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Background: Programmed cell death protein 1 (PD-1) blockade is essential in treating progressive colorectal cancer (CRC). However, some patients with CRC do not respond well to immunotherapy, possibly due to the exhaustion of CD8 + T cells in the tumor microenvironment. N-Acetylcysteine (NAC) can reduce CD8 + T cell exhaustion in vitro and induce their differentiation into long-lasting phenotypes, thus enhancing the anti-tumor effect of adoptive T cell transfer. However, whether NAC can be combined with PD-1 blockade in CRC treatment and how NAC regulates CD8 + T cell differentiation remain unclear. Hence, in this study, we aimed to investigate whether NAC has a synergistic effect with PD-1 blockers against CRC progression., Methods: We constructed a mouse CRC model to study the effect of NAC on tumors. The effect of NAC on CD8 + T cell differentiation and its potential mechanism were explored using cell flow assay and other studies in vitro and ex vivo., Results: We demonstrated that NAC synergized PD-1 antibodies to inhibit CRC progression in a mouse CRC model mediated by CD8 + T cells. We further found that NAC can induce TCF1 + PD1 + CD8 + T cell differentiation and reduce the formation of exhausted T cells in vitro and in vivo. Moreover, NAC enhanced the expression of Glut4 in CD8 + T cells, promoting the differentiation of TCF1 + PD1 + CD8 + T cells., Conclusions: Our study provides a novel idea for immunotherapy for clinically progressive CRC and suggests that Glut4 may be a new immunometabolic molecular target for regulating CD8 + T cell differentiation., (© 2024. The Author(s).)

Background: Acupuncture is an effective complementary therapy for nausea and vomiting during pregnancy (NVP). Nevertheless, the utilization of acupuncture for NVP has been minimally explored in current scholarly research, with a paucity of systematic randomized clinical trials (RCTs) in it. We aim to evaluate the effects of acupuncture on NVP after assisted reproductive techniques (ART) and explore the metabolism-related mechanism of the efficacy., Methods: This single-blind, randomized, controlled trial will randomize 68 patients with NVP after ART to a traditional acupuncture (tACP) or a sham acupuncture (sACP) group. The tACP group will receive tACP thrice a week for 2 weeks with a day interval between sessions, while the sACP group will undergo the same number of nonpenetrative acupuncture at non-acupoints for the same period. Pregnancy-specific quantification of emesis will be used to evaluate symptom severity. Routine blood and urine tests, liver and kidney function tests, human chorionic gonadotropin, nuchal translucency thickness, and embryonic development measured using ultrasound will be used to evaluate safety during pregnancy. Non-targeted metabolomic analysis will be performed to explore the association between metabolic changes and clinical symptoms., Discussion: This study will elucidate the effects and safety of acupuncture in treating NVP in women undergoing ART. The results of this study will contribute to optimizing acupuncture therapies by combining the body and auricular points and exploring the underlying therapeutic mechanism using a metabolomics approach., Trial Registration: Chinese Clinical Trial Registry, ChiCTR2300075259., (© 2024. The Author(s).)

Background: Hygienic behavior, a specialized form of immune response evolved in social insects, plays a crucial role in safeguarding colonies from disease spread. In honeybee colonies, such behavior typically entails the dual steps of uncapping and removal of unhealthy and deceased brood. Although in recent years, numerous studies have examined the development of hygienic behavior, the mechanisms underlying the division in the performance of uncapping and removal have yet to be sufficiently elucidated. In this regard, long non-coding RNAs (lncRNAs) have been evidenced to be engaged in regulating the physiological activities of honeybees; however, whether lncRNAs are likewise involved in the uncapping and removal tasks has not been clarified., Results: In this study, the strong hygienic Apis cerana worker bees were used and the processes of uncapping and removal behaviors in three colonies were assayed with freeze-killed brood in the field. We then sequenced the antennal RNAs of honeybees to identify differentially expressed lncRNAs and performed lncRNA-mRNA association analysis to establish the differences between uncapping and removal. We detected 1,323 differentially expressed lncRNAs in the antennae, and the findings of lncRNA-mRNA association analyses revealed that the target genes of differentially expressed lncRNAs between uncapping and removal worker bees were predominantly linked to response to stimulus, receptor activity, and synapse. Notably, among the lncRNAs enriched in cellular response to stimulus, XR_001766094.2 was exclusively expressed in the uncapping worker bees. Based on these findings, we hypothesize that XR_001766094.2 plays a key role in distinguishing uncapping from removal behaviors by responding to external stimulus, thereby suggesting that the division of hygienic behaviors is governed by differential thresholds of responsiveness to environmental cues., Conclusion: We characterized differences in the uncapping and removal behaviors of worker bees from a perspective of lncRNAs. Uncapping bees may be equipped with a more rapid stimulatory response and more acute olfactory sensitivity, contributing to the rapid hygienic behavior in honeybee colonies. Our results thus establish a foundation for potential lncRNA-mediated gene expression regulation in hygienic behavior., (© 2024. The Author(s).)

Background: Saccharomyces cerevisiae has been considered a harmless yeast, but in recent years, increasing evidence has shown that it can cause disease in humans, especially invasive infections in infants/children and vulvovaginal infections in women. This study aimed to investigate the clinical information and antifungal susceptibility of clinical cases with S. cerevisiae and establish a foundation for the prevention and treatment of fungal infections., Methods: This study was conducted from May 2018 to May 2023 at a national regional medical center in Southwest China for women and children. The demographic and clinical characteristics of patients isolated with S. cerevisiae were collected and analyzed. All the isolates were cultured on Sabouraud medium plates and identified by MALDI-TOF MS. The antifungal susceptibility of S. cerevisiae to 10 agents (amphotericin B, fluconazole, itraconazole, voriconazole, micafungin, caspofungin, terbinafine and 5-flucytosine) was determined via the microdilution broth method to determine the minimum inhibitory concentrations (MICs)., Results: A total of 75 cases of S. cerevisiae isolated from patients with vulvovaginal candidiasis (VVC, 44 cases), pneumonia (13 cases), or diarrhea (18 cases) were included after data review. The MICs of voriconazole and flucytosine for S. cerevisiae isolated from different body sites differed, with higher resistance in intestinal isolates. In this study, S. cerevisiae caused VVC, but there was no clear evidence that it was involved in pneumonia or diarrhea. Compared with those of Candida albicans, the primary pathogen of VVC, the MICs of fluconazole (11.96 ± 5.78 µg/mL vs. 67.64 ± 16.62 µg/mL, p = 0.002), itraconazole (0.77 ± 0.19 µg/mL vs. 2.31 ± 0.53 µg/mL, p = 0.008), voriconazole (0.22 ± 0.09 µg/mL vs. 5.02 ± 1.09 µg/mL, p < 0.001), and terbinafine (10.41 ± 0.84 µg/mL vs. 14.93 ± 4.77 µg/mL, p < 0.001) for S. cerevisiae (isolated from the genital tract) were significantly lower, while those of micafungin (0.14 ± 0.01 µg/mL vs. 0.06 ± 0.01 µg/mL, p < 0.001) and caspofungin (0.27 ± 0.04 µg/mL vs. 0.06 ± 0.01 µg/mL, p < 0.001) were significantly greater., Conclusion: Azoles remain the recommended regimen for S. cerevisiae-related VVC, and the use of amphotericin B vaginal effervescent tablets could be considered for the treatment of azole-resistant isolates. The antifungal susceptibility of S. cerevisiae varies according to the isolated source, and the pathogenicity trend of S. cerevisiae should be studied., (© 2024. The Author(s).)

Purpose: To explore the impact of mobile social media on the psychological well-being of Chinese international students and analyze the mechanisms of influence to enhance their overall psychological health and social interactions in a foreign environment., Methods: Convenience sampling was employed, using questionnaires on Mobile Social Media, Psychological Resilience, Body Image, Health Goal Setting, Physical Activity Level, and Mental Health Status as measurement tools. Data were gathered from 378 Chinese international students across 33 universities in South Korea, including Kangwon National University, Myongji University, Kunsan National University, Seoul National University, and Chonbuk National University. Confirmatory factor analysis, correlation analysis, common method bias testing, and chain mediation effect analysis were conducted using SPSS and AMOS 23.0., Results: Mobile social media has significant indirect effects on the mental health of international students through various factors: psychological resilience and physical activity level (effect 'adg' = 0.080, 95% CI [0.029, 0.144]), body image and physical activity level (effect 'beg' = 0.122, 95% CI [0.044, 0.247]), and health goal setting and physical activity level (effect 'cfg' = 0.255, 95% CI [0.123, 0.428])., Conclusion: The study shows that mobile social media benefits the mental health of Chinese international students by enhancing psychological resilience, physical activity, body image perception, and health goal setting. Collaboration between educational institutions and social media platforms is recommended to promote physical activity among international students. This collaboration can involve sharing encouraging messages, joining health communities, setting goals, and providing accessible exercise resources. Utilizing mobile apps or social media for tracking progress and goal-setting can also improve self-management skills., (© 2024. The Author(s).)

Objective: Early diagnosis and prediction of organ dysfunction are critical for intervening and improving the outcomes of septic patients. The study aimed to find novel diagnostic and predictive biomarkers of organ dysfunction for perioperative septic patients., Method: This is a prospective, controlled, preliminary, and single-center study of emergency surgery patients. Mass spectrometry, Gene Ontology (GO) functional analysis, and the protein-protein interaction (PPI) network were performed to identify the differentially expressed proteins (DEPs) from sepsis patients, which were selected for further verification via enzyme-linked immunosorbent assay (ELISA). Logistic regression analysis was used to estimate the relative correlation of selected serum protein levels and clinical outcomes of septic patients. Calibration curves were plotted to assess the calibration of the models., Results: Five randomized serum samples per group were analyzed via mass spectrometry, and 146 DEPs were identified. GO functional analysis and the PPI network were performed to evaluate the molecular mechanisms of the DEPs. Six DEPs were selected for further verification via ELISA. Cathepsin B (CatB), vascular cell adhesion protein 1 (VCAM-1), neutrophil gelatinase-associated lipocalin (NGAL), protein S100-A9, prosaposin, and thrombospondin-1 levels were significantly increased in the patients with sepsis compared with those of the controls (p < 0.001). Logistic regression analysis showed that CatB, S100-A9, VCAM-1, prosaposin, and NGAL could be used for preoperative diagnosis and postoperative prediction of organ dysfunction. CatB and S100-A9 were possible predictive factors for preoperative diagnosis of renal failure in septic patients. Internal validation was assessed using the bootstrapping validation. The preoperative diagnosis of renal failure model displayed good discrimination with a C-index of 0.898 (95% confidence interval 0.843-0.954) and good calibration., Conclusion: Serum CatB, S100-A9, VCAM-1, prosaposin, and NGAL may be novel markers for preoperative diagnosis and postoperative prediction of organ dysfunction. Specifically, S100-A9 and CatB were indicators of preoperative renal dysfunction in septic patients. Combining these two biomarkers may improve the accuracy of predicting preoperative septic renal dysfunction., Trial Registration: The study was registered at the Chinese Clinical Trials Registry (ChiCTR2200060418) on June 1, 2022., (© 2024. The Author(s).)

Background: Miscarriage is a frustrating complication of pregnancy that is common among women of reproductive age. Insufficient decidualization which not only impairs embryo implantation but disturbs fetomaternal immune-tolerance, has been widely regarded as a major cause of miscarriage; however, the underlying mechanisms resulting in decidual impairment are largely unknown., Methods: With informed consent, decidual tissue from patients with spontaneous abortion or normal pregnant women was collected to detect the expression profile of UCHL1. Human endometrial stromal cells (HESCs) were used to explore the roles of UCHL1 in decidualization and dNK modulation, as well as the mechanisms involved. C57/BL6 female mice (7-10 weeks old) were used to construct pregnancy model or artificially induced decidualization model to evaluate the effect of UCHL1 on mice decidualization and pregnancy outcome., Results: The Ubiquitin C-terminal hydrolase L1 (UCHL1), as a deubiquitinating enzyme, was significantly downregulated in decidua from patients with miscarriage, along with impaired decidualization and decreased dNKs. Blockage of UCHL1 led to insufficient decidualization and resultant decreased expression of cytokines CXCL12, IL-15, TGF-β which were critical for generation of decidual NK cells (dNKs), whereas UCHL1 overexpression enhanced decidualization accompanied by increase in dNKs. Mechanistically, the promotion of UCHL1 on decidualization was dependent on its deubiquitinating activity, and intervention of UCHL1 inhibited the activation of JAK2/STAT3 signaling pathway, resulting in aberrant decidualization and decreased production of cytokines associated with dNKs modulation. Furthermore, we found that inhibition of UCHL1 also disrupted the decidualization in mice and eventually caused adverse pregnancy outcome., Conclusions: UCHL1 plays significant roles in decidualization and dNKs modulation during pregnancy in both humans and mice. Its deficiency indicates a poor pregnancy outcome due to defective decidualization, making UCHL1 a potential target for the diagnosis and treatment of miscarriage., (© 2024. The Author(s).)

Glycolysis-related metabolic reprogramming is a central hallmark of human cancers, especially in renal cell carcinoma. However, the regulatory function of glycolytic signature in papillary RCC has not been well elucidated. In the present study, the glycolysis-immune predictive signature was constructed and validated using WGCNA, glycolysis-immune clustering analysis. PPI network of DEGs was constructed and visualized. Functional enrichments and patients' overall survival were analyzed. QRT-PCR experiments were performed to detect hub genes' expression and distribution, siRNA technology was used to silence targeted genes; cell proliferation and migration assays were applied to evaluate the biological function. Glucose concentration, lactate secretion, and ATP production were measured. Glycolysis-Immune Related Prognostic Index (GIRPI) was constructed and combined analyzed with single-cell RNA-seq. High-GIRPI signature predicted significantly poorer outcomes and relevant clinical features of pRCC patients. Moreover, GIRPI also participated in several pathways, which affected tumor immune microenvironment and provided potential therapeutic strategy. As a key glycolysis regulator, PFKFB3 could promote renal cancer cell proliferation and migration in vitro. Blocking of PFKFB3 by selective inhibitor PFK-015 or glycolytic inhibitor 2-DG significantly restrained renal cancer cells' neoplastic potential. PFK-015 and sunitinib could synergistically inhibit pRCC cells proliferation. Glycolysis-Immune Risk Signature is closely associated with pRCC prognosis, progression, immune infiltration, and therapeutic response. PFKFB3 may serve as a pivotal glycolysis regulator and mediates Sunitinib resistance in pRCC patients., (© 2024. The Author(s).)

Background: Nurses with a strong professional self-concept tend to exhibit a positive mindset and strong work engagement, delivering high-quality patient care. Although numerous quantitative studies have examined the factors impacting professional self-concept, there remains a limited exploration of these factors from the perspective of nurses themselves., Methods: This qualitative descriptive study uses the PERMA theory and Social Cognitive Theory as the theoretical framework. Semi-structured interviews were conducted with 15 nurses from six public hospitals in China. The data were analyzed thematically using a combination of inductive and deductive approaches., Results: Nurses' understanding of professional self-concept could be divided into four categories: professional identity, competence, care, and knowledge. Factors influencing nurses' professional self-concept were categorized into eight subthemes in three domains: (1) personal factors, including psychological qualities and attitude towards the nursing profession; (2) occupational-related behavioral factors, including role-oriented behavior and knowledge-oriented behavior; and (3) work environment and external factors, including external evaluation and perceptions of nurses, time allocation, nursing work tasks, work atmosphere, school education, and perceived supports., Conclusions: This study found that, although nurses had different personal experiences, their perceptions of professional self-concept were similar. Nurses' professional self-concept is a multidimensional concept and involves various factors, such as personality, work-related characteristics, environment, and family. To thrive in a nursing career, nurses must discern the factors that can enhance or hinder their professional self-concept. By identifying and adjusting these factors, personalized support and positive interventions can be tailored to meet nurses' specific needs, which ultimately nurtures their professional development., Trial Registration: This study was registered on December 14, 2022, in the Chinese Clinical Trial Registry (ChiCTR2200066699) as part of our ongoing study., (© 2024. The Author(s).)

Background: Anthocyanins are the most important compounds for nutritional quality and economic values of blood orange. However, there are few reports on the pre-harvest treatment accelerating the accumulation of anthocyanins in postharvest blood orange fruit. Here, we performed a comparative transcriptome and metabolomics analysis to elucidate the underlying mechanism involved in seasonal drought (SD) treatment during the fruit expansion stage on anthocyanin accumulation in postharvest 'Tarocco' blood orange fruit., Results: Our results showed that SD treatment slowed down the fruit enlargement and increased the sugar accumulation during the fruit development and maturation period. Obviously, under SD treatment, the accumulation of anthocyanin in blood orange fruit during postharvest storage was significantly accelerated and markedly higher than that in CK. Meanwhile, the total flavonoids and phenols content and antioxidant activity in SD treatment fruits were also sensibly increased during postharvest storage. Based on metabolome analysis, we found that substrates required for anthocyanin biosynthesis, such as amino acids and their derivatives, and phenolic acids, had significantly accumulated and were higher in SD treated mature fruits compared with that of CK. Furthermore, according to the results of the transcriptome data and weighted gene coexpression correlation network analysis (WGCNA) analysis, phenylalanine ammonia-lyase (PAL3) was considered a key structural gene. The qRT-PCR analysis verified that the PAL3 was highly expressed in SD treated postharvest stored fruits, and was significantly positively correlated with the anthocyanin content. Moreover, we found that other structural genes in the anthocyanin biosynthesis pathway were also upregulated under SD treatment, as evidenced by transcriptome data and qRT-PCR analysis., Conclusions: The findings suggest that SD treatment promotes the accumulation of substrates necessary for anthocyanin biosynthesis during the fruit ripening process, and activates the expression of anthocyanin biosynthesis pathway genes during the postharvest storage period. This is especially true for PAL3, which co-contributed to the rapid accumulation of anthocyanin. The present study provides a theoretical basis for the postharvest quality control and water-saving utilization of blood orange fruit., (© 2024. The Author(s).)

Background: Sepsis is a severe systemic inflammatory disorder manifested by a dysregulated immune response to infection and multi-organ failure. Numerous studies have shown that elevated ferritin levels exist as an essential feature during sepsis and are able to suggest patients' prognoses. At the same time, the specific mechanism of ferritin-induced inflammatory injury remains unclear., Methods: Hyper-ferritin state during inflammation was performed by injecting ferritin into a mouse model and demonstrated that injection of ferritin could induce a systemic inflammatory response and increase neutrophil extracellular trap (NET) formation.Padi4 -/- , Elane -/- and Cybb -/- mice were used for the NETs formation experiment. Western blot, immunofluorescence, ELISA, and flow cytometry examined the changes in NETs, inflammation, and related signaling pathways., Results: Ferritin induces NET formation in a peptidylarginine deiminase 4 (PAD4), neutrophil elastase (NE), and reactive oxygen species (ROS)-dependent manner, thereby exacerbating the inflammatory response. Mechanistically, ferritin induces the expression of neutrophil macrophage scavenger receptor (MSR), which promotes the formation of NETs. Clinically, high levels of ferritin in patients with severe sepsis correlate with NETs-mediated cytokines storm and are proportional to the severity of sepsis-induced lung injury., Conclusions: In conclusion, we demonstrated that hyper-ferritin can induce systemic inflammation and increase NET formation in an MSR-dependent manner. This process relies on PAD4, NE, and ROS, further aggravating acute lung injury. In the clinic, high serum ferritin levels are associated with elevated NETs and worse lung injury, which suggests a poor prognosis for patients with sepsis. Our study indicated that targeting NETs or MSR could be a potential treatment to alleviate lung damage and systemic inflammation during sepsis. Video Abstract., (© 2024. The Author(s).)

Background: Wilforine (WFR) is a monomeric compound of the anti-RA plant Tripterygium wilfordii Hook. f. (TwHF). Whether WFR has anti-RA effect, its molecular mechanism has not been elucidated., Aim of the Study: Our study aims to clarify how WFR inhibits fibroblast-like synovial cells (FLS) activation and improves RA through Wnt11 action on the Wnt11/β-catenin signaling pathway., Methods: The therapeutic effect of WFR on collagen-induced arthritis (CIA) rats was evaluated using methods such as rat arthritis score. The inhibitory effects and signaling pathways of WFR on the proliferation and inflammatory response of CIA FLS and RA FLS were studied using ELISA, CCK-8, RT-qPCR, Western blot, and immunofluorescence methods., Results: WFR could effectively alleviate the arthritis symptoms of CIA rats; reduce the levels of IL-6, IL-1β, and TNF-α in the peripheral blood of CIA rats; and inhibit the expression of MMP3 and fibronectin. The data showed that WFR has a significant inhibitory effect on FLS proliferation. Furthermore, WFR inhibited the activation of Wnt/β-catenin signaling pathway and decreased the expression of Wnt11, β-catenin, CCND1, GSK-3β, and c-Myc, while the effects of WFR were reversed after overexpression of Wnt11., Conclusions: WFR improves RA by inhibiting the Wnt11/β-catenin signaling pathway, and Wnt11 is the direct target of WFR. This study provides a new molecular mechanism for WFR to improve RA and contributes to the clinical promotion of WFR., (© 2023. The Author(s).)

Background: This study aimed to establish a clinical-based nomogram for predicting the success rate of high-volume Foley catheterization for labor induction., Methods: This retrospective study included 1149 full-term pregnant women who received high-volume Foley catheterization for labor induction from January 2019 to December 2021 in Changshu No.1 People's Hospital. Univariate and multivariate logistic regression analyses were performed, in which the labor induction success was set as dependent variables and the characteristics (including age, height, weight, BMI, gravidity, parity, gestational age, uterine height, abdominal circumference, cervical Bishop score, amniotic fluid index, cephalic presentation, neonatal weight, pregnancy complications, etc.) were set as independent variables. A nomogram scoring model was established based on these risk factors, and a calibration curve was plotted to verify the predictive accuracy of the model., Results: The success rate of labor induction was 83.55% (960/1149). Univariate analysis revealed that the risk factors associated with the success rate of high-volume Foley catheterization for labor induction were height, pregnancy, birth, age, weight, BMI, uterine height, abdominal circumference, and hypertension. Multivariate logistic regression analysis showed that age (OR = 0.950; 95% CI: 0.904 ~ 0.998), height (OR = 1.062; 95% CI: 1.026 ~ 1.100), BMI (OR = 0.871; 95% CI: 0.831 ~ 0.913), and parity (OR = 8.007; 95% CI: 4.483 ~ 14.303) were independent risk factors for labor induction success by high-volume Foley catheterization. The area under the curve (AUC) of the receiver operating characteristic (ROC) curve in the prediction model was 0.752 (95% CI 0.716 ~ 0.788). A nomogram was constructed based on the final multivariate analysis with a corrected C-index of 0.748, which indicated that the model was calibrated reasonably., Conclusion: Four risk factors were used to construct a nomogram to evaluate the success rate of high-volume Foley catheterization for labor induction. The nomogram provides a visual clinical tool to assist in the selection of the most appropriate mode of labor induction for pregnant women of different risk levels., (© 2023. The Author(s).)

Background: Several kinds of physical activities have been applied to improve the prognosis of patients with hemodialysis (HD). However, the comparative efficacy of physical activities on the outcomes in HD patients is still unknown. This study explored the effectiveness and safety of all exercise types in HD patients., Methods: We searched randomized clinical trials from the PubMed, EMBASE, and Cochrane Library databases. Physical exercises interventions included resistance exercise (RE), aerobic exercise (AE), electrical muscle stimulation (EMS), range of motion (ROM), resistance exercise + aerobic exercise (RE + AE), stretching exercise (STE), respiratory muscle training (RMT), peripheral muscle training (PMT), walking exercise (WE), or usual care/sham exercise (UC/SE). Primary outcomes were six-minute walk test (6-mwt) and quality of life (QOL). Secondary outcomes were Kt/V, VO 2max , hemoglobin (Hb), C-reactive protein (CRP), interleukin-6 (IL-6), and systolic and diastolic blood pressure (sbp and dbp). Frequentist network meta-analysis with multivariate random effects models provided mean with 95% confidence intervals (95%CI)., Results: A total of 58 eligible studies were included. AE, RMT, and RE + AE significantly improved 6-mwt compared with UC/SE. SE was the worst intervention and reduced QOL much more than the UC/SE and other exercise types. AE and RE + AE were associated with higher VO 2max , while ROM and RE + AE induced higher Hb levels. All physical activities did not elevate blood pressure, CRP and IL-6. Only ROM decreased sbp/dbp. CRP is significantly lower in RE., Conclusion: Physical activities play a crucial role in the different outcomes of HD patients. They can be applied to specific area for their specific efficacy., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: N6-methyladenosine (m6A) methylation modification is involved in the regulation of various biological processes, including inflammation, antitumor, and antiviral immunity. However, the role of m6A modification in the pathogenesis of autoimmune diseases has been rarely reported., Methods: Based on a description of m6A modification and the corresponding research methods, this review systematically summarizes current insights into the mechanism of m6A methylation modification in autoimmune diseases, especially its contribution to rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE)., Results: By regulating different biological processes, m6A methylation is involved in the pathogenesis of autoimmune diseases and provides a promising biomarker for the diagnosis and treatment of such diseases. Notably, m6A methylation modification is involved in regulating a variety of immune cells and mitochondrial energy metabolism. In addition, m6A methylation modification plays a role in the pathological processes of RA, and m6A methylation-related genes can be used as potential targets in RA therapy., Conclusions: M6A methylation modification plays an important role in autoimmune pathological processes such as RA and SLE and represents a promising new target for clinical diagnosis and treatment, providing new ideas for the treatment of autoimmune diseases by targeting m6A modification-related pathways., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Previous studies have reported that inflammatory responses can promote the onset of cardiovascular diseases; however, its association with cardiac conduction disorders remains unclear. The present community-based cohort study aimed to elucidate the effects of inflammatory responses on the risk of developing cardiac conduction disorders., Methods: After the exclusion of participants failing to meet the inclusion criteria, 86,234 eligible participants (mean age: 50.57 ± 11.88 years) were included. The participants were divided into high-sensitivity C-reactive protein (hsCRP)  ≤  3 mg/L, and hsCRP > 3 mg/L groups based on hsCRP values. Multivariate Cox proportional hazard model was used to analyze the relationship between inflammatory responses and various cardiac conduction disorders., Results: After adjusting for confounding factors, we observed that compared with the hsCRP ≤ 3 mg/L group, the hsCRP > 3 mg/L group exhibited increased risks of atrioventricular block (hazard ratio [HR]:1.64, 95%confidence interval [CI] 1.44-1.87) and left (HR:1.25, 95% CI 1.07-1.45) and right bundle branch block (HR:1.31, 95% CI 1.17-1.47). Moreover, the risk of various cardiac conduction disorders increased for every 1 standard deviation increase in log (hsCRP). The restricted cubic spline function confirmed a linear relationship between log (hsCRP) and the risk of developing cardiac conduction disorders (All nonlinearity P > 0.05)., Conclusions: High hsCRP levels are an independent risk factor for cardiac conduction disorders, and hsCRP levels are dose-dependently associated with the risk of conduction disorders. Our study results may provide new strategies for preventing cardiac conduction disorders., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Myosin heavy chain 9 (MYH9) plays an important role in a number of diseases. Nevertheless, the function of MYH9 in glioma is unclear. The present research aimed to investigate the role of MYH9 in glioma and determine whether MYH9 is involved in the temozolomide chemoresistance of glioma cells. Our results showed that MYH9 increased the proliferation and temozolomide resistance of glioma cells. The mechanistic experiments showed that the binding of MYH9 to NAP1L1, a potential promoter of tumor proliferation, inhibited the ubiquitination and degradation of NAP1L1 by recruiting USP14. Upregulation of NAP1L1 increased its binding with c-Myc and activated c-Myc, which induced the expression of CCND1/CDK4, promoting glioma cell temozolomide resistance and proliferation. Additionally, we found that MYH9 upregulation was strongly related to patient survival and is therefore a negative factor for patients with glioma. Altogether, our results show that MYH9 plays a role in glioma progression by regulating NAP1L1 deubiquitination. Thus, targeting MYH9 is a potential therapeutic strategy for the clinical treatment of glioma in the future., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Neutrophil extracellular traps (NETs) promote neuroinflammation and, thus, central nervous system (CNS) disease progression. However, it remains unclear whether CNS-associated NETs affect pain outcomes. A fasting-mimicking diet (FMD) alleviates neurological disorders by attenuating neuroinflammation and promoting nerve regeneration. Hence, in this study, we explore the role of NETs in the CNS during acute pain and investigate the role of FMD in inhibiting NETs and relieving pain., Methods: The inflammatory pain model was established by injecting complete Freund's adjuvant (CFA) into the hind paw of mice. The FMD diet regimen was performed during the perioperative period. PAD4 siRNA or CI-amidine (PAD4 inhibitor) was used to inhibit the formation of NETs. Monoamine oxidase-B (MAO-B) knockdown occurred by AAV-GFAP-shRNA or AAV-hSyn-shRNA or was inhibited by selegiline (an MAO-B inhibitor). The changes in NETs, neuroinflammation, and related signaling pathways were examined by western blot, immunofluorescence, ELISA, and flow cytometry., Results: In the acute phase of inflammatory pain, NETs accumulate in the spinal cords of mice. This is associated with exacerbated neuroinflammation. Meanwhile, inhibition of NETs formation alleviates allodynia and neuroinflammation in CFA mice. FMD inhibits NETs production and alleviates inflammatory pain, which is enhanced by treatment with the NETs inhibitor CI-amidine, and reversed by treatment with the NETs inducer phorbol 12-myristate 13-acetate (PMA). Mechanistically, the neutrophil-recruiting pathway MAO-B/5-hydroxyindoleacetic acid (5-HIAA) / G-protein-coupled receptor 35 (GPR35) and NETs-inducing pathway MAO-B/ Reactive oxygen species (ROS) are significantly upregulated during the development of inflammatory pain. MAO-B is largely expressed in astrocytes and neurons in the spinal cords of CFA mice. However, knockdown or inhibition of MAO-B effectively attenuates CFA-induced inflammatory pain, NETs formation, and neuroinflammation in the spinal cord. Moreover, within rescue experiments, MAO-B inhibitors synergistically enhance FMD-induced pain relief, NETs inhibition, and neuroinflammation attenuation, whereas supplementation with MAO-B downstream molecules (i.e., 5-HIAA and PMA) abolished this effect., Conclusions: Neutrophil-released NETs in the spinal cord contribute to pain development. FMD inhibits NETs formation and NETs-induced neuroinflammation by inhibiting the MAO-B/5-HIAA/GPR35 and MAO-B/ROS pathways in astrocytes and neurons, thereby relieving pain progression. Video Abstract., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Mindfulness yoga is a type of exercise that emphasizes the integration of mindfulness or meditation into yoga. The aim of this study was to determine the effectiveness of mindfulness yoga intervention on major depressive disorder (MDD) patients., Methods: A systematic review and meta-analysis of randomized controlled trials (RCTs) was conducted by searching nine databases, including PubMed, EMBASE, Web of Science, The Cochrane Library, MEDLINE, China National Knowledge Infrastructure (CNKI), Wanfang Data knowledge service platform, Chinese Biomedical Literature Database (CBM), and China Science and Technology Journal Database (VIP) from inception to April 2023. Primary outcomes included the severity of depression. Secondary outcomes included anxiety and rumination., Results: Nine RCTs met our inclusion criteria (n = 581). The meta-analysis showed that mindfulness yoga significantly has a significant effect on depression (SMD = -0.53; 95%CI = -0.96 to -0.11; P < 0.05) among MDD patients. The only two RCTs involved also showed that mindfulness yoga could alleviate the anxiety level of MDD patients after intervention (SMD = -1.08; 95%CI = -1.64 to -0.52; P < 0.05). Meta-analysis did not reveal positive effects of the mindfulness yoga groups on rumination after intervention based on three RCTs (SMD = -0.33; 95%CI = -0.89 to 0.23; P > 0.05), but found a significant difference in the follow-up period based on two RCTs (MD = -7.42; 95%CI = -11.27 to -3.56; P < 0.05), compared with the control groups., Conclusion: Although we were unable to provide conclusive evidence to support the effectiveness of mindfulness yoga in improving symptoms in MDD patients, we found the literature included in this study indicated that mindfulness yoga might have a potential benefit for MDD patients and should be a feasible, acceptable, and promising intervention., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Saikosaponin A (SSA) shows a series of pharmacological activities, such as anti-inflammatory, antioxidant and antitumor. However, there is a lack of comprehensive research or sufficient evidence regarding the efficacy of SSA in treating gastric cancer (GC), and the specific mechanisms by which it inhibits GC growth and progression are still not fully understood., Methods: MTT and clonogenic assays were employed to detect the effect of SSA on the proliferation of GC cells. Bioinformatics predicted the SSA targets in the treatment of GC. The core genes and the underlying mechanism of SSA in anti-GC were obtained by analyzing the intersecting targets; molecular docking and Western blot were used to check the reliability of core genes. Flow cytometry was used to analyze apoptosis and cell cycle in GC cells treated with varying concentrations of SSA. Western blot was employed to detect the expression levels of related proteins., Results: SSA significantly blocked GC cells in the S phase of the cell cycle and induced apoptosis to suppress the proliferation of GC cells. Network pharmacology revealed that the underlying mechanisms through which SSA acts against GC involve the modulation of several signaling pathways, including the PI3K-Akt, MAPK, RAS, and T-cell signaling pathways. Molecular docking showed pivotal target genes with a high affinity to SSA, including STAT3, MYC, TNF, STAT5B, Caspase-3 and SRC. Furthermore, western blot results revealed that SSA significantly increased the protein levels of Bax and Cleaved Caspase-3, whereas decreased the expression levels of p-JAK, p-STAT3, MYC, Bcl-2, p-PI3K, p-AKT and p-mTOR, confirming that the reliability of hub targets and SSA could promote GC cell apoptosis by suppressing PI3K/AKT/mTOR pathway., Conclusions: The results suggest that SSA has the ability to trigger apoptosis in GC cells by blocking the PI3K/AKT/mTOR pathway. These findings highlight the potential of SSA as a promising natural therapeutic agent for the treatment of GC., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Hepatic fibrosis (HF) is a pathological process caused by excessive accumulation of extracellular matrix caused by a series of causes, leading to the formation of fiber scar. RNA methylation is a newly discovered epigenetic modification that exists widely in eukaryotes and prokaryotes and plays a crucial role in the pathogenesis of many diseases., Results: The occurrence and development of HF are regulated by many factors, including excessive deposition of extracellular matrix, activation of hepatic stellate cells, inflammation, and oxidative stress. RNA methylations of different species have become a crucial regulatory mode of transcript expression, And participate in the pathogenesis of tumors, nervous system diseases, autoimmune diseases, and other diseases. In addition, there are five common types of RNA methylation, but only m6A plays a crucial regulatory role in HF. The pathophysiological regulation of m6A on HF is achieved by the combination of the methylated transferase, demethylated enzyme, and methylated reading protein., Conclusions: RNA methylated methyltransferase, demethylase, and reading protein extensively affect the pathological mechanism of HF, which may be a new therapeutic and diagnostic target, representing a new class of therapeutic strategies., (© 2023. The Author(s).)

Background: African swine fever (ASF) is a highly fatal disease in domestic pigs caused by ASF virus (ASFV), for which there is currently no commercial vaccine available. The genome of ASFV encodes more than 150 proteins, some of which have been included in subunit vaccines but only induce limited protection against ASFV challenge., Methods: To enhance immune responses induced by ASFV proteins, we expressed and purified three fusion proteins with each consisting of bacterial lipoprotein OprI, 2 different ASFV proteins/epitopes and a universal CD4 + T cell epitope, namely OprI-p30-modified p54-TT, OprI-p72 epitopes-truncated pE248R-TT, and OprI-truncated CD2v-truncated pEP153R-TT. The immunostimulatory activity of these recombinant proteins was first assessed on dendritic cells. Then, humoral and cellular immunity induced by these three OprI-fused proteins cocktail formulated with ISA206 adjuvant (O-Ags-T formulation) were assessed in pigs., Results: The OprI-fused proteins activated dendritic cells with elevated secretion of proinflammatory cytokines. Furthermore, the O-Ags-T formulation elicited a high level of antigen-specific IgG responses and interferon-γ-secreting CD4 + and CD8 + T cells after stimulation in vitro. Importantly, the sera and peripheral blood mononuclear cells from pigs vaccinated with the O-Ags-T formulation respectively reduced ASFV infection in vitro by 82.8% and 92.6%., Conclusions: Our results suggest that the OprI-fused proteins cocktail formulated with ISA206 adjuvant induces robust ASFV-specific humoral and cellular immune responses in pigs. Our study provides valuable information for the further development of subunit vaccines against ASF., (© 2023. The Author(s).)

Background: Remimazolam tosilate (RT) is a novel short-acting GABA (A) receptor agonist that has a rapid recovery from procedural sedation and can be fully reversed by flumazenil. To date, there have been relatively few articles comparing RT and propofol for general anesthesia. This study aimed to assess the efficacy and safety of RT with or without flumazenil compared with propofol in general anesthesia for day surgery., Methods: 115 patients scheduled for day surgery were randomized into three groups: RT (n = 39), RT + flumazenil (n = 38) and propofol (n = 38). The primary endpoints were anesthesia induction time and time until fully alert. Anesthesia success rate, bispectral index (BIS) values, injection pain, opioid and vasopressor dosages, postoperative recovery profiles and perioperative inflammatory and cognitive changes were assessed. Any adverse events were recorded., Results: Induction times were similar among the three groups (P = 0.437), but the median time until fully alert in patients treated with RT was longer than that of the propofol or RT + flumazenil groups (17.6 min vs. 12.3 min vs. 12.3 min, P < 0.001). The three groups had comparable postoperative recovery quality and inflammatory and cognitive state changes (P > 0.05). Smaller percentages of patients who received RT (26.3%) and RT + flumazenil (31.6%) developed hypotension during anesthesia maintenance compared with propofol (68.4%), and consequently less ephedrine (P < 0.001) and phenylephrine (P = 0.015) were needed in the RT group. Furthermore, serum triglyceride levels were lower (P < 0.001) and injection pain was much less frequent in the RT with or without flumazenil groups compared with the propofol group (5.3% vs. 0% vs. 18.4%)., Conclusion: RT permits rapid induction and comparable recovery profile compared with propofol in general anesthesia for day surgery, but has a prolonged recovery time without flumazenil. The safety profile of RT was superior to propofol in terms of hypotension and injection pain., Trial Registration: The study was registered at Chinese Clinical Trial Registry http://www.chictr.org.cn/ (Registration date: 19/7/2021; Trial ID: ChiCTR2100048904)., (© 2023. The Author(s).)

Background: The failure of novel therapies effective in preclinical animal models largely reflects the fact that current models do not really mimic the pathological/therapeutic features of glioblastoma (GBM), in which the most effective temozolomide chemoradiotherapy (RT/TMZ) regimen can only slightly extend survival. How to improve RT/TMZ efficacy remains a major challenge in clinic., Methods: Syngeneic G422 TN -GBM model mice were subject to RT/TMZ, surgery, piperlongumine (PL), αPD1, glutathione. Metabolomics or transcriptomics data from G422 TN -GBM and human GBM were used for gene enrichment analysis and estimation of ROS generation/scavenging balance, oxidative stress damage, inflammation and immune cell infiltration. Overall survival, bioluminescent imaging, immunohistochemistry, and immunofluorescence staining were used to examine therapeutic efficacy and mechanisms of action., Results: Here we identified that glutathione metabolism was most significantly altered in metabolomics analysis upon RT/TMZ therapies in a truly refractory and reliable mouse triple-negative GBM (G422 TN ) preclinical model. Consistently, ROS generators/scavengers were highly dysregulated in both G422 TN -tumor and human GBM. The ROS-inducer PL synergized surgery/TMZ, surgery/RT/TMZ or RT/TMZ to achieve long-term survival (LTS) in G422 TN -mice, but only one LTS-mouse from RT/TMZ/PL therapy passed the rechallenging phase (immune cure). Furthermore, the immunotherapy of RT/TMZ/PL plus anti-PD-1 antibody (αPD1) doubled LTS (50%) and immune-cured (25%) mice. Glutathione completely abolished PL-synergistic effects. Mechanistically, ROS reduction was associated with RT/TMZ-resistance. PL restored ROS level (mainly via reversing Duox2/Gpx2), activated oxidative stress/inflammation/immune responses signature genes, reduced cancer cell proliferation/invasion, increased apoptosis and CD3 + /CD4 + /CD8 + T-lymphocytes in G422 TN -tumor on the basis of RT/TMZ regimen., Conclusion: Our findings demonstrate that PL reverses RT/TMZ-reduced ROS and synergistically resets tumor microenvironment to cure GBM. RT/TMZ/PL or RT/TMZ/PL/αPD1 exacts effective immune cure in refractory GBM, deserving a priority for clinical trials., (© 2023. The Author(s).)

Background: Lumbar spinal stenosis (LSS) is a prevalent and disabling cause of low back and leg pain in elderly people and nerve root sedimentation sign (NRSS) has been demonstrated to have high sensitivity and specificity in diagnosing LSS in selected patients. The purpose of this study was to investigate the diagnosis of LSS and the predictive value of NRSS., Methods: The clinical and imaging data of 176 patients diagnosed with LSS and 156 patients with non-specific low back pain (LBP) were analyzed retrospectively. Transverse magnetic resonance images (MRI) of the narrowest spinal canal in all patients were acquired and graded by two experienced doctors using the Braz classification, Schizas classification and Chen Jia classification. Receiver operating curve (ROC) was used to compare the diagnostic efficacy of the three classifications. Univariate and multivariate logistic regression models were established to predict the surgical indications of LSS patients., Result: The diagnostic efficacy of Schizas classification (AUC:0.943; 95%CI:0.918,0.969) and Chen Jia classification (AUC:0.942; 95%CI:0.918,0.966) was significantly higher than that of Braz classification (AUC:0.853; 95%CI:0.808,0.898). Chen Jia classification had the highest correlation with the degree of dural sac cross-sectional area (DCSA) stenosis. In the multivariate analysis of LSS surgical indications, Chen Jia classification (odds ratio [OR], 2.127; 95%CI:1.596,2.835), DCSA (OR,0.398; 95%CI:0.169,0.802) and intermittent claudication (OR,9.481; 95%CI:3.439,26.142) were associated with surgical indications., Conclusion: Among the three types, it is found that Chen Jia classification has better diagnostic efficacy in differentiating LSS from LBP. In addition, Chen Jia classification is simple to be implemented in clinical practice and has high clinical application value. Hence, Chen Jia classification can be used as an effective surgical treatment indicator for LSS patients., (© 2023. The Author(s).)

Background: This study evaluated vitamin A (VA), copper (Cu), and zinc (Zn) levels in the population with autism spectrum disorder (ASD) in Jilin Province, China. Furthermore, we examined their links to core symptoms and neurodevelopment, as well as gastrointestinal (GI) comorbidities and sleep disorders., Methods: This study included 181 children with autism and 205 typically developing (TD) children. The participants had not taken vitamin/mineral supplements in the prior three months. High-performance liquid chromatography was used to measure serum VA levels. By using inductively coupled plasma-mass spectrometry, Zn and Cu concentrations in plasma were determined. Importantly, the Childhood Autism Rating Scale, the Social Responsiveness Scale, and the Autism Behavior Checklist were used to measure core ASD symptoms. However, the Griffith Mental Development Scales-Chinese were used to measure neurodevelopment. GI comorbidities and sleep abnormalities were assessed with the 6 Item-Gastrointestinal Severity Index and Children's Sleep Habits Questionnaire, respectively. Children with ASD with GI issues were grouped according to severity (low GI severity and high GI severity groups)., Results: (i) The difference in VA, Zn, Cu levels and the Zn/Cu ratio between ASD and TD children is small. But children with ASD had lower VA levels and Zn/Cu ratio, higher Cu levels than TD children. Cu levels in children with ASD were associated with the severity of core symptoms. (ii) Children with ASD were much more likely than their TD counterparts to suffer from GI comorbidities or sleep problems. Furthermore, it was observed that high GI severity was associated with lower levels of VA, whereas low GI severity was associated with higher levels of VA. (iii) The children with ASD who had both lower VA and lower Zn/Cu ratio had more severe scores on the Autism Behavior Checklist, but not on other measures., Conclusion: Children with ASD had lower VA and Zn/Cu ratio, and higher Cu levels. Cu levels in children with ASD were weakly correlated with one subscale on social or self-help. ASD children with lower VA levels may face more serious GI comorbidities. Children with ASD combined VA-Zn/Cu lower had more severe core symptoms., Trial Registration: Registration number: ChiCTR-OPC-17013502. Date of registration: 2017-11-23., (© 2023. The Author(s).)

Background: Aggressive angiomyxoma (AAM) is a rare mesenchymal tumor that mostly arises from the pelvic and perineal soft tissues. Few studies reported its characteristics and outcomes previously due to its rarity and challenges of treatments. This study aimed to investigate the clinical characteristics as well as surgical and short-term survival outcomes of primary abdominopelvic AAM., Methods: Medical records of patients who were admitted to surgery with pathological confirmation of primary abdominopelvic AAM at Peking University International Hospital from January 2016 through December 2021 were retrospectively retrieved from our retroperitoneal tumor database. Demographics, operative outcomes and pathological findings were collected. Patients received followed-up routinely after the surgery. Survival probabilities were calculated and determined through Kaplan-Meier analysis., Results: A total of 12 consecutive patients (male/female 4:8) were included in this study. The median age was 45 years old. The clinical presentation varied among individuals, consisting of 2 abdominal discomforts, 4 constipations, 1 lumbago, 1 prolonged menstruation, and 1 buttock swelling. R0/R1 resection was achieved in 100% of patients. Postoperatively, 50% of patients developed various complications including 3 fistulas and 3 wound infections. No operative mortality was observed. Histopathology of all patients was suggestive of AAM. Immunohistochemistry was done with a 91.7% positive rate for estrogen and progesterone receptors. The median recurrence-free survival time was 38 months. There were no cases of deceased or presented with distal metastasis during a median of 42 months' follow-up., Conclusions: The clinical manifestations of abdominopelvic AAM are mostly atypical. Surgical resection with curative intents remains the mainstay treatment of this disease, which was strongly suggested in experienced sarcoma centers due to the high probability of severe postoperative complications. In addition, long-term follow-up is necessary due to the high rate of local recurrences., (© 2023. The Author(s).)

Background: The ubiquitin-proteasome and autophagy-lysosomal systems collaborate in regulating the levels of intracellular proteins. Dysregulation of protein homeostasis is a central feature of malignancy. The gene encoding 26S proteasome non-ATPase regulatory subunit 2 (PSMD2) of the ubiquitin-proteasome system is an oncogene in various types of cancer. However, the detailed role of PSMD2 in autophagy and its relationship to tumorigenesis in esophageal squamous cell carcinoma (ESCC) remain unknown. In the present study, we have investigated the tumor-promoting roles of PSMD2 in the context of autophagy in ESCC., Methods: Molecular approaches including DAPgreen staining, 5-Ethynyl-2'-deoxyuridine (EdU), cell counting kit 8 (CCK8), colony formation, transwell assays, and cell transfection, xenograft model, immunoblotting and Immunohistochemical analysis were used to investigate the roles of PSMD2 in ESCC cells. Data-independent acquisition (DIA) quantification proteomics analysis and rescue experiments were used to study the roles of PSMD2 in ESCC cells., Results: We demonstrate that the overexpression of PSMD2 promotes ESCC cell growth by inhibiting autophagy and is correlated with tumor progression and poor prognosis of ESCC patients. DIA quantification proteomics analysis shows a significant positive correlation between argininosuccinate synthase 1 (ASS1) and PSMD2 levels in ESCC tumors. Further studies indicate that PSMD2 activates the mTOR pathway by upregulating ASS1 to inhibit autophagy., Conclusions: PSMD2 plays an important role in repressing autophagy in ESCC, and represents a promising biomarker to predict prognosis and a therapeutic target of ESCC patients., (© 2023. The Author(s).)

Acute kidney injury (AKI) is a common and serious complication of cardiac surgery and is associated with increased mortality and morbidity, accompanied by a substantial economic burden. The pathogenesis of cardiac surgery-associated acute kidney injury (CSA-AKI) is multifactorial and complex, with a variety of pathophysiological theories. In addition to the existing diagnostic criteria, the exploration and validation of biomarkers is the focus of research in the field of CSA-AKI diagnosis. Prevention remains the key to the management of CSA-AKI, and common strategies include maintenance of renal perfusion, individualized blood pressure targets, balanced fluid management, goal-directed oxygen delivery, and avoidance of nephrotoxins. This article reviews the pathogenesis, definition and diagnosis, and pharmacological and nonpharmacological prevention strategies of AKI in cardiac surgical patients., (© 2023. The Author(s).)

Background: Exposure to cyclophosphamide (CTX) induces premature ovarian insufficiency (POI). Quercetin is a natural flavonoid that exhibits anti-inflammatory and antioxidant properties, and its antioxidant activity is correlated with POI. However, the mechanism underlying its protective role in CTX-induced ovarian dysfunction is unclear. This study aimed to explore whether quercetin can protect ovarian reserves by activating mitochondrial biogenesis and inhibiting pyroptosis., Methods: Thirty-six female C57BL/6 mice were randomly subdivided into six groups. Except for the control group, all groups were injected with 90 mg/kg CTX to establish a POI model and further treated with coenzyme 10 or various doses of quercetin. The mice were sacrificed 48 h after 10 IU pregnant mare serum gonadotropin was injected four weeks after treatments. We used enzyme-linked immunosorbent assays to detect serum hormone expression and light and transmission electron microscopy to assess ovarian tissue morphology and mitochondria. Additionally, we tested oxidant and antioxidant levels in ovarian tissues and mitochondrial function in granulosa cells (GCs). The expression of mitochondrial biogenesis and pyroptosis-related proteins and mRNA was analyzed using western blotting and RT-qPCR., Results: Quercetin elevated serum anti-Müllerian hormone, estradiol, and progesterone levels, decreased serum follicle-stimulating hormone and luteinizing hormone levels, and alleviated ovarian pathology. It reduced the mitochondrial DNA content and mitochondrial membrane potential. Furthermore, it upregulated ATP levels and the mRNA and protein expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), mitochondrial transcription factor A, and superoxide dismutase 2. In addition, it suppressed NOD-like receptor pyrin domain containing 3, caspase-1, interleukin-1β, and gasdermin D levels in the GCs of POI mice., Conclusions: Quercetin protected the ovarian reserve from CTX-induced ovarian damage by reversing mitochondrial dysfunction and activating mitochondrial biogenesis via the PGC1-α pathway. Moreover, quercetin may improve ovarian functions by downregulating pyroptosis in the CTX-induced POI model. Thus, quercetin can be considered a potential agent for treating POI., (© 2022. The Author(s).)

Background: Homocystinuria due to methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare autosomal recessive disorder. The purpose of this study is to expand the mutation site of the MTHFR gene and provide genetic counseling for this family., Methods: A couple came to our hospital for pre-pregnancy genetic counseling. We collected the family history and detailed clinical information, then performed whole-exome sequencing, and analyzed the pathogenicity of the candidate mutations., Results: We found that the father of the proband had homocystinuria, the proband and his brother had low blood methionine levels at birth, and the brain MRI showed brain dysplasia. The third fetus was found to have a broadened triangle of the bilateral ventricle at 19 weeks of pregnancy. The compound heterozygous variants of c.602 A > C (p.His201Pro) and c.1316T > C (p.Leu439Pro) of the MTHFR gene in the first three fetuses were found by whole-exome sequencing. The heterozygous c.602 A > C variant of the MTHFR gene is a novel missense variant that has been submitted to the ClinVar with Variation ID 992,662., Conclusion: In consideration of the clinical phenotype, family history, and result of genetic testing, we speculated that both patients may have homocystinuria due to MTHFR deficiency. Homocystinuria due to MTHFR deficiency caused by compound heterozygous mutations composed of the MTHFR gene in this family may be associated with cerebral atrophy and cerebral dysplasia. The novel compound heterozygous mutations broaden the mutation spectrum of the MTHFR gene and enhance the application of genetic counseling and carrier screening in rare diseases., (© 2022. The Author(s).)

Background: Renal clear cell carcinoma (ccRCC) is the most prevalent tumors worldwide. Discovering effective biomarkers is essential to monitor the prognosis and provide alternative clinical options. SPTBN1 is implicated in various cancerous processes. However, its role in ccRCC remains unelucidated. This study intends to explore the biological function and mechanism of SPTBN1 in ccRCC., Methods: Single-cell and bulk RNA-seq, tissue microarray, real-time quantitative PCR, and western blotting were applied to verify the expression and predictive value of SPTBN1 in ccRCC. Gain or loss of functional ccRCC cell line models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Actinomycin D experiment, RNA immunoprecipitation (RIP), specific inhibitors, and rescue experiments were carried out to define the molecular mechanisms., Results: SPTBN1 was down-regulated in ccRCC and knockdown of SPTBN1 displayed a remarkably oncogenic role both in vitro and in vivo; while overexpressing SPTBN1 reversed this effect. SPTBN1 mediated ccRCC progression via the pathway of glutamate pyruvate transaminase 2 (GPT2)-dependent glycolysis. The expression of GPT2 was significantly negatively correlated with that of SPTBN1. As an RNA binding protein SPTBN1, regulated the mRNA stability of GPT2., Conclusion: Our research demonstrated that SPTBN1 is significantly down-regulated in ccRCC. SPTBN1 knockdown promotes ccRCC progression via activating GPT2-dependent glycolysis. SPTBN1 may serve as a therapeutic target for the treatment of ccRCC., (© 2022. The Author(s).)

Background: The pathogenesis of inflammatory bowel diseases (IBD) is multifactorial, and diagnostic and treatment strategies for IBD remain to be developed. RhoB regulates multiple cell functions; however, its role in colitis is unexplored., Results: Here, we found RhoB was dramatically increased in colon tissues of ulcerative colitis (UC) patients and mice with DSS-induced colitis. Compared with wild type mice, RhoB +/- and RhoB -/- mice developed milder DSS-induced colitis and increased goblet cell numbers and IEC proliferation. Decreased RhoB promoted goblet cell differentiation and epithelial regeneration through inhibiting Wnt signaling pathway and activating p38 MAPK signaling pathway. Moreover, increased SCFA-producing bacteria and SCFA concentrations were detected in intestinal microbiome of both RhoB +/- and RhoB -/- mice and upregulated SCFA receptor expression was also observed., Conclusions: Taken together, a higher level of RhoB is associated with UC, which also contributes to UC development through modulating cell signaling and altering intestinal bacterial composition and metabolites. These observations suggest that RhoB has potential as a biomarker and a treatment target for UC. Video Abstract., (© 2022. The Author(s).)

Objective: To investigate pegylated recombinant human granulocyte colony-stimulating factor (PEG-rhG-CSF) safety and efficacy in preventing hematological toxicity during concurrent chemoradiotherapy (CCRT) for small-cell lung cancer (SCLC)., Methods: We retrospectively assessed 80 SCLC patients treated with CCRT from January 2013 to December 2018 who received PEG-rhG-CSF within 48 hours after the end of chemotherapy, defined as prophylactic use, as the experimental group. An additional 80 patients who were not treated with PEG-rhG-CSF were matched 1:1 by the propensity score matching method and served as the control group. The main observations were differences in hematological toxicity, neutrophil changes, febrile neutropenia (FN) incidence and adverse reactions. Progression-free survival (PFS) and overall survival (OS) were analyzed with regular assessment and follow-up., Results: The leukocyte, neutrophil, erythrocyte, and platelet counts and hemoglobin level decreased after CCRT, but the experimental group had slightly higher leukocyte and neutrophil counts than the control group (P < 0.05). The incidences of grade III-IV leukopenia (18.75% vs. 61.25%) and neutropenia (23.75% vs. 67.5%) in the experimental group were significantly lower than those in the control group (P < 0.05). The absolute neutrophil count was 4.17 ± 0.79 (× 10 9 /L) on day 1 and peaked 6.81 ± 2.37 (× 10 9 /L) on day 10 in the experimental group; the value in the control group was 2.81 ± 0.86 (× 10 9 /L) on day 1. It decreased significantly and reached the minimum 0.91 ± 0.53 (× 10 9 /L) on day 10 (P < 0.05). The experimental group had a lower FN incidence than the control group (P < 0.05). There was also no significant acute esophagitis or pulmonary toxicity. The treatment had no significant effect on PFS (11.4 months vs. 8.7 months, P = 0.958) or OS (23.9 months vs. 17.3 months, P = 0.325) over an 18.6-month median follow-up time., Conclusion: PEG-rhG-CSF has good efficacy and safety in preventing hematological toxicity in SCLC patients during CCRT and has no significant effects on PFS or OS., (© 2022. The Author(s).)

Objective: Diabetic nephropathy (DN) is regarded as the main vascular complication of diabetes mellitus, directly affecting the outcome of diabetic patients. Inflammatory factors were reported to participate in the progress of DN. Wingless-type family member 5 (WNT5A), myeloid zinc finger 1 (MZF1), and lysine methyltransferase 8 (SETD8) have also been reported to elevate inflammatory factor levels and activate the nuclear factor kappa B (NF-κB) pathway to induce endothelial dysfunction. In the current study, it was assumed that MZF1 associates with SETD8 to regulate WNT5A transcription, thus resulting in hyperglycemia-induced glomerular endothelial inflammation in DN., Methods: The present study recruited 25 diagnosed DN patients (type 2 diabetes) and 25 control participants (nondiabetic renal cancer patients with normal renal function, stage I-II) consecutively. Moreover, a DN rat and cellular model was constructed in the present study. Immunohistochemistry, Western blot, and quantitative polymerase chain reaction (qPCR) were implemented to determine protein and messenger RNA (mRNA) levels. Coimmunoprecipitation (CoIP) and immunofluorescence were implemented in human glomerular endothelial cells (HGECs). Chromatin immunoprecipitation assays and dual luciferase assays were implemented to determine transcriptional activity., Results: The results of this study indicated that levels of WNT5A expression, p65 phosphorylation (p-p65), and inflammatory factors were all elevated in DN patients and rats. In vitro, levels of p-p65 and inflammatory factors increased along with the increase of WNT5A expression in hyperglycemic HGECs. Moreover, high glucose increased MZF1 expression and decreased SETD8 expression. MZF1 and SETD8 inhibit each other under the stimulus of high glucose, but cooperate to regulate WNT5A expression, thus influencing p-p65 and endothelial inflammatory factors levels. Overexpression of MZF1 and silencing of SETD8 induced endothelial p-p65 and inflammatory factors levels, which can be reversed by si-WNT5A. Mechanistic research indicated that MZF1, SETD8, and its downstream target histone H4 lysine 20 methylation (H4K20me1) all occupied the WNT5A promoter region. sh-SETD8 expanded the enrichment of MZF1 on WNT5A promoter. Our in vivo study proved that SETD8 overexpression inhibited levels of WNT5A, p-p65 expression, and inflammatory factors in DN rats., Conclusions: MZF1 links with SETD8 to regulate WNT5A expression in HGECs, thus elevating levels of hyperglycemia-mediated inflammatory factors in glomerular endothelium of DN patients and rats. Trial registration ChiCTR, ChiCTR2000029425. 2020/1/31, http://www.chictr.org.cn/showproj.aspx?proj=48548., (© 2022. The Author(s).)

Background: Liquid lipases are widely used to convert oil into biodiesel. Methanol-resistant lipases with high catalytic activity are the first choice for practical production. Rhizomucor miehei lipase (RML) is a single-chain α/β-type protein that is widely used in biodiesel preparation. Improving the catalytic activity and methanol tolerance of RML is necessary to realise the industrial production of biodiesel., Results: In this study, a semi-rational design method was used to optimise the catalytic activity and methanol tolerance of ProRML. After N-glycosylation modification of the α-helix of the mature peptide in ProRML, the resulting mutants N218, N93, N115, N260, and N183 increased enzyme activity by 66.81, 13.54, 10.33, 3.69, and 2.39 times than that of WT, respectively. The residual activities of N218 and N260 were 88.78% and 86.08% after incubation in 50% methanol for 2.5 h, respectively. In addition, the biodiesel yield of all mutants was improved when methanol was added once and reacted for 24 h with colza oil as the raw material. N260 and N218 increased the biodiesel yield from 9.49% to 88.75% and 90.46%, respectively., Conclusions: These results indicate that optimising N-glycosylation modification in the α-helix structure is an effective strategy for improving the performance of ProRML. This study provides an effective approach to improve the design of the enzyme and the properties of lipase mutants, thereby rendering them suitable for industrial biomass conversion., (© 2021. The Author(s).)

Background: This study aimed to determine whether ultrasound-guided continuous erector spinae plane block (ESPB) had an effect on opioid consumption and postoperative rehabilitation in patients undergoing video-assisted thoracic surgery (VATS)., Methods: In this prospective study, 120 patients aged 20-70 years who underwent elective VATS were randomly allocated to one of three groups: group C (general anesthesia with patient-controlled intravenous analgesia [PCIA]), group T (general anesthesia with patient-controlled epidural analgesia [PCEA]), or group E (general anesthesia with continuous ESPB and PCIA). Perioperative opioid consumption, visual analog scale (VAS) scores, preoperative and postoperative Quality of Recovery-15 scores, and postoperative opioid-related adverse events were all assessed., Results: Intraoperative sufentanil consumption in groups T and E was significantly lower than that in group C (both P < 0.001), and the postoperative sufentanil consumption in group E was also significantly lower than that in group C (P = 0.001). Compared with group C, the VAS scores at rest or during coughing immediately out of the post-anesthesia care unit at 6 h, 12 h, and 24 h postoperatively were significantly lower in group T (P < 0.05). However, the VAS scores at rest at 6 h and 12 h postoperatively in group E were lower than those of group C (P < 0.05), but were significantly higher than those of group T at all study times (P < 0.05)., Conclusion: Ultrasound-guided continuous ESPB significantly reduced perioperative opioid consumption during VATS and improved postoperative rehabilitation. However, these effects were inferior to those of thoracic epidural anesthesia., Trial Registration: The present study was prospectively registered at http://www.chictr.org/cn /(registration number: ChiCTR1900023050 ); registration date: May 82,019., (© 2021. The Author(s).)

Background: Gas embolism induced by CO 2 pneumoperitoneum is commonly identified as a risk factor for morbidity, especially cardiopulmonary morbidity, after laparoscopic liver resection (LLR) in adults. Increasing pneumoperitoneum pressure (PP) contributes to gas accumulation following laparoscopy. However, few studies have examined the effects of PP in the context of LLR. In LLR, the PP-central venous pressure (CVP) gradient is increased due to hepatic vein rupture, hepatic sinusoid exposure, and low CVP management, which together increase the risk of CO 2 embolization. The aim of this study is to primarily determine the role of low PP (10 mmHg) on the incidence of severe gas embolism., Methods: Adult participants (n = 140) undergoing elective LLR will be allocated to either a standard (15 mmHg) or low (10 mmHg) PP group. Anesthesia management, postoperative care, and other processes will be performed similarly in both groups. The occurrence of severe gas embolism, which is defined as gas embolism ≥ grade 3 according to the Schmandra microbubble method, will be detected by transesophageal echocardiography (TEE) and recorded as the primary outcome. The subjects will be followed up until discharge and followed up by telephone 1 and 3 months after surgery. Postoperative outcomes, such as the Post-Operative Quality of Recovery Scale, pain severity, and adverse events, will be assessed. Serum cardiac markers and inflammatory factors will also be assessed during the study period. The correlation between intraoperative inferior vena cava-collapsibility index (IVC-CI) under TEE and central venous pressure (CVP) will also be explored., Discussion: This study is the first prospective randomized clinical trial to determine the effect of low versus standard PP on gas embolism using TEE during elective LLR. These findings will provide scientific and clinical evidence of the role of PP., Trial Status: Protocol version: version 1 of 21-08-2020 TRIAL REGISTRATION: ChiCTR2000036396 ( http://www.chictr.org.cn ). Registered on 22 August 2020., (© 2021. The Author(s).)

Background: Diabetic nephropathy (DN) is currently the leading cause of end-stage renal disease globally. The endothelial-to-mesenchymal transition (EndMT) of glomerular endothelial cells has been reported to play a crucial role in DN. As a specific form of epithelial-to-mesenchymal transition, EndMT and epithelial-to-mesenchymal transition may exhibit mutual modulators. Profilin 2 (PFN2) has been reported to participate in epithelial-to-mesenchymal transition. Moreover, ETS proto-oncogene 1 (ets1) and lysine methyltransferase 5A (KMT5A) have been reported to contribute to high glucose-mediated endothelial injury and epithelial-to-mesenchymal transition. In this study, we hypothesize ets1 associates with KMT5A to modulate PFN2 transcription, thus participating in high glucose-mediated EndMT in glomerular endothelial cells., Methods: Immunohistochemistry (IHC) was performed to detect protein levels in the kidney tissues and/or aorta tissues of human subjects and rats. Western blot, qPCR and immunofluorescence were performed using human umbilical vein endothelial cells (HUVECs). Chromatin immunoprecipitation (ChIP) assays and dual luciferase assays were performed to assess transcriptional activity. The difference between the groups was compared by two-tailed unpaired t-tests or one-way ANOVAs., Results: Our data indicated that vimentin, αSMA, S100A4 and PFN2 levels were increased, and CD31 levels were reduced in glomerular endothelial cells of DN patients and rats. Our cell experiments showed that high glucose induced EndMT by augmenting PFN2 expression in HUVECs. Moreover, high glucose increased ets1 expression. si-ets1 suppressed high glucose-induced PFN2 levels and EndMT. ets1 overexpression-mediated EndMT was reversed by si-PFN2. Furthermore, ets1 was determined to associate with KMT5A. High glucose attenuated KMT5A levels and histone H4 lysine 20 methylation (H4K20me1), one of the downstream targets of KMT5A. KMT5A upregulation suppressed high glucose-induced PFN2 levels and EndMT. sh-KMT5A-mediated EndMT was counteracted by si-PFN2. Furthermore, H4K20me1 and ets1 occupied the PFN2 promoter region. sh-KMT5A cooperated with ets1 overexpression to activate PFN2 promoter activity. Our in vivo study demonstrated that KMT5A was reduced, while ets1 was augmented, in glomerular endothelial cells of DN patients and rats., Conclusions: The present study indicated that ets1 cooperated with KMT5A to transcribe PFN2, thus contributing to hyperglycemia-induced EndMT in the glomerular endothelial cells of DN patients and rats. Trial registration ChiCTR, ChiCTR2000029425. 2020/1/31, http://www.chictr.org.cn/showproj.aspx?proj=48548.

Background: Ubiquitylation modification is one of the multiple post-transcriptional process to regulate cellular physiology, including cell signaling, cycle regulation, DNA repair and transcriptional regulation. Members of TRIM family proteins could be defined as E3 ubiquitin ligases as they contain a RING-finger domain, and alterations of TRIM proteins are involved into a broad range of diverse disorders including cancer. TRIM37 is a novel discovered E3 ubiquitin ligase and acts as a oncoprotein in multiple human neoplasms, however its biological role in RCC still remains elusive., Methods: RCC microarray chips and public datasets were screened to identify novel TRIMs member as TRIM37, which was dysregulated in RCC. Gain or loss of functional cancer cell models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Interactive network analyses were utilized to define intrinsic mechanism., Results: We identified TRIM37 was upregulated in RCC tumors, and its aberrant function predicted aggressive neoplastic phenotypes, poorer survival endings. TRIM37 promoted RCC cells EMT and malignant progression via TGF-β1 signaling activation, as a consequence of directly mediated by ubiquitinating-H2A modifications., Conclusions: Our findings identified a previously unappreciated role of TRIM37 in RCC progression and prognostic prediction. Importantly, we declared a novel ubiquitination-dependent link between TRIM ubiquitin ligases and TGF-β1 signaling in regulating cancerous malignancies.

Background: Risk factors that predispose the development of severe community-acquired pneumonia (CAP) among pediatric CAP patients of different age ranges are yet to be identified., Methods: We retrospectively analyzed pediatric in-patients (< 6 years old) diagnosed with CAP in our hospital. We subdivided patients into four age groups (< 6 months, 6 months-1 year, 1-2 years, and 2-6 years). Their medical records, including demographic information, clinical features, laboratory findings, and chest radiographic reports, were reviewed and collected for further analysis. Univariate logistic regression analysis and stepwise regression analysis were applied to identify risk factors associated with severe CAP and ICU admission for overall patients and age-stratified subgroups., Results: A total of 20,174 cases were initially included. Among them, 3309 (16.40%) cases were identified as severe CAP, and 2824 (14.00%) cases required ICU admission. Potential risk factors for severe CAP and ICU admission identified by univariate analysis included younger age, rural residency, premature birth, low birth weight (LBW), formula feeding, congenital heart disease (CHD), history of pneumonia or neonatal jaundice, patients with other health issues, certain symptoms (manifesting wheezing, dyspnea, cyanosis, but have no cough or fever), abnormal laboratory findings (abnormal levels of white blood cells, albumin, and C-reactive protein and RSV infection), and chest X-ray (odds ratio [OR] > 1 for all). CHD, low albumin, proteinuria, abnormal chest x-ray were independent risks factors across different age groups, whereas birth or feeding history, history of pneumonia, cyanosis or dyspnea on admission, and RSV infection were independent risk factors for only younger kids (< 1 year), and wheezing was an independent risk factor only for older children (2-5 years old)., Conclusions: Risk factors predicting disease severity among children hospitalized with CAP vary with age. Risk factor stratification of pediatric CAP based on age-specific risk factors can better guide clinical practice., Trial Registration: This study has been registered in China, with the registration number being ChiCTR2000033019 .

Background: Cell division cycle-associated 7 (CDCA7), as a member of the cell division cycle associated family, was reported to be aberrantly expressed in both solid tumors and hematological tumors, suggesting its essential role in promoting tumorigenesis. Hence, we aimed to explore its comprehensive roles of overall survival (OS) in clear cell renal cell carcinoma (ccRCC) and emphasize its associations with immunity., Methods: The RNA sequencing data and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. Gene set enrichment analysis (GSEA) was adopted to explore CDCA7 associated signaling pathways. Univariate and multivariate Cox regression analyses were carried out to assess independent prognostic factors. Furthermore, roles of CDCA7 in human immunity were also investigated., Results: Our results suggested that CDCA7 was overexpressed in ccRCC and its elevated expression was related to shorter OS (P < 0.01). Univariate and multivariate Cox regression analyses identified CDCA7 as an independent prognostic factor (both P < 0.05). The prognostic nomogram integrating CDCA7 expression level and clinicopathologic variables was constructed to predict 1-, 3- and 5-year OS. GSEA indicated that high CDCA7 expression was related to the apoptosis pathway, cell cycle pathway, JAK-STAT pathway, NOD like receptor pathway, P53 pathway, T cell receptor pathway and toll like receptor pathway, etc. Moreover, CDCA7 was significantly related to microsatellite instability (MSI, P < 0.001) and tumor mutational burden (TMB, P < 0.001). As for immunity, CDCA7 was remarkably associated with immune infiltration, tumor microenvironment, immune checkpoint molecules and immune pathways., Conclusions: CDCA7 could serve as an independent prognostic factor for ccRCC and it was closely related to MSI, TMB, and immunity.

Background: Diabetic encephalopathy is a severe diabetes complication with cognitive dysfunction and neuropsychiatric disability. The mechanisms underlying diabetic encephalopathy is believed to be relevant with oxidative stress, vascular amylin deposition, immune receptors, inflammation, etc. This study wanted to evaluate the ability of curcumin and its analog A13 to alleviate oxidative stress and inflammation in diabetes-induced damages in brain., Methods: Sixty adult male Sprague-Dawley rats were divided into 5 groups: normal control (NC) group, diabetes mellitus (DM) group, curcumin-treated diabetes mellitus (CUR) group, high dose of A13-treated diabetes mellitus (HA) group, low dose of A13-treated diabetes mellitus (LA) group. Activation of the nuclear factor kappa-B (NF-κB p65) pathway was detected by RT-qPCR, immunohistochemical (IHC) staining and Western blot; oxidative stress was detected by biochemical detection kit; brain tissue sections were stained with hematoxylin-eosin (HE) staining and Myelin staining., Results: RT-qPCR, IHC staining and Western blot showed that curcumin and A13 treatment could inhibit the NF-κB p65 pathway. Curcumin and A13 increased the activity of superoxide dismutase and decreased the malondialdehyde level in the brain of diabetic rats. Furthermore, HE staining and Myelin staining demonstrated that the histological lesions of the brain in diabetic rats could be significantly ameliorated by curcumin and A13., Conclusion: Curcumin analog A13 could alleviate the damages in the brain of diabetes rats by regulating the pathways of inflammation and oxidative stress. A13 may be a new potential therapeutic agent for diabetic encephalopathy.

Background: Rebound pain after a single-shot nerve block challenges the real benefit of this technique. We aimed to investigate whether perineural dexamethasone addition decreased the incidence of rebound pain after a single-shot nerve block., Methods: We randomly allocated 132 patients scheduled for open reduction internal fixation of an upper extremity closed fracture under single-shot peripheral nerve block and sedation into two groups. Patients in the dexamethasone group received nerve block with 0.375% ropivacaine and 8 mg dexamethasone, while those in the control group received ropivacaine only. Sixty-three patients in the dexamethasone group and 60 patients in the control group were analyzed for the incidence of rebound pain 48 h after block administration, which was the primary outcome. The secondary outcomes included the highest self-reported numeric rating scale (NRS) pain score, and NRS at 8, 12, 24, and 48 h after the block, sufentanil consumption, sleep quality on the night of surgery, patient satisfaction with the pain therapy, blood glucose at 6 h after the block, pain and paresthesia at 30 days after surgery., Results: The incidence of rebound pain was significantly lower in the dexamethasone group (7 [11.1%] of 63 patients) than in the control group (28 [48.8%] of 60 patients [RR = 0.238, 95% CI (0.113-0.504), p = 0.001]. Dexamethasone decreased opioid consumption in 24 h after surgery (p < 0.001) and improved the sleep quality score on the night of surgery (p = 0.01) and satisfaction with pain therapy (p = 0.001). Multivariate logistic regression analysis showed that only group allocation was associated with the occurrence of rebound pain [OR = 0.062, 95% CI (0.015-0.256)]. Patients in the dexamethasone group reported later onset pain (19.7 ± 6.6 h vs 14.7 ± 4.8 h since block administration, mean ± SD, p < 0.001) and lower peak NRS scores [5 (3, 6) vs 8 (5, 9), median (IQR), p < 0.001] than those in the control group., Conclusions: The perineural administration of 8 mg dexamethasone reduces rebound pain after a single-shot nerve block in patients receiving ORIF for an upper limb fracture., Trial Registration: This study was retrospectively registered in the Chinese Clinical Trial Registry ( ChiCTR-IPR-17011365 ) on May 11th, 2017.

Background: The ideal fraction of nitrous oxide (N 2 O) in oxygen (O 2 ) for rapid lung collapse remains unclear. Accordingly, this prospective trial aimed to determine the 50% effective concentration (EC 50 ) and 95% effective concentration (EC 95 ) of N 2 O in O 2 for rapid lung collapse., Methods: This study included 38 consecutive patients undergoing video-assisted thoracoscopic surgery (VATS). The lung collapse score (LCS) of each patient during one-lung ventilation was evaluated by the same surgeon. The first patient received 30% N 2 O in O 2 , and the subsequent N 2 O fraction in O 2 was determined by the LCS of the previous patient using the Dixon up-and-down method. The testing interval was set at 10%, and the lowest concentration was 10% (10, 20, 30, 40%, or 50%). The EC 50 and EC 95 of N 2 O in O 2 for rapid lung collapse were analyzed using a probit test., Results: According to the up-and-down method, the N 2 O fraction in O 2 at which all patients exhibited successful lung collapse was 50%. The EC 50 and EC 95 of N 2 O in O 2 for rapid lung collapse were 27.7% (95% confidence interval 19.9-35.7%) and 48.7% (95% confidence interval 39.0-96.3%), respectively., Conclusions: In patients undergoing VATS, the EC 50 and EC 95 of N 2 O in O 2 for rapid lung collapse were 27.7 and 48.7%, respectively., Trial Registration: http://www.chictr.org/cn/ Identifier ChiCTR19 00021474 , registered on 22 February 2019.

Background: The levels of tight junction proteins (TJs), especially occludin, correlate with blood-brain barrier (BBB) disruption caused by inflammation in central nervous system (CNS). It has been reported that propofol, the most commonly used anesthetic, could inhibit inflammation response in CNS. In this study, we investigated the effects of tumor necrosis factor-α (TNF-α) and propofol on occludin expression in human cerebral microvascular endothelial cell line, D3 clone (hCMEC/D3 cells), and explored the underlying mechanisms., Methods: The hCMEC/D3 cells were treated with propofol, followed by TNF-α. The expression and phosphorylation of Hif-1α, VEGF, VEGFR-2, ERK, p38MAPK and occludin were measured by Western blot analysis. The cell viability of hCMEC/D3 cells was measured by cell counting kit-8., Results: TNF-α (10 ng/ml, 4 h) significantly decreased the expression of occludin, which was attenuated by propofol (25 μM). TNF-α induced Hif-1α/VEGF/VEGFR-2/ERK signaling pathway, while propofol could inhibit it. TNF-α induced the phosphorylation of p38MAPK, while propofol had no effect on it. In addition, the inhibitors of Hif-1α, VEGFR-2, and ERK could reduce the effect of TNF-α on occludin expression., Conclusion: TNF-α could decrease the expression of occludin via activating Hif-1α/ VEGF/ VEGFR-2/ ERK signaling pathway, which was attenuated by propofol.

Background: Hyperspectral reflectance data in the visible, near infrared and shortwave infrared range (VIS-NIR-SWIR, 400-2500 nm) are commonly used to nondestructively measure plant leaf properties. We investigated the usefulness of VIS-NIR-SWIR as a high-throughput tool to measure six leaf properties of maize plants including chlorophyll content (CHL), leaf water content (LWC), specific leaf area (SLA), nitrogen (N), phosphorus (P), and potassium (K). This assessment was performed using the lines of the maize diversity panel. Data were collected from plants grown in greenhouse condition, as well as in the field under two nitrogen application regimes. Leaf-level hyperspectral data were collected with a VIS-NIR-SWIR spectroradiometer at tasseling. Two multivariate modeling approaches, partial least squares regression (PLSR) and support vector regression (SVR), were employed to estimate the leaf properties from hyperspectral data. Several common vegetation indices (VIs: GNDVI, RENDVI, and NDWI), which were calculated from hyperspectral data, were also assessed to estimate these leaf properties., Results: Some VIs were able to estimate CHL and N (R 2  > 0.68), but failed to estimate the other four leaf properties. Models developed with PLSR and SVR exhibited comparable performance to each other, and provided improved accuracy relative to VI models. CHL were estimated most successfully, with R 2 (coefficient of determination) > 0.94 and ratio of performance to deviation (RPD) > 4.0. N was also predicted satisfactorily (R 2  > 0.85 and RPD > 2.6). LWC, SLA and K were predicted moderately well, with R 2 ranging from 0.54 to 0.70 and RPD from 1.5 to 1.8. The lowest prediction accuracy was for P, with R 2  < 0.5 and RPD < 1.4., Conclusion: This study showed that VIS-NIR-SWIR reflectance spectroscopy is a promising tool for low-cost, nondestructive, and high-throughput analysis of a number of leaf physiological and biochemical properties. Full-spectrum based modeling approaches (PLSR and SVR) led to more accurate prediction models compared to VI-based methods. We called for the construction of a leaf VIS-NIR-SWIR spectral library that would greatly benefit the plant phenotyping community for the research of plant leaf traits., Competing Interests: Competing interestsThe authors declare that they have no competing interests.

Background: The mammalian homologs of Lin-28, Lin28 (also called Lin28A) and Lin28B, are promising cancer biomarkers. This meta-analysis was performed to evaluate the prognostic values of Lin28A and Lin28B in multiple human malignancies., Methods: Systematic searches of the PubMed, Web of Science and Embase were used to identify relevant studies. Pooled hazard ratios (HRs) with 95% confidence intervals (CI) for overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), or progression-free survival (PFS) were respectively calculated., Results: 3772 Lin28A-associated patients and 1730 Lin28B-related cases were ultimately enrolled in this meta-analysis. The elevated expression level of Lin28A was significantly associated with poor OS (HR = 1.60, P < 0.001) and poor RFS/DFS/PFS (HR = 1.62, P < 0.001) in patients with malignancies. Lin28B overexpression significantly correlated with unfavorable OS (HR = 1.72, P < 0.001) and RFS/DFS/PFS (HR = 2.35, P < 0.001) of human malignancies., Conclusions: Lin28A and Lin28B possess significant prognostic values in various human malignancies. Overexpression of Lin28A or Lin28B suggests poor prognosis for cancer patients., Competing Interests: The authors declare that they have no competing interests.

Background: Metanephric adenoma is a rare, benign renal neoplasm with occasional misdiagnosis. However, its molecular characterization is not fully understood., Methods: In this study, we use the hybrid capture-based Next-Generation Sequencing to sequence a panel of 295 well-established oncogene or tumor suppressor genes in 28 cases of MA patients in China. Novel clinicopathological markers associated with the mitogen-activated protein kinase (MAPK) pathway in metanephric adenoma were detected by immunohistochemistry., Results: It was found that except for BRAF (22/28) mutations (c.1799 T > A, p.V600E), NF1 (6/28), NOTCH1 (5/28), SPEN (5/28), AKT2 (4/28), APC (4/28), ATRX (3/28), and ETV4 (3/28) mutations could also be detected. Meanwhile, a novel and rare gene fusion of STARD9-BRAF, CUX1-BRAF, and LOC100507389-BRAF was detected in one MA patient. In addition, although MEK phosphorylation was normally activated, the phosphorylation level of ERK was low in metanephric adenoma cases. Highly expressed p16 and DUSP6 may have contributed to these results, which maintained MA as a benign renal tumor., Conclusions: This study provides novel molecular and pathological markers for metanephric adenoma, which could improve its diagnosis and increase the understanding of its pathologic mechanism.

Background: Integrins are essential regulators of angiogenesis. However, the antiangiogenic potential of peptides derived from the integrin cytoplasmic tails (CT) remains mostly undetermined., Methods: Here we designed a panel of membrane-penetrating peptides (termed as mβCTPs), each comprising a C-terminal NxxY motif from one of the conserved integrin β CTs, and evaluated their antiangiogenic ability using both in vitro and in vivo approaches., Results: We found that mβ3CTP, mβ5CTP and mβ6CTP, derived respectively from the integrin β3, β5 and β6 CTs, but not others, exhibit antiangiogenic ability. Interestingly, we observed that the integrin β3, β5 and β6 CTs but not others are able to interact with β 3 -endonexin. In addition, the antiangiogenic core in mβ3CTP is identical to a previously identified β 3 -endonexin binding region in the integrin β3 CT, indicating that the antiangiogenic mβCTPs may function via their binding to β 3 -endonexin. Consistently, knockdown of endogenous β 3 -endonexin in HUVECs significantly suppresses tube formation, suggesting that β 3 -endonexin is proangiogenic. However, neither treatment with the antiangiogenic mβCTPs nor knockdown of endogenous β 3 -endonexin affects integrin-mediated HUVEC adhesion and migration, indicating that their antiangiogenic effect may not rely on directly regulating integrin activity. Importantly, both treatment with the antiangiogenic mβCTPs and knockdown of endogenous β 3 -endonexin in HUVECs inhibit VEGF expression and cell proliferation, thereby providing mechanistic explanations for the functional consequences., Conclusion: Our results suggest that the antiangiogenic mβCTPs can interact with β 3 -endonexin in vascular endothelial cells and suppress its function in regulating VEGF expression and cell proliferation, thus disclosing a unique pathway that may be useful for developing novel antiangiogenic strategies.