Salsolinol as an RNA m6A methylation inducer mediates dopaminergic neuronal death by regulating YAP1 and autophagy.

JOURNAL/nrgr/04.03/01300535-202503000-00032/figure1/v/2024-06-17T092413Z/r/image-tiff Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline, Sal) is a catechol isoquinoline that causes neurotoxicity and shares structural similarity with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, an environmental toxin that causes Parkinson's disease. However, the mechanism by which Sal mediates dopaminergic neuronal death remains unclear. In this study, we found that Sal significantly enhanced the global level of N6-methyladenosine (m6A) RNA methylation in PC12 cells, mainly by inducing the downregulation of the expression of m6A demethylases fat mass and obesity-associated protein (FTO) and alkB homolog 5 (ALKBH5). RNA sequencing analysis showed that Sal downregulated the Hippo signaling pathway. The m6A reader YTH domain-containing family protein 2 (YTHDF2) promoted the degradation of m6A-containing Yes-associated protein 1 (YAP1) mRNA, which is a downstream key effector in the Hippo signaling pathway. Additionally, downregulation of YAP1 promoted autophagy, indicating that the mutual regulation between YAP1 and autophagy can lead to neurotoxicity. These findings reveal the role of Sal on m6A RNA methylation and suggest that Sal may act as an RNA methylation inducer mediating dopaminergic neuronal death through YAP1 and autophagy. Our results provide greater insights into the neurotoxic effects of catechol isoquinolines compared with other studies and may be a reference for assessing the involvement of RNA methylation in the pathogenesis of Parkinson's disease.

The association of isocarbophos and isofenphos with different types of glucose metabolism: The role of inflammatory cells.

To investigate the associations between isocarbophos and isofenphos with impaired fasting glucose (IFG) and type 2 diabetes mellitus (T2DM), and to assess the mediation roles of inflammation cells. There were 2701 participants in the case-control study, including 896 patients with T2DM, 900 patients with IFG, 905 subjects with NGT. Plasma isocarbophos and isofenphos concentrations were measured using gas chromatography and triple quadrupole tandem mass spectrometry. Generalized linear models were used to calculate the relationships between plasma isofenphos and isocarbophos levels with inflammatory factor levels and T2DM. Inflammatory cell was used as mediators to estimate the mediating effects on the above associations. Isocarbophos and isofenphos were positively related with T2DM after adjusting for other factors. The odds ratio (95% confidence interval) (OR (95%CI)) for T2DM was 1.041 (1.015, 1.068) and for IFG was 1.066 (1.009, 1.127) per unit rise in ln-isocarbophos. The prevalence of T2DM increased by 6.4% for every 1 unit more of ln-isofenphos (OR (95% CI): 1.064 (1.041, 1.087)). Additionally, a 100% rise in ln-isocarbophos was linked to 3.3% higher ln-HOMA2IR and a 0.029 mmol/L higher glycosylated hemoglobin (HbA1c) (95% CI: 0.007, 0.051). While a 100% rise in ln-isofenphos was linked to increase in ln-HOMA2 and ln-HOMA2IR of 5.8% and 3.4%, respectively. Furthermore, white blood cell (WBC) and neutrophilic (NE) were found to be mediators in the relationship between isocarbophos and T2DM, and the corresponding proportions were 17.12% and 17.67%, respectively. Isofenphos and isocarbophos are associated with IFG and T2DM in the rural Chinese population, WBC and NE have a significant role in this relationship.

[Immune mechanism of Daphnes Cortex and its processed products on CIA rats based on B7/CD28/CTLA-4 pathway].

This study investigates the effects of Daphnes Cortex and its processed products on the differentiation of Th17/Treg cells in SD rats with type Ⅱ collagen-induced arthritis(CIA).Sixty-four SD rats were randomly divided into the normal group(normal),model group(model),fried Daphne giraldii Nitsche low-dose and high-dose groups(FDGN-L group, FDGN-H group),raw D. giraldii Nitsche low-dose and high-dose groups(RDGN-L group, RDGN-H group),daphnetin group(DAPH group),and tripterygium glycosides group(GTW group).Except for the normal group, the CIA model was immunized on the seventh day after the first immunization, and was gavaged for 28 days after the second immunization.After sampling, the inflammation of articular synovial membrane in CIA rats was observed by hematoxylin-eosin(HE)staining; the levels of transforming growth factor-ß(TGF-ß),interferon-γ(IFN-γ),interleukin(IL)-2,IL-4,and IL-10 in serum were detected by enzyme-linked immunosorbent assay(ELISA); real-time reverse transcription-PCR(qRT-PCR)and Western blot were used to detect the mRNA and protein expressions of cluster of differentiation(CD) 80(B7-1),CD 86(B7-2),CD28,and cytotoxic T lymphocyte-associated antigen 4(CTLA-4)in the synovial membrane of rats; flow cytometry was used to detect the proportion of Th17 and Treg cells in the synovial membrane of rats.The results showed that compared with the normal group, the joint synovial inflammation of rats in the model group was significantly aggravated, the arthritis index was significantly increased, and the immune organ index was increased(P<0.01).Compared with the model group, each drug administration group could improve the joint inflammation of rats to varying degrees, reduce the arthritis index, inhibit synovial hyperplasia, and reduce the immune organ index; compared with the model group, the serum levels of IL-2 and IFN-γ in each drug administration group were significantly decreased(P<0.01),TGF-ß,IL-4,and IL-10 were significantly increased(P<0.01),the mRNA and protein expressions of B7-1 and CTLA-4 in the synovial membrane were significantly increased(P<0.01),and the proportion of Th17 cells and Treg cells in the joint tissue was significantly decreased(P<0.01).In conclusion, Daphnes Cortex inhibits the expression of Th17 cells in CIA rats and promotes the expression of Treg cells by regulating the B7/CD28/CTLA-4 pathway and the balance of Th17/Treg, thereby treating rheumatoid arthritis.

Immunosuppressive effects of triptolide via interleukin-2/receptor signaling.

BACKGROUND: Triptolide (TP) has been confirmed to possess many beneficial functions including anti-inflammation and immunosuppression. OBJECTIVE: The present study aimed to explore the potential involvement of IL-2/IL-2R pathway in the immunosuppressive activities of TP. METHODS: Cultured CTLL-2 cells were utilized to evaluate the potential benefits of TP. Then cell viability was determined by CCK-8 assay, IFN-γ level by ELISA assay, Annexin V-FITC/PI double-staining and CD25 expression by flow cytometry, and protein expression by western blotting. Additionally, rhIL-2-driven lymphocytes following ConA activation were investigated. The interactions of TP with IL-2 and IL-2Rα were investigated by binding assays and molecular dynamics simulations. RESULTS: TP treatment attenuated IFN-γ level and cell viability in both rhIL-2-induced CTLL-2 cells and rhIL-2-driven splenic lymphocytes. TP treatment increased cellular apoptosis/necrosis and cleaved PARP-1 level, while suppressed c-Myc level in rhIL-2-induced CTLL-2 cells. Additionally, TP treatment reduced CD25 expression on CTLL-2 cell surface. Notably, the phosphorylation protein levels in IL-2R signaling pathways were inhibited by TP exposure prior to rhIL-2 stimulation. SPR and BLI assays verified TP that directly bound to rhIL-2 and rmIL-2Rα, respectively. Molecular simulations suggested that TP bound at the interface of IL-2 and IL-2Rα near the hydrophobic patch composed of F62, L92 on IL-2 and L23, I46, V139 on IL-2Rα, resulting in decreased binding free energy between IL-2 and IL-2Rα. CONCLUSIONS: These findings collectively emphasized that TP interfered IL-2/IL-2Rα interactions, down-regulated IL-2Rα expression, and inhibited IL-2R signaling pathways activation, thereby leading to the immune cells being desensitized to rhIL-2 and exhibiting immunosuppressive properties.

SUV39H1 epigenetically modulates the MCPIP1-AURKA signaling axis to enhance neuroblastoma tumorigenesis.

Epigenetic regulation is a pivotal factor during neuroblastoma (NB) pathogenesis and investigations into cancer epigenetics are actively underway to identify novel therapeutic strategies for NB patients. SUV39H1, a member of the H3K9 methyltransferase family, contributing to tumorigenesis across multiple malignancies. However, its specific role in NB remains unexplored. In this study, we conducted a high-throughput screen utilizing a compound library containing 288 epigenetic drugs, leading to the identification of chaetocin as the most potent NB inhibitor by targeting SUV39H1. Genetic manipulation and therapeutic inhibition of SUV39H1 significantly impacted proliferation, migration, cell cycle phases, and apoptosis in NB cells. Concurrently, chaetocin demonstrated robust anti-tumor efficacy in vivo with tolerable toxicity. RNA-seq unveiled that SUV39H1 knockdown and inhibition down-regulated cell cycle pathways, impacting vital genes such as AURKA. Besides, MCPIP1 emerged as a novel tumor suppressor following SUV39H1 inhibition, which decreased AURKA expression in NB. In detail, SUV39H1 mediated the enrichment of H3K9me3 at the promoter region of MCPIP1, repressing the MCPIP1-mediated degradation of AURKA and facilitating the subsequent accumulation of AURKA, which revealed the oncogenic role of SUV39H1 via the SUV39H1-MCPIP1-AURKA signaling axis in NB. Therapeutic inhibition of SUV39H1 using chaetocin emerges as an effective and safe strategy for NB patients. Illustration of the oncogenic pathway regulated by SUV39H1 in NB.

Efficacy and safety evaluation of first-line systemic treatments for unresectable esophageal squamous cell carcinoma: a network meta-analysis.

Objective: To evaluate the efficacy and safety of various first-line initial treatment systemic regimens for patients with unresectable esophageal squamous carcinoma(ESCC), utilizing a network meta-analysis approach. Methods: A comprehensive search for randomized controlled trials focusing on the primary treatment of esophageal cancer ESCC was conducted across multiple databases including PubMed, Embase, Cochrane Library, and Web of Science, up until November 17, 2023. The quality of the included studies was rigorously assessed using Review Manager software. Subsequently, data analysis was meticulously carried out employing R software. The first-line treatment regimens examined were: CD (Cisplatin + Docetaxel), CET-CF (Cetuximab + Cisplatin + Fluorouracil), CF (Cisplatin + Fluorouracil), N-CF (Nivolumab + Cisplatin + Fluorouracil), NI (Nivolumab + Ipilimumab), Nim-CF (Nimotuzumab + Cisplatin + Fluorouracil), P-CF (Pembrolizumab + Cisplatin + Fluorouracil), and Ser-CF (Serplulimab + Cisplatin + Fluorouracil). The Primary endpoints included the overall survival(OS),progression-free survival (PFS),objective response rate (ORR) and disease control rate (DCR).The secondary endpoint was adverse effects(AEs). Results: The analysis encompassed eight studies, incorporating a total of 3,051 patients with untreated esophageal cancer. There are 45 people in the CD regimen,32 in the CET-CF regimen,1,212 in the CF regimen,447 in the N-CF regimen,456 in the NI regimen,53 in the Nim-CF regimen,447 in the P-CF regimen and 368 in the Ser-CF regimen. The network meta-analysis revealed that, in comparison to the CF regimen, the other regimens (CD, CET-CF, N-CF, NI, Nim-CF, P-CF, and Ser-CF) did not demonstrate a statistically significant impact on overall survival (OS) or progression-free survival (PFS). However, Ser-CF potentially offers superior outcomes in terms of OS and PFS when juxtaposed with other regimens. Notably, N-CF was associated with a substantial increase in the objective response rate (ORR), and CET-CF markedly improved the disease control rate (DCR). In terms of adverse effects, N-CF was more likely to cause anorexia, whereas CET-CF was significantly associated with nausea, vomiting, neutropenia, and skin disorders. Conclusion: The current evidence suggests that N-CF may provide the most favorable outcomes in terms of ORR, while CET-CF could be the optimal choice for enhancing DCR in patients with untreated esophageal cancer.

Decoding the diabetic bone paradox: How AGEs sabotage skeletal integrity.

Diabetes patients often suffer from fractures despite normal or high bone mineral density, a phenomenon known as the diabetic bone paradox. Gao et al.1 identify AGEs as disrupting bone quality and compromising skeletal integrity in diabetic bone disease.

Yeast ß-glucan attenuates dextran sulfate sodium-induced colitis: Involvement of gut microbiota and short-chain fatty acids.

Yeast ß-glucan intervention offers a promising strategy for managing colitis; however, the mechanisms remain unknown. In the present work, the protective effects of yeast ß-glucan on DSS-induced colitis in mice was evaluated, focusing on its interaction with gut microbiota. The result showed yeast ß-glucan significantly alleviated colitis symptoms, evidenced by reduced weight loss, lower disease activity index (DAI) scores, and minimized intestinal damage. It enhanced intestinal barrier integrity via upregulation of tight junction proteins, suppressed lipopolysaccharide (LPS) release, and decreased pro-inflammatory cytokines production. Additionally, yeast ß-glucan boosted short-chain fatty acids (SCFAs) production, and activated their receptors, increased the relative abundances of beneficial microbes like Lactobacillus and Lachnospiraceae_UCG-006. Transcriptomic analyses suggest that yeast ß-glucan mitigates inflammation by downregulating gene expression related to IL-17 pathway. Our findings highlight potential of yeast ß-glucan as a therapeutic agent for colitis through modulation of gut microbiota and inflammatory responses.

Combination of circulating tumor cells, lncRNAs and DNA methylation for the diagnosis of endometrial carcinoma.

Endometrial carcinoma (EC) is one of the most common gynecological malignant neoplasms, the prognosis of which is strongly related to the time of diagnosis, with an earlier diagnosis leading to a better prognosis. Therefore, effective diagnostic indicators and methods are needed to ensure early detection. The present study explored the following in EC: Circulating tumor cells (CTCs); the long noncoding RNAs (lncRNAs) RP4-616B8.5, RP11-389G6.3 and carboxy-terminal domain (CTD)-2377D24.6; and the methylation of cysteine dioxygenase type 1 (CDO1) and CUGBP Elav-like family member 4 (CELF4). In total, 85 patients, including 71 with EC, and 14 without EC (NO-EC) but with uterine fibroids or polyps, were included in the present study. In total, 46 patients with EC and 8 NO-EC patients underwent CTC detection. In the evaluation of the EC vs. NO-EC groups, the results showed that the CTC-positive rate of the EC group was 80.43% and that the area under the curve (AUC) value of CTCs was 0.8872 (P=0.0098). A total of 35 patients with EC and 14 NO-EC patients underwent detection of the RP4-616B8.5, RP11-389G6.3 and CTD-2377D24.6 lncRNAs. When the levels of the three lncRNAs RP4-616B8.5, RP11-389G6.3 and CTD-2377D24.6 were compared between the EC and NO-EC groups, they were higher in the EC group; the P-values were 0.0002, 0.0001 and <0.0001, respectively, and the AUC values were 0.8184, 0.8347 and 0.8265, respectively. In addition, a total of 35 patients with EC and 8 NO-EC patients underwent CDO1 and CELF4 DNA methylation analysis. The positive rates of the methylated genes CDO1 and CELF4 were 20% (7/35) and 5.71% (2/35), and the P-values of the comparisons between the EC and NO-EC groups were 0.1748 and 0.5004, respectively; the AUC values were 0.6000 and 0.5286. Furthermore, the combination of CTCs, and lncRNAs RP4-616B8.5, RP11-389G6.3 and CTD-2377D24.6 exhibited high performance in the detection of EC (AUC=0.9375).

Didymin ameliorates ulcerative colitis-associated secondary liver damage by facilitating Notch1 degradation.

BACKGROUND: Didymin is a dietary flavonoid originally discovered by our group as a potent anti-ulcerative colitis (UC) agent. However, whether didymin plays a protective role in UC-associated inflammatory liver injury is still unclear. PURPOSE: This study aimed to evaluate the therapeutic potential of didymin on UC-associated inflammatory liver injury and explore the underlying mechanism. STUDY DESIGN AND METHODS: Colitis model was established in C57BL/6 mice by exposure to DSS, and didymin was administrated intragastrically for consecutive 10 days. The inflammatory liver injury was assessed by levels of alanine aminotransferase (ALT) and aspartate transaminase (AST) in serum and histopathological damage in the liver. In vitro Kupffer cells and RAW264.7 cells challenged with lipopolysaccharides (LPS) were used to explore the modulatory activity of didymin on pro-inflammatory cytokines secretion and Notch1 signaling pathway activation. RESULTS: Didymin significantly mitigated liver coefficiency, ALT and AST levels in serum, and the hepatic histopathological damage caused by DSS-induced acute and chronic colitis. The mRNA expressions of pro-inflammatory factors including Tnf, Il1, and Il6 in liver tissues, Kupffer cells, and RAW264.7 cells stimulated by the influx of LPS was significantly deprived after didymin treatment. Mechanistically, didymin obstructed the protein expression, nuclear translocation of notch intracellular domain 1 (Notch1-ICD) and mRNA expression of hairy and enhancer of split 1 (Hes1). Further, the inhibitory mechanism of the Notch1-Hes1 pathway was dependent on c-Cbl-mediated Notch1-ICD lysosomal degradation. CONCLUSION: Our study verified for the first time that didymin could prevent UC-associated diseases, such as inflammatory liver injury, and the mechanism was related to facilitating Notch1 lysosomal degradation rather than proteasome degradation via promoting protein expression of c-Cbl in macrophages. Our findings that the inhibition of Notch1 signaling transduction helps to alleviate UC-associated liver injury provides possible therapeutics for the treatment of colitis and also furnishes a research paradigm for the study of flavonoids with similar structures.

The growth-promoting effect of water extract of Chuanminshen violaceum stem and leaf on broilers.

Currently, developing nonantibiotic growth promoters is a broad consensus in broiler industry, which is one of the effective ways to reduce drug-resistant strains. Chuanminshen violaceum is a traditional Chinese medicinal herb that is commonly used for its roots, while the stems and leaves are often discarded, resulting in a huge amount of waste. This study optimized the preparation process of water extract of Chuanminshen violaceum stems and leaves (CVSLE) by response surface analysis based on the yields of polysaccharide and protein. The CVSLE and herbal powder (CVSL) were then processed into granules before being used as feed additives. The Macleaya cordata powder was used as positive control. The results showed that the addition of CVSLE (0.5% of the feed) showed the highest growth-promoting activity than other CVSLE groups (0.2% and 1%), 1% CVSL group and positive control (0.05%). CVSLE at the dosage of 0.5% could significantly increase the ADG and reduce the FCR from d 21 to 42, d 0 to 42. The HI antibody titers against Newcastle disease virus and avian influenza virus were significantly enhanced at 21, 28 and 42 d. CVSLE did not affect the slaughtering performances, but could significantly elevate the spleen, thymus and bursa of Fabricius indices and the transcriptional levels of IL-2, IL-4, IL-10 and IFN-γ in spleen. The intestinal barrier function of broilers was significantly enhanced by increased levels of immune barrier (sIgA), physical barrier (ZO-1, OCL and Muc-2) and flora barrier (Lactobacillus and Bifidobacterium). These results suggest that CVSLE was a promising herbal additive candidate for broilers.

A point mutation in VIG1 boosts development and chilling tolerance in rice.

The rice paddy-direct seeding system has been widely adopted due to its low cost and convenience, whereas its application is mainly constrained by low seedling vigor, cold sensitivity, eventually resulting in reduced grain yield. Here, we show vig1a and vig1b, two allelic mutants of OsbZIP01, that both demonstrate greatly enhanced seedling vigor and chilling tolerance but differ in final grain production. The vig1a phenotype can be obtained via simultaneous mutation of the genes OsbZIP01 and OsbZIP18, or by selectively manipulating the basic region of OsbZIP01. Destroying the leucine zipper region of OsbZIP01 in vig1a turns vig1a to be vig1b. Further analysis reveals that OsbZIP01 and OsbZIP18 function cooperatively in diverse crucial biological programs that determine seedling establishment, chilling tolerance, and grain yield through their interactions. These findings provide a strategy toward simultaneously improving seedling vigor, chilling tolerance, and grain yield for rice production.

Droplet-based single-cell sequencing: Strategies and applications.

Notable advancements in single-cell omics technologies have not only addressed longstanding challenges but also enabled unprecedented studies of cellular heterogeneity with unprecedented resolution and scale. These strides have led to groundbreaking insights into complex biological systems, paving the way for a more profound comprehension of human biology and diseases. The droplet microfluidic technology has become a crucial component in many single-cell sequencing workflows in terms of throughput, cost-effectiveness, and automation. Utilizing a microfluidic chip to encapsulate and profile individual cells within droplets has significantly improved single-cell research. Therefore, this review aims to comprehensively elaborate the droplet microfluidics-assisted omics methods from a single-cell perspective. The strategies for using droplet microfluidics in the realms of genomics, epigenomics, transcriptomics, and proteomics analyses are first introduced. On this basis, the focus then turns to the latest applications of this technology in different sequencing patterns, including mono- and multi-omics. Finally, the challenges and further perspectives of droplet-based single-cell sequencing in both foundational research and commercial applications are discussed.

[Interaction of hypertensive comorbidity patterns and social participation on depressive symptoms].

OBJECTIVE: To explore the relationship between hypertensive comorbidity patterns and social participation and depressive symptoms in middle-aged and elderly hypertensive patients. METHODS: Using the data from the 2015, 2018 and 2020 of the China Health and Retirement Longitudinal Study, 2786 middle and elderly adults aged 45 and above with hypertension were included. Data analysis was performed in Stata 17.0 statistical software, using frequency and percentage to describe baseline characteristics. The generalized estimation equation(GEE) was used to to analyze the data, and GEE was constructed with the depressive symptoms of middle and elderly people as the dependent variable. The unifactorial and multifactorial analysis of the effects of hypertensive comorbidity patterns and social participation on depressive symptoms, and the influence of the interaction between hypertensive comorbidity patterns and social participation on depressive symptoms were analyzed. RESULTS: Among the baseline characteristics of 2786 middle and older adults with hypertension, 2319(83.24%) had hypertensive comorbidity and 1558(55.92%) had social participant. The result of unifactorial GEE analysis of depressive symptoms in middle and older adults showed that the risk of depressive symptoms was higher in hypertensive comorbidity than in hypertension without comorbidity(OR=2.31, 95%CI 1.97-2.71, P<0.01), and lower in middle and older adults with social participation than in those without social participation(OR=0.71, 95%CI 0.64-0.78, P<0.01). The result of multifactorial GEE analysis of depressive symptoms in middle and older adults showed that the risk of depressive symptoms was higher in hypertensive comorbidity than in hypertension without comorbidity(OR=2.06, 95%CI 1.75-2.41, P<0.01), and lower in middle and older adults with social participation than in those without social participation(OR=0.78, 95%CI 0.70-0.87, P<0.01). Analysis of the interaction of hypertensive comorbidity and social participation on depressive symptoms in middle and older adults showed that middle and older adults with hypertensive comorbidity and no social participation had a 2.20 times higher risk of depressive symptoms than those with hypertension without comorbidity and no social participation(OR=2.20, 95%CI 1.78-2.72, P<0.01). CONCLUSION: Comorbidity is severe in the hypertensive population, and social participation in the hypertensive comorbidity population may reduce the risk of developing depressive symptoms.

Mitochondrial phylogeography of grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) endemic to the Qinghai-Tibetan plateau.

Grassland caterpillars (Lepidoptera: Lymantriinae: Gynaephora) are the most damaging pests to alpine meadows in the Qinghai-Tibetan Plateau (QTP). Here, we conducted extensive sampling from 39 geographic populations covering almost the entire distribution of the eight QTP Gynaephora (Hübner) species to investigate phylogeographic patterns and speciation based on two mitochondrial genes (COI and ND5). A total of 40 haplotypes were detected in the 39 populations, with >70% of all haplotypes not shared between populations. The monophyletic QTP Gynaephora migrated from non-QTP regions during the Pliocene, corresponding to the uplift of the QTP, suggesting a mode of transport into the QTP. Among the eight QTP Gynaephora species described by morphological characteristics, two species (G. alpherakii and G. menyuanensis) were recovered as monophyletic groups (Clades B and C), while the remaining six formed two monophyletic clades: Clade A (G. qinghaiensis, G. jiuzhiensis, and G. qumalaiensis) and Clade D (G. aureata, G. ruoergensis, and G. minora). These results suggested that the number of the QTP Gynaephora species may be overestimated and further studies based on both morphological and nuclear gene data are needed. Genetic differentiation and speciation of the QTP Gynaephora were likely driven by the QTP uplifts and associated climate fluctuations during the Pleistocene, indicated by divergence time estimation, suggesting that isolation and subsequent divergence was the dominant mode of speciation. The Sanjiangyuan region (i.e., Clade A, characterized by high genetic diversity) may have been a glacial refugium of the QTP Gynaephora, as supported by analyses of gene flow and biogeography. High levels of genetic diversity were found in QTP Gynaephora, without population expansion, which may explain the high-altitude adaptation and outbreaks of grassland caterpillars in alpine meadows of the QTP. This study provides the largest phylogeographic analysis of QTP Gynaephora and improves our understanding of the diversity and speciation of QTP insects.

Vedolizumab for second-line treatment of steroid-refractory gastrointestinal late acute graft-versus-host disease.

Background: Late acute graft-versus-host disease (aGVHD) is a complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with little data regarding treatment and outcomes. There is no standard treatment for gastrointestinal (GI) late aGVHD, especially for steroid-refractory (SR) GI late aGVHD. Vedolizumab, a monoclonal antibody inhibiting the migration of both naive and activated lymphocytes into the GI endothelium, has been verified to be effective for SR GI aGVHD. Methods: We retrospectively analyzed the clinical efficacy and safety of vedolizumab as the second line for SR GI late aGVHD in seven patients after allo-HSCT. Results: Four patients received two doses of vedolizumab infusion, while three patients received only one dose of vedolizumab infusion. The complete response and partial response rates were 57.1% (4/7) and 42.9% (3/7), respectively. No patient progressed to chronic GVHD during the period of follow-up. There was no severe adverse event related to vedolizumab. Conclusion: Our data suggest that vedolizumab is expected to ameliorate SR GI late aGVHD. Further data on the treatment timing, efficacy, and safety of vedolizumab are warranted in prospective clinical trials.

Bibliometric analysis of research on spinal cord and sacral neuromodulation in spinal cord injury.

STUDY DESIGN: Qualitative studies. OBJECTIVES: Spinal cord injury (SCI) is one of the most devastating injuries to the central nervous system that places a major burden on society. Neuromodulation technology involving spinal cord stimulation (SCS) and sacral nerve modulation (SNM) is a promising technique for patients with SCI. However, there has been no bibliometric analysis of research in this field to date. SETTING: Not applicable. METHODS: Systematic analyses of countries, institutions, authors, journals, co-cited documents, keywords, genes and diseases were performed. Related gene and disease data from the citexs platform were also reviewed. A total of 7437 articles on SCS and SNM in SCI were retrieved from the Web of Science database. The search time was limited to 1985-01-01 to 2022-12-31. RESULTS: We identified a significant increase in research output on SCS and SNM in SCI in recent years, with a concentrated period of high publication activity. Multiple publications were identified on neuropathic pain, electronic stimulation, TNF, BDNF and STAT3 gene expression, indicating that complications and potential therapeutic strategies for SCI are a key focus in the field. CONCLUSION: Our study provides insights that may help to advance scientific research and potentially improve outcomes in patients with SCI.

Epitranscriptomic regulation of lipid oxidation and liver fibrosis via ENPP1 mRNA m6A modification.

BACKGROUND: Dysregulated lipid oxidation occurs in several pathological processes characterized by cell proliferation and migration. Nonetheless, the molecular mechanism of lipid oxidation is not well appreciated in liver fibrosis, which is accompanied by enhanced fibroblast proliferation and migration. METHODS: We investigated the causes and consequences of lipid oxidation in liver fibrosis using cultured cells, animal models, and clinical samples. RESULTS: Increased ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP1) expression caused increased lipid oxidation, resulting in the proliferation and migration of hepatic stellate cells (HSCs) that lead to liver fibrosis, whereas fibroblast-specific ENPP1 knockout reversing these results. Elevated ENPP1 and N6-methyladenosine (m6A) levels were associated with high expression of Wilms tumor 1 associated protein (WTAP). Mechanistically, WTAP-mediated m6A methylation of the 3'UTR of ENPP1 mRNA and induces its translation dependent of YTH domain family proteins 1 (YTHDF1). Additionally, ENPP1 could interact with hypoxia inducible lipid droplet associated (HILPDA) directly; overexpression of ENPP1 further recruits HILPDA-mediated lipid oxidation, thereby promotes HSCs proliferation and migration, while inhibition of ENPP1 expression produced the opposite effect. Clinically, increased expression of WTAP, YTHDF1, ENPP1, and HILPDA, and increased m6A mRNA content, enhanced lipid oxidation, and increased collagen deposition in human liver fibrosis tissues. CONCLUSIONS: We describe a novel mechanism in which WTAP catalyzes m6A methylation of ENPP1 in a YTHDF1-dependent manner to enhance lipid oxidation, promoting HSCs proliferation and migration and liver fibrosis.

The male slings: an effective and safe alternative surgical treatment to the artificial urinary sphincter for male stress urinary incontinence?-a narrative review.

Background and Objective: The ideal candidate for a male sling (MS) should have a mild to moderate degree of stress urinary incontinence (SUI). This narrative review article evaluates the current MS devices in the commercial market and examines the role of MS as an effective and safe alternative treatment option for male SUI. Methods: The available literature on MS was reviewed and relevant clinical studies pertaining to each MS were summarised with emphasis on device design and technology as well as specific surgical findings relating to clinical outcomes. Key Content and Findings: Over the past two decades, there have been considerable scientific advances in MS design and technology, and MS is an attractive alternative for patients who might not require or want an artificial urinary sphincter. The modern MS can be classified as adjustable or non-adjustable types and is placed either through a retropubic or transobturator (TO) approach. Strict patient selection and counselling, selection of MS with proven clinical records, and safe surgical practice are paramount to ensure a high continence rate, good patient satisfaction, and low postoperative complications. Published data on various MS materials and devices showed reasonable clinical efficacy and safety outcomes, although many of these synthetic MS devices may not be available worldwide due to a lack of regulatory approval in many countries. While the ideal MS is probably yet to be developed, continued scientific advances in slings design, mesh technology, and more refined surgical techniques will improve the continence rate and deliver better safety records. Conclusions: As clinical data matures with longer-term outcomes coupled with advances in scientific designs and technology, the ability to have and select the optimal MS for a particular patient will come to fruition.

Enhanced drought tolerance and photosynthetic efficiency in Arabidopsis by overexpressing phosphoenolpyruvate carboxylase from a single-cell C4 halophyte Suaeda aralocaspica.

In crop genetic improvement, the introduction of C4 plants' characteristics, known for high photosynthetic efficiency and water utilization, into C3 plants has been a significant challenge. This study investigates the effects of the desert halophyte Suaeda aralocaspica SaPEPC1 gene from a single-cell C4 photosythetic pathway, on drought resistance and photosynthetic performance in Arabidopsis. We used transgenic Arabidopsis with Zea mays ZmPEPC1 from C4 plant with classic Kranz anatomical structure and Arabidopsis AtPEPC1 from C3 photosynthetic cycle plants as controls. The results demonstrated that C4 photosynthetic-type PEPCs could improve drought resistance in plants through stomatal closure, promoting antioxidant enzyme accumulation, and reducing reactive oxygen species (ROS) accumulation. Overexpression of SaPEPC1 was significantly more effective than ZmPEPC1 in enhancing drought tolerance. Notably, overexpressed SaPEPC1 significantly improved light saturation intensity, electron transport rate (ETR), photosynthetic rate (Pn), and photoprotection ability under intense light. Furthermore, overexpression SaPEPC1 or ZmPEPC1 enhanced the activity of key C4 photosynthetic enzymes, including phosphoenolpyruvate carboxylase (PEPC), pyruvate orthophosphate dikinase (PPDK) and NADP-malic enzyme (NADP-ME), and promoted photosynthetic product sugar accumulation. However, with AtPEPC1 overexpression showing no obvious improvement effect on drought and photosynthetic performance. Therefore, these results indicated that introducing C4-type PEPC into C3 plants can significantly enhance drought resistance and photosynthetic performance. However, SaPEPC1 from a single-cell C4 cycle plant exhibits more significant effect in ETR and PSII photosynthesis performance than ZmPEPC1 from a classical C4 anatomical structure plant, although the underlying mechanism requires further exploration.