Corrigendum: Bioinformatic analysis of related immune cell infiltration and key genes in the progression of osteonecrosis of the femoral head.

[This corrects the article DOI: 10.3389/fimmu.2023.1340446.].

Robot-assisted total knee arthroplasty system provides more precise control of the femoral rotation angle: A retrospective study.

BACKGROUND: Rotational alignment in total knee arthroplasty (TKA) is a crucial technical point that needs attention. We conducted a retrospective study to investigate whether a new robot-assisted TKA (RA-TKA) could improve the accuracy of rotational alignment and whether rotational alignment affects postoperative pain and functional evaluation of the knee. METHODS: A total of 136 consecutive patients who underwent TKA were included in this study. Half of the patients underwent RA-TKA and the other half underwent conventional TKA (CON-TKA) by the same group of surgeons. Collect the relevant parameters. RESULTS: The postoperative femoral rotation angle (FRA) was -0.72 ± 2.59° in the robot-assisted group and 1.13 ± 2.73° in the conventional group, and were statistically significantly different (p < 0.001). CONCLUSION: This study provides preliminary evidence that the RA-TKA provides more precise control of FRA than CON-TKA, and verifies that tibial rotation angle and combined rotation angle affect postoperative knee pain and functional evaluation.

Dehydroandrographolide alleviates rheumatoid arthritis by inhibiting neutrophil activation via LMIR3 in collagen induced arthritis rats.

Rheumatoid arthritis (RA) is an inflammatory disease which causes severe pain and disability. Neutrophils play essential roles in the onset and progression of RA; thus, inhibition of neutrophil activation is becoming a popular therapeutic strategy. Dehydroandrographolide has provided satisfactory outcomes in inflammatory diseases; however, its therapeutic effects and mechanism in RA are not fully understood. Leukocyte mono-immunoglobulin-like receptor 3 (LMIR3) is a negative regulator highly expressed in neutrophils. To determine whether dehydroandrographolide negatively regulated neutrophils activation via LMIR3, cytokines release and collagen-induced arthritis (CIA) rats were used in vitro and in vivo. Biacore, molecular docking analysis and molecular dynamics simulation were performed to prove the target of dehydroandrographolide. Moreover, the downstream signaling pathways of LMIR3 activation were analyzed by western blotting. Results showed that oral dehydroandrographolide administration of 2 mg/kg/day to CIA rats attenuated synovitis and bone and cartilage damage after the 28-day intervention, revealed using HE sections and micro-CT. Dehydroandrographolide significantly inhibited cytokine release and chemotaxis of LPS/TNF-α-activated neutrophils in vitro. Dehydroandrographolide inhibited neutrophils activation via binding to LMIR3. Moreover, dehydroandrographolide up-regulated the phosphorylation of SHP-1 and SHP-2, which are the essential kinases in the LMIR3 signaling pathways. This study revealed that dehydroandrographolide attenuated collagen-induced arthritis by suppressing neutrophil activation via LMIR3.

[Melatonin promotes osteogenesis of bone marrow mesenchymal stem cells by improving the inflammatory state in ovariectomized rats].

Objective: To investigate the effects of melatonin (MT) on bone mass and serum inflammatory factors in rats received ovariectomy (OVX) and to investigate the effects of MT on the levels of inflammatory factors in culture medium and osteogenic ability of bone marrow mesenchymal stem cells (BMSCs) stimulated by lipopolysaccharide. Methods: Fifteen 12-week-old Sprague Dawley (SD) rats were randomly divided into 3 groups. The rats in Sham group only received bilateral lateral abdominal incision and suture, the rats in OVX group received bilateral OVX, and the rats in OVX+MT group received 100 mg/(kg·d) MT oral intervention after bilateral OVX. After 8 weeks, the levels of serum inflammatory factors [interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor α (TNF-α)] were detected using ELISA assay. Besides, the distal femurs were detected by Micro-CT to observe changes in bone mass and microstructure, and quantitatively measured bone volume fraction, trabecular thickness, and trabecular number. The BMSCs were extracted from the femurs of three 3-week-old SD rats using whole bone marrow culture method and passaged. The 3rd-5th passage BMSCs were cultured with different concentrations of MT (0, 1, 10, 100, 1 000 µmol/L), and the cell viability was then detected using cell counting kit 8 (CCK-8) to select the optimal concentration of MT for subsequent experiments. Cells were devided into osteogenic induction group (group A) and osteogenic induction+1/5/10 µg/mL lipopolysaccharide group (group B-D). The levels of inflammatory factors (IL-1ß, IL-6 and TNF-α) in cell culture medium were detected using ELISA assay after corresponding intervention. According to the results of CCK-8 method and ELISA detection, the cells were intervened with the most significant concentration of lipopolysaccharide for stimulating inflammation and the optimal concentration of MT with osteogenic induction, defining as group E, and the cell culture medium was collected to detect the levels of inflammatory factors by ELISA assay. After that, alkaline phosphatase (ALP) staining and alizarin red staining were performed respectively in groups A, D, and E, and the expression levels of osteogenic related genes [collagen type Ⅰ alpha 1 chain (Col1a1) and RUNX family transcription factor 2 (Runx2)] were also detected by real time fluorescence quantitative PCR (RT-qPCR). Results: ELISA and Micro-CT assays showed that compared with Sham group, the bone mass of the rats in the OVX group significantly decreased, and the expression levels of serum inflammatory factors (IL-1ß, IL-6, and TNF-α) in OVX group significantly increased (P<0.05). Significantly, the above indicators in OVX+MT group were all improved (P<0.05). Rat BMSCs were successfully extracted, and CCK-8 assay showed that 100 µmol/L was the maximum concentration of MT that did not cause a decrease in cell viability, and it was used in subsequent experiments. ELISA assays showed that compared with group A, the expression levels of inflammatory factors (IL-1ß, IL-6, and TNF-α) in the cell culture medium of groups B-D were significantly increased after lipopolysaccharide stimulation (P<0.05), and in a concentration-dependent manner. Moreover, the expression levels of inflammatory factors in group D were significantly higher than those in groups B and C (P<0.05). After MT intervention, the expression levels of inflammatory factors in group E were significantly lower than those in group D (P<0.05). ALP staining, alizarin red staining, and RT-qPCR assays showed that compared with group A, the percentage of positive area of ALP and alizarin red and the relative mRNA expressions of Col1a1 and Runx2 in group D significantly decreased, while the above indicators in group E significantly improved after MT intervention (P<0.05). Conclusion: MT may affect the bone mass of postmenopausal osteoporosis by reducing inflammation in rats; MT can reduce the inflammation of BMSCs stimulated by lipopolysaccharide and weaken its inhibition of osteogenic differentiation of BMSCs.

Understanding of Stress-Driven Internal Short Circuit Mechanisms in Lithium-Ion Batteries with High SOCs.

The characteristics of internal short circuits (ISC) play a critical role in determining the thermal runaway behaviors and associated hazards of lithium-ion batteries (LIBs). However, due to safety concerns and limitations in operando characterization at high state-of-charges (SoCs), the fundamental understanding of stress-driven ISCs under high SOC situations (above 30%) is still lacking. In this study, combined post-mortem characterization and multiphysics modeling is employed to clarify the evolution of ISC modes in LIBs with high SOCs. These findings reveal that the triggered ISC mode is SOC-dependent, with the Al current collector (Al)-Anode coating (An) mode dominant in high SOC situations. Experimentally obtained ISC resistance for the specified ISC mode is then assigned to the corresponding ISC region in the established multiphysics model, allowing for accurate coupling of the electromechanical relationship and prediction of mechanical-electrical-thermal responses of the LIB. Finally, a simple yet effective approach is proposed for avoiding the Al-An mode after battery fractures, achieved through surface notches on electrodes. Results discover novel phenomena for ISC in high SOC cells and reveal the underlying mechanisms, highlighting the importance and potential of battery structural design for developing next-generation robust batteries.

Learning curve and short-term clinical outcomes of a new seven-axis robot-assisted total knee arthroplasty system: a propensity score-matched retrospective cohort study.

OBJECTIVE: The purpose of the present study was to determine the learning curve for a novel seven-axis robot-assisted (RA) total knee arthroplasty (TKA) system and to explore whether it could provide superior short-term clinical and radiological outcomes compared with conventional surgery. METHODS: In the present retrospective study, 90 patients who underwent RA-TKA were included in robot-assisted system (RAS) group and 90 patients who underwent conventional TKA were included in the conventional group. The duration of surgery and robot-related complications were recorded to evaluate the learning curve through cumulative sum and risk-adjusted cumulative sum methods. The demographic data, preoperative clinical data, preoperative imaging data, duration of surgery, alignment of the prosthesis, lower limb force line alignment, Knee Society score, 10-cm visual analog scale pain score and range of motion were compared between the RAS and conventional groups. In addition, the proficiency group was compared with the conventional group using propensity score matching. RESULTS: RA-TKA was associated with a learning curve of 20 cases for the duration of surgery. There was no significant difference in indicators representing the accuracy of the prosthetic installation between the learning and proficiency phases in RA-TKA group patients. A total of 49 patients in the proficiency group were matched with 49 patients from the conventional group. The number of postoperative hip-knee-ankle (HKA) angle, component femoral coronal angle (CFCA), component tibial coronal angle (CTCA), and sagittal tibial component angle (STCA) outliers in the proficiency phase was lower than that in the conventional group, while deviations of the HKA angle, CFCA, CTCA, and STCA in the proficiency phase were significantly lower than those in the conventional group (P < 0.05). CONCLUSION: In summary, from the learning curve data, 20 cases are required for a surgeon using a novel seven-axis RA-TKA system to enter the proficiency phase. In the proficiency group, compared with the conventional group using propensity score matching, the RAS was found to be superior to the conventional group in prosthesis and lower limb alignment.

Prediction of early functional outcomes in patients after robotic-assisted total knee arthroplasty: a nomogram prediction model.

BACKGROUND: Robotic-assisted total knee arthroplasty (RA-TKA) is becoming more and more popular as a treatment option for advanced knee diseases due to its potential to reduce operator-induced errors. However, the development of accurate prediction models for postoperative outcomes is challenging. This study aimed to develop a nomogram model to predict the likelihood of achieving a beneficial functional outcome. The beneficial outcome is defined as a postoperative improvement of the functional Knee Society Score (fKSS) of more than 10 points, 3 months after RA-TKA by early collection and analysis of possible predictors. METHODS: This is a retrospective study on 171 patients who underwent unilateral RA-TKA at our hospital. The collected data included demographic information, preoperative imaging data, surgical data, and preoperative and postoperative scale scores. Participants were randomly divided into a training set ( N =120) and a test set ( N =51). Univariate and multivariate logistic regression analyses were employed to screen for relevant factors. Variance inflation factor was used to investigate for variable collinearity. The accuracy and stability of the models were evaluated using calibration curves with the Hosmer-Lemeshow goodness-of-fit test, consistency index and receiver operating characteristic curves. RESULTS: Predictors of the nomogram included preoperative hip-knee-ankle angle deviation, preoperative 10-cm Visual Analogue Scale score, preoperative fKSS score and preoperative range of motion. Collinearity analysis with demonstrated no collinearity among the variables. The consistency index values for the training and test sets were 0.908 and 0.902, respectively. Finally, the area under the receiver operating characteristic curve was 0.908 (95% CI 0.846-0.971) in the training set and 0.902 (95% CI 0.806-0.998) in the test set. CONCLUSION: A nomogram model was designed hereby aiming to predict the functional outcome 3 months after RA-TKA in patients. Rigorous validation showed that the model is robust and reliable. The identified key predictors include preoperative hip-knee-ankle angle deviation, preoperative visual analogue scale score, preoperative fKSS score, and preoperative range of motion. These findings have major implications for improving therapeutic interventions and informing clinical decision-making in patients undergoing RA-TKA.

Exploring the prognostic function of TMB-related prognostic signature in patients with colon cancer.

Tumor mutation burden (TMB) level is identified as a useful predictor in multiple tumors including colon adenocarcinoma (COAD). However, the function of TMB related genes has not been explored previously. In this study, we obtained patients' expression and clinical data from The Cancer Genome Atlas (TCGA) and the National Center for Biotechnology Information (NCBI). TMB genes were screened and subjected to differential expression analysis. Univariate Cox and LASSO analyses were utilized to construct the prognostic signature. The efficiency of the signature was tested by using a receiver operating characteristic (ROC) curve. A nomogram was further plotted to assess the overall survival (OS) time of patients with COAD. In addition, we compared the predictive performance of our signature with other four published signatures. Functional analyses indicated that patients in the low-risk group have obviously different enrichment of tumor related pathways and tumor infiltrating immune cells from that of high-risk patients. Our findings suggested that the ten genes' prognostic signature could exert undeniable prognostic functions in patients with COAD, which might provide significant clues for the development of personalized management of these patients.

The effectiveness and influencing factors of the "Y" line technique in reducing the leg length discrepancy after total hip arthroplasty.

Objective: To introduce a surgical technique (the "Y" line technique) that will control leg length discrepancy (LLD) after total hip arthroplasty and to observe its effectiveness and influencing factors. Methods: According to the inclusion and exclusion criteria, a total of 350 patients were selected in this study; 134 patients in whom used the "Y" line technique was used to control lower limb length were included in Group A and 166 patients treated with freehand methods to control lower limb length were included in Group B. A total of 50 patients in whom the standard anteroposterior x-ray of bilateral hips was taken preoperatively and in whom the "Y" line technique was used during the operation were included in Group C. Results: The postoperative LLD of Group A was 4.74 mm (3.93), that of Group B was 5.85 mm (4.60), and that of Group C was 2 mm (1.00)-the difference was statistically significant (p < 0.001). There were significant statistical differences when comparisons were made between any two groups (p < 0.01). The distribution of postoperative LLD in Group A was better than that in Group B, and this factor was better in Group C than in Group A-the difference was statistically significant (p < 0.001). Severe unequal length rates of the lower extremities (LLD > 10 mm) were 5.97% (8/134) in Group A, 14.3% (24/166) in Group B, and 0% (0/50) in Group C-the difference was statistically significant (p < 0.001). There were significant differences between Group A and Group B and between Group B and Group C (p < 0.05), but there was no significant difference between Group A and Group C (p = 0.078). Conclusion: The "Y" line technique, which does not increase the operating time and patient cost, can effectively reduce postoperative LLD. Insufficient internal rotation of the healthy lower extremity and the low projection position in the preoperative anteroposterior x-ray of the bilateral hips were important factors affecting the accuracy of the "Y" line technique.

Precise acetabular positioning, discrepancy in leg length, and hip offset using a new seven-axis robot-assisted total hip arthroplasty system requires no learning curve: a retrospective study.

OBJECTIVE: The purpose of the present study was to determine the learning curve for a novel seven-axis robot-assisted total hip arthroplasty (RA-THA) system, and to explore whether it was able to provide greater accuracy in acetabular cup positioning, superior leg length discrepancy (LLD), and hip offset than conventional methods. METHODS: A total of 160 patients in which unilateral THA was performed in the second affiliated Hospital of Xi'an Jiaotong University from July 2021 to September 2022 were studied. The first 80 patients underwent robot-assisted THA, while conventional THA was performed on the subsequent 80 by the same team of experienced surgeons. The learning curve for the RA-THA system was evaluated using cumulative sum (CUSUM) analysis. The demographic data, preoperative clinical data, duration of surgery, postoperative Harris hip score (HHS) and postoperative radiographic data from patients that had conventional THA were compared. RESULTS: The 80 patients who underwent primary unilateral RA-THA comprised 42 males and 38 females and were followed up for 12 weeks. Using analysis by CUSUM, the learning curve of the RA-THA system could be divided into learning and proficiency phases, the former of which consisted of the first 17 cases. There was no significant difference between the learning and proficiency phases in terms of LLD, hip offset, or accuracy of acetabular prosthesis position in the RA-THA groups. The proportion of acetabular prostheses located in the Lewinnek safe zone was 90.5% in the proficiency group and 77.5% in the conventional group, respectively, a difference that was statistically significant (P < 0.05). The absolute error between target angle and postoperative measured angle of anteversion was statistically significant in the proficiency group and the conventional group((P < 0.05). Postoperative acetabular anteversion and LLD were 19.96 ± 5.68° and 6.00 (5.00) mm in the proficiency group, respectively, and 17.84 ± 6.81° and 8.09 (4.33) mm using conventional surgery, respectively (anteversion: P = 0.049; LLD: P < 0.001). CONCLUSIONS: The surgical team required a learning curve of 17 cases using the RA-THA system to become proficient. There was no learning curve for other parameters, namely LLD, hip offset, or accuracy of acetabular prosthesis positioning. During the proficiency phase, the RA system was superior to conventional THA for control of leg length and accuracy of acetabular cup placement.

Robotic-assisted total knee arthroplasty is more advantageous for knees with severe deformity: a randomized controlled trial study design.

OBJECTIVE: A prospective, multicenter, randomized controlled trial was conducted to explore the short-term effect of a new robotic-assisted total knee arthroplasty (TKA) system, and the clinical and radiographic effectiveness between the robotic-assisted system and conventional TKA were compared and analyzed. MATERIALS AND METHODS: Overall, 144 patients were randomly divided into two groups, wherein 72 patients underwent TKA using the robotic­assisted system and 72 underwent conventional TKA. The demographic data and radiographic parameters of the patients were collected. The factors influencing postoperative hip-knee-ankle (HKA) angle deviation were determined by multiple linear regression. Clinical outcomes including postoperative Knee Society score, 10-cm visual analog scale, and range of motion (ROM) and radiographic results including the deviation value of coronal tibial component angle, coronal femoral component angle (CFCA), sagittal tibial component angle, sagittal femoral component angle (SFCA), and HKA angle as well as the rate of outliers in each angle were observed and compared between the two groups. RESULTS: The preoperative demographic data and imaging parameters, including Knee Society score, ROM, sex, surgical side, age, BMI, preoperative HKA angle, preoperative HKA angle deviation, and visual analog scale, showed no significant differences between groups. The robotic­assisted system group (RAS group) showed a postoperative malalignment of 3.2% for a mechanical axis higher than 3° and the conventional techniques group (CON group) showed a postoperative malalignment of 41.0% for a mechanical axis higher than 3°; the difference was statistically significant ( P <0.001). According to the results of multiple linear regression analysis, when the preoperative HKA angle deviation increased by 1°, the postoperative HKA angle deviation increased by 0.134° ( ß =0.134 min; 95% CI: 0.045-0.222). Therefore, patients were divided into a slight lower extremity alignment deviation group (preoperative HKA angle deviation <6°) and severe lower extremity alignment deviation group (preoperative HKA angle deviation ≥6°). For the patients with preoperatively slight lower extremity alignment deviation, the rate of postoperative HKA angle outlier in the RAS group was better than that in the CON group, and the operation duration in the RAS group was significantly longer than that in the CON group ( P <0.05). In the patients with a preoperative HKA angle deviation ≥6°, the rate of postoperative HKA angle and CFCA outliers in the RAS group was better than that in the CON group; the operation duration in the RAS group was significantly longer than that in the CON group, and the HKA angle deviation and CFCA deviation in the RAS group were significantly lower than those in the CON group ( P <0.05). No significant difference was observed in other indexes between the two groups ( P >0.05). CONCLUSION: This new robotic-assisted TKA system is safe and effective. The authors found that preoperative HKA angle deviation affects the postoperative HKA angle deviation. The robotic-assisted system has similar results to those reported by the traditional method with regard to restoring the mechanical axis of the leg and improving prosthesis alignment and clinical outcomes in patients with slight lower extremity alignment deviations preoperatively. For patients with severe preoperative lower extremity alignment deviations, the effectiveness in terms of the improvement in mechanical axis of the leg and prosthesis alignment were better with the robotic-assisted system, whereas the effectiveness of clinical outcomes was similar. A larger sample size and longer follow-up period are needed to determine whether the improved mechanical axis of the leg and prosthesis alignment observed with the robotic-assisted system can achieve better long-term radiographic and clinical outcomes.

Bioinformatic analysis of related immune cell infiltration and key genes in the progression of osteonecrosis of the femoral head.

Objective: Osteonecrosis of the femoral head (ONFH) is a common orthopedic condition that will prompt joint dysfunction, significantly impacting patients' quality of life. However, the specific pathogenic mechanisms underlying this disease remain elusive. The objective of this study is to examine the differentially expressed messenger RNAs (DE mRNAs) and key genes linked to ONFH, concurrently investigating the immune cell infiltration features in ONFH patients through the application of the CIBERSORT algorithm. Methods: Microarray was applied to scrutinize mRNA expression profiles in both ONFH patients and healthy controls, with data integration sourced from the GEO database. DE mRNAs were screened using the Limma method. The biological functions of DE mRNAs were explored through the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, Gene Ontology (GO) functional analysis, and Gene Set Enrichment Analysis (GSEA). Additionally, support vector machine-recursive feature elimination (SVM-RFE) and the least absolute shrinkage and selection operator (LASSO) were employed to discern diagnostic biomarkers associated with the disease. Receiver operating characteristic (ROC) analysis was utilized to assess the statistical performance of the feature genes. The validation of key genes was performed using qRT-PCR in bone tissues obtained from ONFH patients and healthy controls. Osteogenic differentiation of BMSC was then performed and detected by alkaline phosphatase staining (ALP) and qRT-PCR to verify the correlation between key genes and osteogenic differentiation. Finally, immune cell infiltration analysis was executed to evaluate immune cell dysregulation in ONFH, concurrently exploring the correlation between the infiltration of immune cells and key genes. Results: After consolidating the datasets, the Limma method revealed 107 DEGs, comprising 76 downregulated and 31 upregulated genes. Enrichment analysis revealed close associations of these DE mRNAs with functions such as cell migration, osteoblast differentiation, cartilage development and extracellular region. Machine learning algorithms further identified APOD, FBXO43 and LRP12 as key genes. ROC curves demonstrated the high diagnostic efficacy of these genes. The results of qRT-PCR showed that the expression levels of key genes were consistent with those of microarray analysis. In addition, the results of in vitro experiments showed that APOD was closely related to osteogenic differentiation of BMSC. Immune infiltration analysis suggested a close correlation between ONFH and imbalances in levels of Neutrophils, Monocytes, Macrophages M2, Dendritic cells activated and Dendritic cells resting. Conclusion: APOD is closely related to osteogenic differentiation of BMSCs and can be used as a diagnostic marker of ONFH. Immune cell infiltration significantly differs between controls and ONFH patients.

LncRNA PSR Regulates Vascular Remodeling Through Encoding a Novel Protein Arteridin.

RATIONALE: Vascular smooth muscle cells (VSMCs) phenotype switch from contractile to proliferative phenotype is a pathological hallmark in various cardiovascular diseases. Recently, a subset of long noncoding RNAs was identified to produce functional polypeptides. However, the functional impact and regulatory mechanisms of long noncoding RNAs in VSMCs phenotype switching remain to be fully elucidated. OBJECTIVES: To illustrate the biological function and mechanism of a VSMC-enriched long noncoding RNA and its encoded peptide in VSMC phenotype switching and vascular remodeling. RESULTS: We identified a VSMC-enriched transcript encoded by a previously uncharacterized gene, which we called phenotype switching regulator (PSR), which was markedly upregulated during vascular remodeling. Although PSR was annotated as a long noncoding RNA, we demonstrated that the lncPSR (PSR transcript) also encoded a protein, which we named arteridin. In VSMCs, both arteridin and lncPSR were necessary and sufficient to induce phenotype switching. Mechanistically, arteridin and lncPSR regulate downstream genes by directly interacting with a transcription factor YBX1 (Y-box binding protein 1) and modulating its nuclear translocation and chromatin targeting. Intriguingly, the PSR transcription was also robustly induced by arteridin. More importantly, the loss of PSR gene or arteridin protein significantly attenuated the vascular remodeling induced by carotid arterial injury. In addition, VSMC-specific inhibition of lncPSR using adeno-associated virus attenuated Ang II (angiotensin II)-induced hypertensive vascular remodeling. CONCLUSIONS: PSR is a VSMC-enriched gene, and its transcript IncPSR and encoded protein (arteridin) coordinately regulate transcriptional reprogramming through a shared interacting partner, YBX1. This is a previously uncharacterized regulatory circuit in VSMC phenotype switching during vascular remodeling, with lncPSR/arteridin as potential therapeutic targets for the treatment of VSMC phenotype switching-related vascular remodeling.

Surfactant Therapy for Respiratory Distress Syndrome in High- and Ultra-High-Altitude Settings.

Objective: The objective of this study is to investigate the therapeutic effect of surfactant replacement therapy (SRT) on respiratory distress syndrome (RDS) in premature infants in the Qinghai-Tibet Plateau. Materials and Methods: This multi-center retrospective cohort study collected and screened reasonable clinical data of 337 premature infants with RDS from 10 hospitals in the Qinghai-Tibet Plateau from 2015 to 2017. We grouped the cases by rationally analyzing their baseline characteristics, using logistic analysis to evaluate each factor's effect on the prognosis of the infants, and comparing the short-term improvement in blood gas and mortality after SRT treatment at different altitudes, in high-altitude (1,500-3,500 m) and ultra-high-altitude (3,500-5,500 m) groups. Results: Independent of altitude, the mortality rate of children with RDS in the SRT group was significantly lower than that of children in the non-SRT group (both P < 0.05). The effect of SRT on preterm infants with RDS in the high-altitude group [odds ratio (OR) = 0.44, 95% confidence interval (CI) = 0.22-0.87, P = 0.02] was better than that in the infants in the ultra-high-altitude group (OR = 0.26, 95% CI = 0.13-0.58, P < 0.01), with death rates of 34.34 and 49.71%, respectively. Similarly, after SRT, the improvement of PaO2/FiO2 and pH of children at high altitude was significantly better than those of children at ultra-high altitude (all P < 0.01). Conclusions: SRT plays a prominent role in curing infants with RDS in both high- and ultra-high-altitude regions, although with better effects at high rather than ultra-high altitude. This study provides a basis for further large-scale studies on SRT for RDS treatment at high altitudes.

Membrane-delimited signaling and cytosolic action of MG53 preserve hepatocyte integrity during drug-induced liver injury.

BACKGROUND & AIMS: Drug-induced liver injury (DILI) remains challenging to treat and is still a leading cause of acute liver failure. MG53 is a muscle-derived tissue-repair protein that circulates in the bloodstream and whose physiological role in protection against DILI has not been examined. METHODS: Recombinant MG53 protein (rhMG53) was administered exogenously, using mice with deletion of Mg53 or Ripk3. Live-cell imaging, histological, biochemical, and molecular studies were used to investigate the mechanisms that underlie the extracellular and intracellular action of rhMG53 in hepatoprotection. RESULTS: Systemic administration of rhMG53 protein, in mice, can prophylactically and therapeutically treat DILI induced through exposure to acetaminophen, tetracycline, concanavalin A, carbon tetrachloride, or thioacetamide. Circulating MG53 protects hepatocytes from injury through direct interaction with MLKL at the plasma membrane. Extracellular MG53 can enter hepatocytes and act as an E3-ligase to mitigate RIPK3-mediated MLKL phosphorylation and membrane translocation. CONCLUSIONS: Our data show that the membrane-delimited signaling and cytosolic dual action of MG53 effectively preserves hepatocyte integrity during DILI. rhMG53 may be a potential treatment option for patients with DILI. LAY SUMMARY: Interventions to treat drug-induced liver injury and halt its progression into liver failure are of great value to society. The present study reveals that muscle-liver cross talk, with MG53 as a messenger, serves an important role in liver cell protection. Thus, MG53 is a potential treatment option for patients with drug-induced liver injury.

Essential role of the endocytic site-associated protein Ecm25 in stress-induced cell elongation.

How cells adopt a different morphology to cope with stress is not well understood. Here, we show that budding yeast Ecm25 associates with polarized endocytic sites and interacts with the polarity regulator Cdc42 and several late-stage endocytic proteins via distinct regions, including an actin filament-binding motif. Deletion of ECM25 does not affect Cdc42 activity or cause any strong defects in fluid-phase and clathrin-mediated endocytosis but completely abolishes hydroxyurea-induced cell elongation. This phenotype is accompanied by depolarization of the spatiotemporally coupled exo-endocytosis in the bud cortex while maintaining the overall mother-bud polarity. These data suggest that Ecm25 provides an essential link between the polarization signal and the endocytic machinery to enable adaptive morphogenesis under stress conditions.

Gastrin Attenuates Renal Ischemia/Reperfusion Injury by a PI3K/Akt/Bad-Mediated Anti-apoptosis Signaling.

Ischemic/reperfusion (I/R) injury is the primary cause of acute kidney injury (AKI). Gastrin, a gastrointestinal hormone, is involved in the regulation of kidney function of sodium excretion. However, whether gastrin has an effect on kidney I/R injury is unknown. Here we show that cholecystokinin B receptor (CCKBR), the gastrin receptor, was significantly up-regulated in I/R-injured mouse kidneys. While pre-administration of gastrin ameliorated I/R-induced renal pathological damage, as reflected by the levels of serum creatinine and blood urea nitrogen, hematoxylin and eosin staining and periodic acid-Schiff staining. The protective effect could be ascribed to the reduced apoptosis for gastrin reduced tubular cell apoptosis both in vivo and in vitro. In vitro studies also showed gastrin preserved the viability of hypoxia/reoxygenation (H/R)-treated human kidney 2 (HK-2) cells and reduced the lactate dehydrogenase release, which were blocked by CI-988, a specific CCKBR antagonist. Mechanistically, the PI3K/Akt/Bad pathway participates in the pathological process, because gastrin treatment increased phosphorylation of PI3K, Akt and Bad. While in the presence of wortmannin (1 µM), a PI3K inhibitor, the gastrin-induced phosphorylation of Akt after H/R treatment was blocked. Additionally, wortmannin and Akt inhibitor VIII blocked the protective effect of gastrin on viability of HK-2 cells subjected to H/R treatment. These studies reveals that gastrin attenuates kidney I/R injury via a PI3K/Akt/Bad-mediated anti-apoptosis signaling. Thus, gastrin can be considered as a promising drug candidate to prevent AKI.

Soybean glycinin impaired immune function and caused inflammation associated with PKC-ζ/NF-κb and mTORC1 signaling in the intestine of juvenile grass carp (Ctenopharyngodon idella).

Glycinin is a major protein and antinutritional factor of soybean. However, how dietary glycinin affect intestinal immune function of fish were largely unknown. In this study, we used juvenile grass carp as a model to investigate the impacts of glycinin on intestinal immune function of fish and involved mechanisms. We set three treatments including control, glycinin and glycinin + glutamine in this trial. For immune components, results revealed that compared with control group, glycinin group had lower acid phosphatase activities in the foregut, midgut and hindgut, lower C3 and C4 content, and lower mRNA abundances of IgM, IgZ, hepcidin, LEAP-2A, LEAP-2B and ß-defensin-1 in the midgut and hindgut rather than foregut of grass carp. For pro-inflammatory cytokines and relevant signaling, glycinin elevated mRNA abundances of IL-1ß, IL-8, IL-12p35, IL-12p40 and IL-17D in the midgut and IL-1ß, IFN-γ2, IL-6, IL-8, IL-12p35, IL-12p40 and IL-17D in the hindgut, and increased protein abundances of PKC-ζ and nuclear NF-κB p65 in the midgut and hindgut in comparison to control. For anti-inflammatory cytokines and relevant signaling, glycinin reduced mRNA abundances of TGF-ß1, TGF-ß2, IL-4/13B (rather than IL-4/13A), IL-10 and IL-11 in the midgut and hindgut, and reduced p-mTOR (Ser 2448), p-S6K1 (Thr 389) and p-4EBP1 (Thr 37/46) protein abundances in the midgut and hindgut rather than foregut. Co-administration of glutamine with glycinin could partially enhance intestinal function and reduce intestinal inflammation compared with glycinin treatment. Concluded, glycinin decreased intestinal immune components and caused intestinal inflammation associated with PKC-ζ/NF-κB and mTORC1 signaling.

The dynamic process of dietary soybean ß-conglycinin in digestion, absorption, and metabolism among different intestinal segments in grass carp (Ctenopharyngodon idella).

The present study aimed to investigate the dynamic process of soybean ß-conglycinin in digestion, absorption, and metabolism in the intestine of grass carp (Ctenopharyngodon idella). Fish fed with 80 g ß-conglycinin/kg diet for 7 weeks, the intestinal digestive enzyme was extracted to hydrolyze ß-conglycinin in vitro, the free amino acid and its metabolism product contents in intestinal segments were analyzed. The present study first found that ß-conglycinin cannot be thoroughly digested by fish intestine digestive enzyme and produces new products (about 60- and 55-kDa polypeptides). The indigestible ß-conglycinin further caused the free amino acid imbalance, especially caused free essential amino acid deficiency in the proximal intestine but excess in the distal intestine. Moreover, these results might be partly associated with the effect of ß-conglycinin in amino acid transporters and tight junction-regulated paracellular pathway. Finally, dietary ß-conglycinin increased the content of amino acid catabolism by-product ammonia while decreased the amino acid anabolism product carnosine content in the proximal intestine and distal intestine. Thus, the current study first and systemically explored the dynamic process of ß-conglycinin in digestion, absorption, and metabolism, which further supported our previous study that dietary ß-conglycinin suppressed fish growth and caused intestine injure.

Mannan oligosaccharide supplementation in diets of sow and (or) their offspring improved immunity and regulated intestinal bacteria in piglet1.

The objectives of the current study were to explore the effects of mannan oligosaccharide (MOS) supplementation in the diets of sow and (or) their offspring on intestinal bacteria, intestinal and systemic inflammation in the piglet. A total of 60 multiparous sows (4 ± 1 parity; Landrace × Yorkshire) were fed either control diet (sCON, n = 30) or a diet containing 400 mg kg-1 MOS (sMOS, n = 30) from day 86 of gestation until weaning (day 20 of postpartum). On day 7 of age, offspring (Duroc × Landrace Yorkshire) were assigned within sow treatments and fed control diet (pCON) or diet containing 800 mg kg-1 MOS (pMOS) for 28 d (end at 35 d of age), resulting in four piglet diet groups (n = 15 litters per diet group): sCON-pCON, sCON-pMOS, sMOS-pCON, and sMOS-pMOS. Results found that piglet diet MOS increased or tend to increase Lactobacillus amount in the ileum digesta (P < 0.01) and jejunum digesta (P = 0.07), respectively; while tend to decrease Escherichia coli amount in jejunum digesta (P =0.06) and cecum digesta (P = 0.08). Both sow and piglet diets add MOS (sMOS-pMOS) increased Lactobacillus amount but decreased E. coli amount in jejunum digesta (P < 0.05) compared with the sCON-pCON diet group. In addition, sow diet MOS (rather than piglet diet MOS) increased sIgA content in piglet jejunum mucosa compared with control (P = 0.04). Sow diet MOS decreased toll-like receptor 2 (TLR2), toll-like receptor 4 (TLR4), and interleukin 8 (IL-8) mRNA levels (P < 0.05) and tended to decrease nuclear factor-κB p65 (NF-κB p65) mRNA level (P = 0.07) in piglet intestinal lymphatic. The interaction effects between sow and piglet diets were found on the mRNA levels of NF- κB p65 (P = 0.03) and IL-8 (P = 0.02) in piglet jejunum. Finally, the sow diet MOS decreased proinflammatory cytokines IL-2 (P < 0.01) and IL-4 (P < 0.01) concentrations in piglet serum. Piglets diet MOS decreased the contents of IL-2 (P = 0.03), IL-4 (P = 0.01) and interferon (IFN)-γ (P < 0.01) while increased anti-inflammatory cytokine IL-10 (P < 0.01) content in serum. The interaction effects between sows and piglet diets on IL-4 (P = 0.02), IL-10 (P < 0.01), and IFN-γ (P = 0.08) were observed. In conclusion, sow and/or piglet diet MOS could improve intestinal microbiota, enhance intestinal mucosal immune competence, and suppress intestinal and systemic inflammation in the piglet.