%. In comparison to the reference strain Wuhan-Hu-1, the 87 sequences exhibited 77–84 nucleotide differences and 27 nucleotide deletions. A total of 69 amino acid variant sites, 9 amino acid deletions, and 1 stop codon mutation were identified across 18 proteins. Among them, the spike (S) protein exhibited the highest number of variant sites, and the ORF8 protein showed a Q27 stop mutation. Multiple proteins displayed variations in glycosylation and phosphorylation sites. Conclusion SARS-CoV-2 continues to evolve, giving rise to new strains with enhanced transmission, stronger immune evasion capabilities, and reduced pathogenicity. The application of high-throughput sequencing technologies in the epidemic prevention and control of COVID-19 provides crucial insights into the evolutionary and variant characteristics of the virus at the genomic level, thereby holding significant implications for the prevention and control of the COVID-19 pandemic.

Abstract Background Exposure to extreme cold or heat temperature is one leading cause of weather-associated mortality and morbidity in animals. Emerging studies demonstrate that the microbiota residing in guts act as an integral factor required to modulate host tolerance to cold or heat exposure, but common and unique patterns of animal-temperature associations between cold and heat have not been simultaneously examined. Therefore, we attempted to investigate the roles of gut microbiota in modulating tolerance to cold or heat exposure in mice. Results The results showed that both cold and heat acutely change the body temperature of mice, but mice efficiently maintain their body temperature at conditions of chronic extreme temperatures. Mice adapt to extreme temperatures by adjusting body weight gain, food intake and energy harvest. Fascinatingly, 16 S rRNA sequencing shows that extreme temperatures result in a differential shift in the gut microbiota. Moreover, transplantation of the extreme-temperature microbiota is sufficient to enhance host tolerance to cold and heat, respectively. Metagenomic sequencing shows that the microbiota assists their hosts in resisting extreme temperatures through regulating the host insulin pathway. Conclusions Our findings highlight that the microbiota is a key factor orchestrating the overall energy homeostasis under extreme temperatures, providing an insight into the interaction and coevolution of hosts and gut microbiota.

Abstract Isochlorate dehydrogenase 1 (IDH1) is an important metabolic enzyme for the production of α-ketoglutarate (α-KG), which has antitumor effects and is considered to have potential antitumor effects. The activation of IDH1 as a pathway for the development of anticancer drugs has not been attempted. We demonstrated that IDH1 can limit glycolysis in hepatocellular carcinoma (HCC) cells to activate the tumor immune microenvironment. In addition, through proteomic microarray analysis, we identified a natural small molecule, scutellarin (Scu), which activates IDH1 and inhibits the growth of HCC cells. By selectively modifying Cys297, Scu promotes IDH1 active dimer formation and increases α-KG production, leading to ubiquitination and degradation of HIF1a. The loss of HIF1a further leads to the inhibition of glycolysis in HCC cells. The activation of IDH1 by Scu can significantly increase the level of α-KG in tumor tissue, downregulate the HIF1a signaling pathway, and activate the tumor immune microenvironment in vivo. This study demonstrated the inhibitory effect of IDH1–α-KG–HIF1a on the growth of HCC cells and evaluated the inhibitory effect of Scu, the first IDH1 small molecule agonist, which provides a reference for cancer immunotherapy involving activated IDH1.

Objective To explore the correlation between markers of tubular injury, 24 h urine protein quantification (24 hUTP) and albumin creatinine ratio (ACR) in patients with diabetic kidney disease (DKD) and explore the relationship between tubular and glomerular injuries to provide guidance for clinical management of DKD. Methods From November 1, 2019 to December 31, 118 proteinuric patients with a definite diagnosis of DKD at outpatient clinic and ward were recruited. And 24 hUTP, ACR, blood creatinine, urinary N-acety1-β-D-glucosaminidase, alpha 1 microglobulin, retinol-binding protein and kidney injury molecule-1 were measured and estimated glomerular filtration rate (eGFR) calculated by the CKD-EPI formula. Linear correlation analysis was utilized for examining the correlation between markers of proximal tubular injury, tubular reabsorption function and 24 hUTP and ACR. Results 24 hUTP at (0.5-3.5) g/24 h, urinary N-acety1-β-D-glucosaminidase, kidney injury molecule-1, alpha 1 microglobulin, retinol-binding protein were correlated linearly with 24 hUTP. The correlation coefficients (adjusted R2) were 0.192, 0.079, 0.054 and 0.040 respectively. Proximal renal tubular injury markers had the highest correlation with 24 hUTP. Urinary N-acety1-β-D-glucosaminidase, kidney injury molecule-1, alpha 1 microglobulin and retinol-binding protein were correlated linearly with ACR. The correlation coefficients (adjusted R2) were 0.367, 0.058, 0.077 and 0.076 respectively with the best correlation between proximal tubular injury markers and ACR. Conclusions In DKD patients, renal tubular injury markers are correlated linearly with 24 hUTP and ACR. Proximal tubular injury markers have the best correlations with 24 hUTP and ACR. Renal tubular injury is correlated closely with the progression of DKD.

Abstract Background To compare the outcomes of hypospadias repair using tubularized incised plate (TIP) urethroplasty and modified TIP with lateral skin to widen the urethral plate (WTIP). Materials and methods Data were obtained from pre-pubertal boys who underwent primary hypospadias repair between May 2018 and July 2023. The cases were divided into two groups; one group underwent TIP with urethral plate ≥ 6 mm width and the other group with urethral plate width

Abstract Background Obesity and hypertension are major risk factors for cardiovascular diseases that affect millions of people worldwide. Both conditions are associated with chronic low-grade inflammation, which is mediated by adipokines such as adiponectin. Adiponectin is the most abundant adipokine that has a beneficial impact on metabolic and vascular biology, while high serum concentrations are associated with some syndromes. This “adiponectin paradox” still needs to be clarified in obesity-associated hypertension. The aim of this study was to investigate how adiponectin affects blood pressure, inflammation, and metabolic function in obesity hypertension using a Chinese adult case-control study. Methods A case-control study that had finished recruiting 153 subjects divided as four characteristic groups. Adiponectin serum levels were tested by ELISA in these subjects among these four characteristic Chinese adult physical examination groups. Waist circumference (WC), body mass index (BMI), systolic blood pressure (SB), diastolic blood pressure (DB), and other clinical laboratory data were collected. Analyzation of correlations between the research index and differences between groups was done by SPSS. Results Serum adiponectin levels in the| normal healthy group (NH group) were significantly higher than those in the newly diagnosed untreated just-obesity group (JO group), and negatively correlated with the visceral adiposity index. With multiple linear egression analysis, it was found that, for serum adiponectin, gender, serum albumin (ALB), alanine aminotransferase (ALT) and high-density lipoprotein cholesterol (HDLC) were the significant independent correlates, and for SB, age and HDLC were the significant independent correlates, and for DB, alkaline phosphatase (ALP) was the significant independent correlate. The other variables did not reach significance in the model. Conclusions Our study reveals that adiponectin’s role in obesity-hypertension is multifaceted and is influenced by the systemic metabolic homeostasis signaling axis. In obesity-related hypertension, compensatory effects, adiponectin resistance, and reduced adiponectin clearance from impaired kidneys and liver all contribute to the “adiponectin paradox”.

Abstract Investigations of one-dimensional segmented heteronanostructures (1D-SHs) have recently attracted much attention due to their potentials for applications resulting from their structure and synergistic effects between compositions and interfaces. Unfortunately, developing a simple, versatile and controlled synthetic method to fabricate 1D-SHs is still a challenge. Here we demonstrate a stress-induced axial ordering mechanism to describe the synthesis of 1D-SHs by a general under-stoichiometric reaction strategy. Using the continuum phase-field simulations, we elaborate a three-stage evolution process of the regular segment alternations. This strategy, accompanied by easy chemical post-transformations, enables to synthesize 25 1D-SHs, including 17 nanowire-nanowire and 8 nanowire-nanotube nanostructures with 13 elements (Ag, Te, Cu, Pt, Pb, Cd, Sb, Se, Bi, Rh, Ir, Ru, Zn) involved. This ordering evolution-driven synthesis will help to investigate the ordering reconstruction and potential applications of 1D-SHs.

Abstract Background For knee osteoarthritis patients, analyzing alignment of lower limbs is essential for therapy, which is currently measured from standing long-leg radiographs of anteroposterior X-ray (LLR) manually. To address the time wasting, poor reproducibility and inconvenience of use caused by existing methods, we present an automated measurement model in portable devices for assessing knee alignment from LLRs. Method We created a model and trained it with 837 conforming LLRs, and tested it using 204 LLRs without duplicates in a portable device. Both manual and model measurements were conducted independently, then we recorded knee alignment parameters such as Hip knee ankle angle (HKA), Joint line convergence angle (JCLA), Anatomical mechanical angle (AMA), mechanical Lateral distal femoral angle (mLDFA), mechanical Medial proximal tibial angle (mMPTA), and the time required. We evaluated the model’s performance compared with manual results in various metrics. Result In both the validation and test sets, the average mean radial errors were 2.778 and 2.447 (P0.05). Furthermore, the Bland-Altman 95% limits of agreement were less than ± 2° for HKA, JCLA, AMA, and mLDFA, and slightly more than ± 2 degrees for mMPTA. Conclusion The automatic measurement tool can assess the alignment of lower limbs in portable devices for knee osteoarthritis patients. The results are reliable, reproducible, and time-saving.

Abstract Background Idiopathic pulmonary fibrosis is a persistent disease of the lung interstitium for which there is no efficacious pharmacological therapy. Protodioscin, a steroidal saponin, possesses diverse pharmacological properties; however, its function in pulmonary fibrosis is yet to be established. Hence, in this investigation, it was attempted to figure out the anti-pulmonary fibrosis influences of protodioscin and its pharmacological properties related to oxidative stress. Methods A mouse lung fibrosis model was generated using tracheal injections of bleomycin, followed by intraperitoneal injection of different concentrations of protodioscin, and the levels of oxidative stress and fibrosis were detected in the lungs. Multiple fibroblasts were treated with TGF-β to induce their transition to myofibroblasts. It was attempted to quantify myofibroblast markers’ expression levels and reactive oxygen species levels as well as Nrf2 activation after co-incubation of TGF-β with fibroblasts and different concentrations of protodioscin. The influence of protodioscin on the expression and phosphorylation of p62, which is associated with Nrf2 activation, were detected, and p62 related genes were predicted by STRING database. The effects of Nrf2 inhibitor or silencing of the Nrf2, p62 and NBR1 genes, respectively, on the activation of Nrf2 by protodioscin were examined. The associations between p62, NBR1, and Keap1 in the activation of Nrf2 by protodioscin was demonstrated using a co-IP assay. Nrf2 inhibitor were used when protodioscin was treated in mice with pulmonary fibrosis and lung tissue fibrosis and oxidative stress levels were detected. Results In vivo, protodioscin decreased the levels of fibrosis markers and oxidative stress markers and activated Nrf2 in mice with pulmonary fibrosis, and these effects were inhibited by Nrf2 inhibitor. In vitro, protodioscin decreased the levels of myofibroblast markers and oxidative stress markers during myofibroblast transition and promoted Nrf2 downstream gene expression, with reversal of these effects after Nrf2, p62 and NBR1 genes were silenced or Nrf2 inhibitors were used, respectively. Protodioscin promoted the binding of NBR1 to p62 and Keap1, thereby reducing Keap1-Nrf2 binding. Conclusion The NBR1-p62-Nrf2 axis is targeted by protodioscin to reduce oxidative stress and inhibit pulmonary fibrosis. Graphical Abstract

Abstract Background Malnutrition is not uncommon among the elderly undergoing pancreatoduodenectomy (PD) and is related to increased complications. Previous studies have shown that the Geriatric Nutritional Risk Index (GNRI) predicts outcomes in various populations. Nevertheless, the research exploring the correlation between GNRI and postoperative outcomes in PD is scarce. This study aimed to investigate the preoperative malnutrition, as measured by GNRI, on outcomes in elderly patients undergoing PD. Materials and Methods This retrospective analysis enrolled 144 elderly patients underwent PD for periampullary tumors from November 2016 to December 2021. Patients were stratified based on the GNRI value: high/moderate nutrition risk (GNRI ≤ 92, N = 54), low nutrition risk (92 98, N = 55). Perioperative outcomes and postoperative surgical complications were compared between these groups. Univariate and multivariate analyses were performed on major postoperative complications and prolonged postoperative length of stay (PLOS). Results Patients in the high/moderate risk group were significantly older, with lower BMI (P = 0.012), higher mortality rate (11.1%, P = 0.024), longer PLOS (P

Abstract Glaesserella parasuis, an important respiratory bacterial pathogen, causes Glässer’s disease in piglets, with potential immunosuppression. We established a piglet infection model and explored the immunosuppression mechanism to improve our understanding of the host immune response to G. parasuis. Twenty piglets were randomly divided into two groups (n = 10). The infection group was intraperitoneally challenged with 2 × 108 CFU of G. parasuis in 2 mL TSB. The control group was intraperitoneally injected with equivalent TSB. After 72 h, the piglets were sacrificed, and spleen tissue was collected. PD-1/PD-L1 expression was determined. The splenocytes were isolated to detect CD3+ T, CD3+CD4+ T, CD3+CD8+ T and CD3−CD21+cell differentiation. Via data-independent acquisition (DIA), we compared the proteomics of healthy and infected spleen tissues. Glaesserella parasuis modified CD3+ T, CD3+CD4+ T, CD3+CD8+ T and CD3−CD21+ cell differentiation and PD-1/PD-L1 expression in the spleen. The infection group had 596 proteins with significant differences in expression, of which 301 were significantly upregulated and 295 downregulated. Differentially expressed proteins (DEPs) were mainly related to immune responses. This is the first study on PD-1/PD-L1 expression in the spleen associated with immunosuppression in a piglet model to explore the protein changes related to immune responses via DIA.

Abstract Cold-induced injuries severely limit opportunities and outcomes of hypothermic therapies and organ preservation, calling for better understanding of cold adaptation. Here, by surveying cold-altered chromatin accessibility and integrated CUT&Tag/RNA-seq analyses in human stem cells, we reveal forkhead box O1 (FOXO1) as a key transcription factor for autonomous cold adaptation. Accordingly, we find a nonconventional, temperature-sensitive FOXO1 transport mechanism involving the nuclear pore complex protein RANBP2, SUMO-modification of transporter proteins Importin-7 and Exportin-1, and a SUMO-interacting motif on FOXO1. Our conclusions are supported by cold survival experiments with human cell models and zebrafish larvae. Promoting FOXO1 nuclear entry by the Exportin-1 inhibitor KPT-330 enhances cold tolerance in pre-diabetic obese mice, and greatly prolongs the shelf-life of human and mouse pancreatic tissues and islets. Transplantation of mouse islets cold-stored for 14 days reestablishes normoglycemia in diabetic mice. Our findings uncover a regulatory network and potential therapeutic targets to boost spontaneous cold adaptation.

Abstract Ten-eleven translocation (TET) 2 is an enzyme that catalyzes DNA demethylation to regulate gene expression by oxidizing 5-methylcytosine to 5-hydroxymethylcytosine, functioning as an essential epigenetic regulator in various biological processes. However, the regulation and function of TET2 in adipocytes during obesity are poorly understood. In this study, we demonstrate that leptin, a key adipokine in mammalian energy homeostasis regulation, suppresses adipocyte TET2 levels via JAK2-STAT3 signaling. Adipocyte Tet2 deficiency protects against high-fat diet-induced weight gain by reducing leptin levels and further improving leptin sensitivity in obese male mice. By interacting with C/EBPα, adipocyte TET2 increases the hydroxymethylcytosine levels of the leptin gene promoter, thereby promoting leptin gene expression. A decrease in adipose TET2 is associated with obesity-related hyperleptinemia in humans. Inhibition of TET2 suppresses the production of leptin in mature human adipocytes. Our findings support the existence of a negative feedback loop between TET2 and leptin in adipocytes and reveal a compensatory mechanism for the body to counteract the metabolic dysfunction caused by obesity.

Abstract Background Rosai-Dorfman Disease (RDD) is a rare self-limiting histiocytosis, more prevalent in children and young adults. It typically manifests as painless bilateral massive cervical lymphadenopathy but may also extend to extra-nodal sites, with intrathoracic RDD noted in 2% of cases. Distinguishing mediastinal RDD from thymoma on imaging poses challenges, underscoring the reliance on pathological features and immunohistochemical staining for diagnosis. Case presentation Patient, male, 33 years old, underwent lung a CT revealing an enlarged round soft tissue shadow in the anterior superior mediastinum, compared to a year ago. Surgical resection removed the entire mass, thymus, and part of the pericardium, confirming RDD on pathology. Genetic testing using second-generation testing technology identified a KRAS gene point mutation. Conclusions No established treatment protocol currently exists for this disease. However, as genetic mutation research progresses, a novel therapeutic avenue is emerging: targeted therapy integrated with surgical interventions.

Objective Closed reduction of pelvic injuries is a prerequisite and critical step in minimally invasive treatment. Achieving non‐invasive closed reduction of pelvic injuries is a challenging clinical problem. This study demonstrated a non‐invasive traction technique for closed reduction called countertraction closed reduction technique (CCRT) and evaluated its effectiveness for type C pelvic ring injuries. Method The data of patients with unstable pelvic fractures treated with CCRT and minimally invasive fixation were retrospectively reviewed from January 2017 to February 2022. Sacroiliac screws were placed to fix the posterior pelvic ring, and internal or external fixation was used to fix the anterior pelvic ring. Operation time, intraoperative blood loss, duration of hospital stay, fracture union and postoperative complications were recorded. Fracture reduction quality was evaluated using the Matta scoring criteria. Functional recovery and general quality of life were evaluated using the Majeed functional scoring criteria. Results Thirteen patients (nine males and four females), with an average age of 49.6 years were treated with CCRT and followed up for a mean of 18.5 months. The average operation time was 137.2 minutes (range 92–195 minutes), the average intraoperative blood loss was 31.2 mL (range 10–120 mL) and the average duration of hospital stay was 14.3 days (range 4–32 days). All patients achieved bony union with an average union time of 11.9 weeks (range 10–16 weeks). According to the Matta radiographic criteria, the quality of fracture reduction was excellent in eight patients, good in four, and fair in one. The average Majeed functional score was 89.7 (range 78–100). The functional evaluation revealed that the outcomes were excellent in nine patients, and good in four patients. Complications included incision fat liquefaction in one patient, and heterotopic ossification in another patient. There were no surgical complications as a result of CCRT. Conclusion CCRT is a non‐invasive closed reduction method for minimally invasive fixation of fresh Tile C1 and C2 pelvic fractures. The advantages of CCRT combined with minimally invasive treatment include a small surgical incision, reduced intraoperative bleeding, satisfactory fracture reduction, bone healing and functional recovery.

To realize an initial objective of the negative ion-based neutral beam injection (N-NBI) at the Comprehensive Research Facility for Fusion Technology (CRAFT) test facility, which targets an H0 beam power of 2 MW at an energy of 200–400 keV and a pulse duration of 100 s, it is crucial to study the cesium dynamics of the negative ion source. Here a numerical simulation program CSFC3D is developed and applied to simulate the distribution and time dynamics of cesium during short pulses. The calculations show that most of the cesium on the plasma grid (PG) area originates from the release of cesium that is accumulated within the ion source in the plasma phase. Increasing the wall temperature reduces the loss of cesium on the wall of the ion source. Furthermore, the thickness of the cesium monolayer is directly influenced by the PG temperature. Both simulated and experimental results demonstrate that maintaining the PG temperature between 180 °C and 200 °C is essential for enhancing the performance of the ion source and optimizing the cesium behavior.

BackgroundOn April 18, 2024, the U.S. Food and Drug Administration officially required updating of the “boxed warning” for T cell malignancies for all chimeric antigen receptor T cell (CAR-T) therapies. Given the clinical significance of these therapies, a rigorous safety assessment is paramount. However, comprehensive real-world safety studies have been lacking for the newly marketed CAR-T products idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), which target B cell maturation antigen, especially regarding the risk of secondary malignancies. Therefore, we aimed to thoroughly analyze the adverse events (AEs) information in the FDA Adverse Event Reporting System (FAERS) database to comprehensively understand the safety risks of ide-cel and cilta-cel.MethodsWe extracted AE reports related to ide-cel and cilta-cel from the FAERS database (https://fis.fda.gov/extensions/FPD-QDE-FAERS/FPD-QDE-FAERS.html.) from January 1, 2019 to December 31, 2023. Disproportionality analysis and Bayesian analysis were used to identify risk signals across subgroups and specific cases (including for death and secondary malignancies). Weibull distribution analysis was employed to determine the time to AE onset.ResultsA total of 695 AE reports for ide-cel and 848 for cilta-cel were included in the FAERS database. This analysis identified 81 positive signals for ide-cel and 74 for cilta-cel. Notably, comparisons with the drug labels revealed “unexpected signals,” including febrile bone marrow aplasia (reporting odds ratio=69.10; confidence interval 39.12–122.03) and plasma cell myeloma (12.45; 8.18–18.95) for ide-cel, and increased serum ferritin (24.98; 8.0–77.58) and large intestine perforation (18.57; 5.98–57.69) for cilta-cel. Both drugs showed a higher AE incidence among male recipients and patients aged ≥65 years, although female recipients faced a greater risk. Most AEs occurred at the early stage of administration. However, secondary malignancies were detected for both drugs, primarily occurring one-year post-administration.ConclusionThis study provides a foundation for understanding the safety profile of CAR-T cell therapy, particularly in relation to the emergence of secondary malignancies. Such insights are helpful for clinical decision-making and the safe and effective utilization of these therapeutic agents.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer and ranks as the third leading cause of cancer-related mortality globally. The liver performs a wide range of tasks and is the primary organ responsible for metabolizing harmful substances and foreign compounds. Oxidative stress has a crucial role in growth and improvement of hepatocellular carcinoma (HCC). Nuclear factor erythroid 2 (1)-related factor 2 (Nrf2) is an element that regulates transcription located in the cytoplasm. It controls the balance of redox reactions by stimulating the expression of many genes that depend on antioxidant response elements. Nrf2 has contrasting functions in the normal, healthy liver and HCC. In the normal liver, Nrf2 provides advantageous benefits, while in HCC it promotes harmful effects that support the growth and survival of HCC. Continuous activation of Nrf2 has been detected in HCC and promotes its advancement and aggressiveness. In addition, Activation of Nrf2 may lead to immune evasion, weakening the immune cells’ ability to attack tumors and thereby promoting tumor development. Furthermore, chemoresistance in HCC, which is considered a form of stress response to chemotherapy medications, significantly impedes the effectiveness of HCC treatment. Stress management is typically accomplished by activating specific signal pathways and chemical variables. One important element in the creation of chemoresistance in HCC is nuclear factor-E2-related factor 2 (Nrf2). Nrf2 is a transcription factor that regulates the activation and production of a group of genes that encode proteins responsible for protecting cells from damage. This occurs through the Nrf2/ARE pathway, which is a crucial mechanism for combating oxidative stress within cells.

BackgroundSystemic immune-inflammatory markers combine various individual inflammatory cell parameters to comprehensively explore their relationship with the development and long-term outcomes of cardiovascular, cerebrovascular, and oncological disorders. The systemic immune-inflammatory marker index has not been extensively studied in terms of its impact on the long-term prognosis following cerebral revascularization in MMD patients. Our research aims to address this gap and improve the prediction of long-term outcomes for these patients.MethodsWe included 851 patients with Moyamoya disease who underwent cerebral revascularization at our medical center from 2009 to 2021. Systemic immune-inflammatory markers were calculated based on routine blood test results at admission, and follow-up was conducted for over 6 months after surgery. During monitoring and upon release, we evaluated patient neurological condition by utilizing the modified Rankin Scale (mRS). We examined the correlation between alterations in mRS ratings and systemic immune-inflammatory markers.ResultsComparing the unfavorable long-term prognosis group to the favorable long-term prognosis group, it was found that the NLR level was markedly higher (p = 0.037), while the LMR was lower in the unfavorable long-term prognosis group (p = 0.004). Results from logistic regression analysis revealed that the high-level LMR group had a lower risk of unfavorable long-term prognosis compared to the low-level group (T3: OR = 0.433, 95% CI [0.204–0.859], p = 0.026). The AUC of the model was 0.750 (95% CI [0.693–0.806]).ConclusionLymphocyte-to-monocyte ratio levels are independently linked to an increased risk of unfavorable long-term prognosis, highlighting LMR as a new and effective predictor for postoperative Moyamoya patients.

Summary: Stapokibart (CM310) is a humanized IL-4Rα monoclonal antibody currently undergoing phase 3 trials for type 2 inflammatory diseases. In contrast to dupilumab, which bound exclusively to human IL-4Rα, stapokibart demonstrated cross-species reactivity to IL-4Rα from human, cynomolgus monkey, and rat. Stapokibart exhibited comparable blocking activity to dupilumab. Epitope mapping revealed that stapokibart bound to distinct sites on IL-4Rα compared to dupilumab. In vitro assays showed that stapokibart was comparable or numerically superior in blocking IL-4Rα-mediated signaling compared to dupilumab. In vivo studies further demonstrated that stapokibart effectively inhibited the progression of type 2 inflammation. Pharmacokinetic studies revealed a circulating half-life of approximately 298–351 h in cynomolgus monkeys and 55–142 h in rats for stapokibart. Toxicity studies indicated a favorable safety profile in cynomolgus monkeys and rats. The preclinical evaluation of stapokibart supports its clinical development.

Background: Myokines play vital roles in both stable coronary artery disease (SCAD) and depression. Meanwhile, there is a pressing necessity to find effective biomarkers for early predictor of major adverse cardiovascular events (MACE) in SCAD patients with depressive symptoms. Methods: A single-center, 5-year follow-up study was investigated. MACE was defined as composite end points, including cardiovascular death, non-fatal stroke, non-fatal myocardial infarction, coronary artery revascularization, or hospitalization for unstable angina. Results: A total of 116 SCAD patients were enrolled, consisting of 30 cases (25.9%) without depressive symptoms and 86 cases (74.1%) with depressive symptoms. During the follow-up, 3 patients (2.6%) were lost. Out of 113 patients, 51 (45.1%) experienced MACE. In the subgroup of 84 SCAD patients with depressive symptoms, 44 cases (52.4%) of MACE were observed. Finally, mature brain-derived neurotrophic factor (mBDNF), pro-brain-derived neurotrophic factor, receptor activator of nuclear factor-κB ligand, smoking history, hypertension and cystatin C were incorporated into the predictive model. Conclusions: Depressive symptoms represent an independent risk factor for MACE in patients with SCAD. Additionally, low mBDNF expression may be an important early predictor for MACE in SCAD patients with depressive symptoms. The predictive model may exhibit a commendable predictive performance for MACE in SCAD patients with depressive symptoms.