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Abstract Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by an insidious onset. Despite the emphasis on motor symptom-based diagnosis, there remains an unmet clinical need for effective diagnostic approaches during the prodromal phase of PD. Recent advances in single-cell RNA sequencing (scRNA-seq) and bulk transcriptomic analyses of PD patients open avenues for identifying potential diagnostic biomarkers. A comprehensive cell trajectory analysis was conducted using scRNA-seq datasets to identify gene expressions associated with the cellular transition from healthy to PD-associated states. Integration of scRNA-seq datasets with weighted gene co-expression network analysis (WGCNA) allowed extraction of pyroptosis-associated differentially expressed genes (PDEGs). Using LASSO logistic regression, support vector machine recursive feature elimination (SVM-RFE) and random forest methods, we developed a diagnostic model centred on PDEGs. In addition, immunoinfiltration, inflammatory signalling pathways and intercellular communication were detected by scRNA-seq analyses. In PD patients, the number of cells including metencephalic-like cells, excitatory neurons, inhibitory neurons and MHB-like cells was significantly reduced, whereas the proportion of astrocytes and microglia, immunoinfiltration and inflammatory signalling pathways were upregulated compared to healthy individuals. Using scRNA-seq and WGCNA analyses, two pyroptosis-related diagnostic genes, POLR2K and TIMM8B, were identified and a diagnostic model based on them was constructed, which showed promising performance upon validation. This study established a pyroptosis-related diagnostic model for PD through the analyses of scRNA-seq combined with bulk transcriptome data, which improved the understanding of the role of PDEGs in PD and provided new insights into the diagnostic strategies for this neurodegenerative disease.

Abstract A fundamental objective of genomics is to track variations in gene expression program. While metabolic RNA labeling-based single-cell RNA sequencing offers insights into temporal biological processes, its limited applicability only to in vitro models challenges the study of in vivo gene expression dynamics. Herein, we introduce Dyna-vivo-seq, a strategy that enables time-resolved dynamic transcription profiling in vivo at the single-cell level by examining new and old RNAs. The new RNAs can offer an additional dimension to reveal cellular heterogeneity. Leveraging new RNAs, we discern two distinct high and low metabolic labeling populations among proximal tubular (PT) cells. Furthermore, we identify 90 rapidly responding transcription factors during the acute kidney injury in female mice, highlighting that high metabolic labeling PT cells exhibit heightened susceptibility to injury. Dyna-vivo-seq provides a powerful tool for the characterization of dynamic transcriptome at the single-cell level in living organism and holds great promise for biomedical applications.

Abstract Background CircRNAs have been demonstrated to play a crucial role in regulating the growth and progression of various cancers, including hepatocellular carcinoma (HCC). Nevertheless, the circRNA's expression pattern and function in HCC need more investigation. Methods Bioinformatics techniques were used to identify differentially expressed circRNAs in HCC. CircASH2L expression in HCC tissues was assessed through qRT-PCR and ISH analysis. To assess circASH2L's impact on HCC progression, a variety of experiments were carried out both in vitro and in vivo, such as CCK8, colony formation, EdU assay, flow cytometry, transwell assay, and xenograft mouse model. Various experimental techniques including qRT-PCR, dual luciferase reporter assay, FISH, RNA pull-down, and RIP experiments were utilized to evaluate the relationship between circASH2L, miR-525-3p, and MTUS2. Additionally, experiments were conducted to explore the impact of m6A modification on circASH2L expression, including RNA stability assay, m6A RNA immunoprecipitation assay (MeRIP), and Co-IP experiments. Results We found that circASH2L was downregulated in HCC tissues and the downregulation of circASH2L was significantly correlated with malignant characteristics as well as poor overall survival of patients with HCC. CircASH2L was found to inhibit cells growth, migration and invasion as well as tumorigenesis and metastasis in vivo. Mechanistically, we established that circASH2L directly interacted with miR-525-3p to enhance MTUS2 expression, subsequently leading to tumor suppression. Moreover, the influence of circASH2L on tumor suppression was attenuated by increasing miR-525-3p levels, and MTUS2 was recognized as an essential intermediary in circASH2L-induced tumor suppression. Additionally, N6−methyladenosine (m6A) modification was identified in circASH2L. Our data suggested that METTL3 was responsible for mediating m6A methylation of circASH2L, ultimately regulating circASH2L expression through the promotion of its degradation. These findings collectively highlight the role of circASH2L as a tumor suppressor through a unique circASH2L/miR-525-3p/MTUS2 axis, shedding light on the significance of m6A modification in regulating circASH2L function. Conclusion The work emphasizes circASH2L as a promising therapeutic target for treating HCC, offering new insights into the role of circRNAs in HCC development.

ObjectiveTo explore the relationship between different dietary patterns and internal exposure levels of cadmium and lead among middle-aged and elderly populations in cadmium-polluted areas, and to provide a scientific basis for adopting reasonable dietary patterns to reduce cadmium and lead internal exposure levels in these populations. MethodsFrom July to December 2019, 600 middle-aged and elderly individuals who had lived in cadmium-polluted areas in northern Guangdong province for ≥ 20 years were randomly recruited to participate in questionnaire surveys, physical examinations, and measurements of urinary cadmium (UCd), blood cadmium (BCd), and blood lead (BPb). Factor analysis was used to determine the dietary patterns of the middle-aged and elderly populations, and a multifactor generalized linear model was used to analyze the relationship between dietary patterns and natural log-transformed heavy metal (LnUCd, LnBCd, LnBPb) levels. ResultsA total of 414 middle-aged and elderly individuals from cadmium-polluted areas in northern Guangdong province were finally included in the analysis. Four dietary patterns were obtained through factor analysis: fruits and vegetables, high-quality protein, protein beverages, and flour, with a cumulative variance contribution rate of 50.618%. The M (P25, P75) of UCd, BCd, and BPb levels in the middle-aged and elderly populations were 7.32 (4.12, 14.85) μg/g Ucr, 6.42 (3.40, 11.55) μg/L, and 55.93 (38.76, 79.12) μg/L, respectively. After adjusting for confounding factors such as gender, age, occupation, region, smoking status, medication history, and body mass index, the results of the multifactor generalized linear model analysis showed that the LnBPb levels of middle-aged and elderly individuals with fruit and vegetable dietary pattern factor scores at the T2 level (β = – 0.121, 95%CI: – 0.225 – – 0.017) and T3 level (β = – 0.108, 95%CI: – 0.213 – – 0.003) were lower than those with factor scores at the T1 level. The LnUCd level (β = – 0.224, 95%CI: – 0.436 – – 0.013) and LnBCd level (β = – 0.245, 95%CI: – 0.434 – – 0.057) of middle-aged and elderly individuals with high-quality protein dietary pattern factor scores at the T3 level were lower than those with factor scores at the T1 level. ConclusionA preference for fruit and vegetable dietary patterns was associated with lower blood lead levels, while a preference for high-quality protein dietary patterns was associated with lower urinary cadmium and blood cadmium levels among middle-aged and elderly populations in cadmium-polluted areas.

Abstract Purpose Rot disease caused by Fusarium poses a formidable threat to the growth of saffron (Crocus sativus L.), resulting in substantial damage to both yield and quality. It is paramount to delve into the root causes of rot disease in saffron to optimize both yield and quality. Existing preventive and treatment modalities have exerted deleterious effects on corms and the natural environment. Consequently, the quest for efficacious and eco-friendly methods such as biological control agents has become an urgent imperative. Methods The disparate distribution of microbial communities between rhizospheric microorganisms and saffron serves as the foundational exploration for uncovering the underlying causes of rot disease. Samples from various saffron organs and rhizosphere soil were gathered, and the sequencing data from the microbial communities were interpreted using 16S rRNA and ITS gene sequencing methods. This facilitated an in-depth examination of the composition and changes of microorganisms in both healthy and diseased saffron plants. Results The findings indicated rot disease reduced the abundance and diversity of microorganisms in saffron, and the fungal co-occurrence networks were less stable and their communities were more sensitive to rot disease than the bacterial community. Fusarium was the predominant genus in diseased samples, accounting for 99.19% and 89.77% of the communities in diseased leaves and corms. With corms and leaves displaying heightened susceptibility to infection compared to other plant organs. Some of the beneficial bacterial taxa enriched in the diseased plants were also identified in networks, they showed an antagonistic relationship with Fusarium, suggesting a potential for these bacteria to be used in biologically based control strategies against rot disease. These insights could prove invaluable for the development of biocontrol agents aimed at combating this plant ailment. Conclusion These findings significantly advance our understanding of saffron-microbiome interactions and could provide fundamental and important data for improving saffron yield and quality in the process of sustainable development.

The aroma-active compounds (AACs) of traditional vinegars are formed through complexed pathways. Moreover, their source is not clear yet. The composition of AACs throughout the entire process of Shanxi aged vinegar (SAV) production from the raw materials, alcohol fermentation (AF), acetic acid fermentation (AAF), fumigation and aging stages were analyzed. A total of 121 AACs were determined by GC × GC-O-TOF-MS, of which 88 were identified by GC–MS/MS. There were 27 and 41 AACs (FD ≥ 400) detected in before-aging and after-aging SAV, respectively. Furthermore, it can be concluded the AAF and fumigation were the main sources of AACs. Also, the AAF was the main source of the compounds with caramel, creamy, floral, fruity, sour, cheesy notes, while the compounds owned roasted, nutty, spicy and woody aromas mainly came from fumigation. Finally, the potential transformation pathway of AACs was mapped and discussed. Overall, GC × GC-O-TOF-MS was a useful technique to enrich the AACs of SAV.

Abstract Angiogenesis is crucial for successful bone defect repair. Co‐transplanting Bone Marrow Stromal Cells (BMSCs) and Endothelial Cells (ECs) has shown promise for vascular augmentation, but it face challenges in hostile tissue microenvironments, including poor cell survival and limited efficacy. In this study, the mitochondria of human BMSCs are isolated and transplanted to BMSCs from the same batch and passage number (BMSCsmito). The transplanted mitochondria significantly boosted the ability of BMSCsmito‐ECs to promote angiogenesis, as assessed by in vitro tube formation and spheroid sprouting assays, as well as in vivo transplantation experiments in balb/c mouse and SD rat models. The Dll4‐Notch1 signaling pathway is found to play a key role in BMSCsmito‐induced endothelial tube formation. Co‐transplanting BMSCsmito with ECs in a rat cranial bone defect significantly improves functional vascular network formation, and improve bone repair outcomes. These findings thus highlight that mitochondrial transplantation, by acting through the DLL4‐Notch1 signaling pathway, represents a promising therapeutic strategy for enhancing angiogenesis and improving bone repair. Hence, mitochondrial transplantation to BMSCS as a therapeutic approach for promoting angiogenesis offers valuable insights and holds much promise for innovative regenerative medicine therapies.

Introduction The prevalence of chronic conditions is increasing. Given that the majority of chronic patients are managed by primary healthcare providers, there is a need to integrate primary care with public health to address the prevailing situation and enhance patient outcomes. The purpose of this study is to establish, implement and evaluate an integrated primary care and public health model in China for patients with chronic conditions.Methods This prospective, multicentre and observational study will be conducted at 12 township hospitals on patients (n=7200) diagnosed with chronic conditions (hypertensive, diabetic or stroke). Participants were divided into two groups: pilot areas and mainstream areas follow-up groups. The primary outcome will be the difference in the proportion of controlled chronic conditions among the two groups. Secondary outcomes will be the differences in mean change in diastolic and systolic blood pressures, fasting glucose, total cholesterol and triglyceride, death from any cause and participant-reported physical and psychological health status.Ethics and dissemination Ethics approval was obtained from the Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology. We plan to publish the results of this study in a peer-reviewed journal article.

Purpose: Road traffic has long been recognized as a considerable source of ecological disturbance, compromising the integrity of natural ecosystems from their pristine baseline state. Pollutant deposition from vehicular emissions significantly contributes to environmental contamination, while associated human activities exacerbate ecosystem disruptions. In designated conservation zones, including nature reserves, land-use practices such as pastoralism and agriculture are subject to regulation. Nevertheless, the influence of road traffic on ecosystem structure and processes, particularly concerning carbon (C) sequestration and its spatial heterogeneity, warrants further research. This consideration is critically relevant in the understanding the intricate C fractions and their dynamic interplay with environmental factors. Materials and methods: In this study, we meticulously selected four distinct locations along a principal roadway within a national reserve. For each site, experimental measuring 2 m * 2 m were established at intervals of 2 m, 10 m, 20 m, 30 m, 40 m, and 50 m from the road's edge. Observational data were accrued during the peak of the vegetative growth seasons in August of both 2020 and 2021. Within each plot, soil and cut-ring samples were procured for comprehensive analysis of soil carbon fractions (Total Carbon, TC, g/kg; Carbon Density, g/m2; Readily Oxidizable Carbon, ROC, g/kg; Dissolved Organic Carbon, DOC, mg/kg; Microbial Biomass Carbon, MBC, mg/kg; Cumulative Mineralization Carbon, CMC, mg(CO2-C)*(kg*soil)−1; Soil Inorganic Carbon, SIC, g/kg), chemical properties (pH; Electrical Conductivity, EC, us/cm; Soil Organic Matter, SOM), and physical properties (Soil Water, SW, %; Bulk Density, BD, g/cm3; area conditions). Vegetation metrics, including above-ground biomass (AGB) and below-ground biomass (BGB), species composition, height, and coverage, were meticulously documented. The four sites were replicated, culminating in 24 uniformly oriented plots to mitigate wind influence. Results: Our analysis revealed that C stock, as determined by TC and C density increased with distance from the road edge, reaching a peak at approximately 30 m (TC: 19.43 g/kg, C density: 39.26 g/m2, SOM: 27.57 g/kg), followed by a subsequent decline. At the 30 m distance, there was a 60.6 %, 41.2 %, and 38.7 % enhancement in TC, C density, and SOM, respectively, compared to the 2 m distance, and a 23.9 %, 25.9 %, and 19.8 % increase relative to the 50 m distance. Levels of DOC, MBC, and CMC exhibited an upward trend from the road edge to 50 m, suggesting more favorable microbiological conditions in less disturbed locales. SEM demonstrated that SIC is directly influenced by BGB (β = −0.31), pH (β = 0.46), and labile C components (β = 0.56), culminating in a reduction of total C storage (total effect, β = −0.28). The dynamic changes of soil C stocks were primarily explained directly by soil labile C (β = 0.475, p < 0.001), and indirectly by vegetation biomass (β = 0.460) and pH (β = −0.570), and were closely correlated with ROC (0.54, the highest eigenvalue among Labile_C). Conclusion: The findings suggest that the buffering effect of the roadside in these nature reserves up to a distance of 30 m has an signficant impact on C stock, and that C losses attributable to biochemical processes and laible soil C fractions may contribute to diminished C levels in less disturbed zones 50 m away from the road. Our findings also substantiate the moderate disturbance hypothesis, particularly in the milieu of road traffic within the Hulunbuir Nature Reserve, Mongolia. A moderate distance from roadways enhances soil C storage compared to areas near the road or undisturbed natural landscapes.

Abstract Background The use of stem cell-derived exosomes (Exos) as therapeutic vehicles is receiving increasing attention. Exosome administration has several advantages over cell transplantation, thus making exosomes promising candidates for large-scale clinical implementation and commercialization. However, exosome extraction and purification efficiencies are relatively low, and therapeutic heterogeneity is high due to differences in culture conditions and cell viability. Therefore, in this study, we investigated a priming procedure to enhance the production and therapeutic effects of exosomes from human umbilical cord mesenchymal stem cells (hucMSCs). After preconditioning hucMSCs with agonists/inhibitors that target the Wnt/β-catenin pathway, we assessed both the production of exosomes and the therapeutic efficacy of the optimized exosomes in the context of diabetic wound healing, hoping to provide a safer, more stable and more effective option for clinical application. Results The Wnt signalling pathway agonist CHIR99021 increased exosome production by 1.5-fold without causing obvious changes in the characteristics of the hucMSCs or the size of the exosome particles. Further studies showed that CHIR99021 promoted the production of exosomes by facilitating exocytosis. This process was partly mediated by SNAP25. To further explore whether CHIR99021 changed the cargo that was loaded into the exosomes and its therapeutic effects, we performed proteomic and transcriptomic analyses of exosomes from primed and control hucMSCs. The results showed that CHIR99021 significantly upregulated the expression of proteins that are associated with cell migration and wound healing. Animal experiments confirmed that, compared to control hucMSC-derived exosomes, CHIR99021-pretreated hucMSC-derived exosomes (CHIR-Exos) significantly accelerated wound healing in diabetic mice, enhanced local collagen deposition, promoted angiogenesis, and reduced chronic inflammation. Subsequent in vitro experiments confirmed that the CHIR-Exos promoted wound healing by facilitating cell migration, inhibiting oxidative stress-induced apoptosis, and preventing cell cycle arrest. Conclusions The Wnt agonist CHIR99021 significantly increased exosome secretion by hucMSCs, which was partly mediated by SNAP25. Notably, CHIR99021 treatment also significantly increased the exosomal levels of proteins that are associated with wound healing and cell migration, resulting in enhanced acceleration of wound healing. All of these results suggested that pretreatment of hucMSCs with CHIR99021 not only promoted exosome production but also improved the exosome therapeutic efficacy, thus providing a promising option for large-scale clinical implementation and commercialization. Graphical Abstract

Objective: This study aims to explore the relationship between different endometrial preparations and pregnancy outcomes among patients with regular ovulatory cycles in order to find the best endometrial preparation methods in the freeze–thaw embryo transfer (FET) cycle. Materials and Methods: This is a retrospective study to investigate FET pregnancy outcomes in women who had a regular menstrual cycle, were younger than 35 years old, and underwent a modified natural cycle (mNC), ovulation induction (OI), or a hormone replacement treatment (HRT) cycle. A total of 1071 frozen cycles were included for analysis. Results: The implantation rate and live birth rate (LBR) in the OI group show a significant difference when compared to the mNC and HRT groups (P < 0.01). After adjusting for confounding factors, the logistic regression analysis revealed that the number of embryos transferred, the embryo stage, and quality were significantly associated with clinical pregnancy rate and LBR. The LBR was additionally affected by the mode of the endometrial preparation; the OI cycle could increase LBR. Conclusions: Endometrial preparation methods affect the LBR in women with a regular menstrual cycle. The OI cycle had an advantage in the LBR of FET.

Abstract This study aimed to determine an immune-related RNA signature as a prognostic marker, in this study, we developed a risk score model for predicting the prognosis of osteosarcoma metastasis. We first downloaded the clinical information and expression data of osteosarcoma samples from the UCSC Xena and GEO databases, of which the former was the training set and the latter was the validation set. Immune infiltration was assessed using the ssGSEA and ESTIMATE algorithms, and the osteosarcoma samples were divided into the Immunity_L and Immunity_H groups. Then, eleven RNAs were identified as the optimal prognostic RNA signatures using LASSO Cox regression analysis for establishing a risk score (RS) model. Kaplan–Meier approach indicated the high-risk group exhibited a shorter survival. Furthermore, we analyzed the tumor metastasis, age, and RS model status were determined to be independent clinical prognostic factors using Cox regression analysis. Decision curve analysis (DCA) indicated that the prognostic factor + RS model had the best net benefit. Finally, nine tumor-infiltrating immune cells (TIICs) showed significant differences in abundance between high- and low-risk groups via CIBERSORT deconvolution algorithm. In conclusion, the immune-related eleven-RNA signature be could served as a potential prognostic biomarker for osteosarcoma metastasis.

Abstract Background The primary screening technique for precancerous lesions and cervical cancer is human papillomavirus (HPV) testing, and HPV self-sampling has been shown to be consistent with clinician sampling in terms of the accuracy of the results and may improve cervical cancer screening rates. The aim of this study was to understand the level of awareness, experience, acceptability, and preference for vaginal HPV self-sampling among women in Jiangsu, Zhejiang, and Shanghai, China, and to analyze the possible influencing factors to determine the feasibility of implementing self-sampling. Methods Overall, 1793 women were included in the data analysis. A self-administered questionnaire was utilized. In addition to descriptive analysis, univariate and multivariate analyses were used to explore the associations between sociodemographic features, history of cervical cancer screening, and the level of awareness, experience, acceptability, and preference for HPV self-samples. Results The participants’ level of awareness of and experience with HPV self-sampling were moderate. A total of 88.8% of participants rated the acceptability as “high”, and self-sampling was preferred by 64.2% of them for cervical cancer screening. People aged 45 to 54 years showed a preference for both clinician sampling(OR = 1.762 (1.116–2.163)) and self-sampling (OR = 1.823 (1.233–2.697)). Those who had graduated from high school or above (OR = 2.305 (1.517–3.503), OR = 2.432 (1.570–3.768), OR = 3.258 (2.024–5.244)) preferred clinician-sampling, and those with a bachelor’s degree or above (OR = 1.664 (1.042–2.657)) preferred self-sampling. Middle- and high-income individuals showed no preference for either sampling method (OR

Abstract Background Weaning from invasive mechanical ventilation (MV) is a complex and challenging process that involves multiple pathophysiological mechanisms. A combined ultrasound evaluation of the heart, lungs, and diaphragm during the weaning phase can help to identify risk factors and underlying mechanisms for weaning failure. This study aimed to investigate the accuracy of lung ultrasound (LUS), transthoracic echocardiography (TTE), and diaphragm ultrasound for predicting weaning failure in critically ill patients. Methods Patients undergoing invasive MV for > 48 h and who were readied for their first spontaneous breathing trial (SBT) were studied. Patients were scheduled for a 2-h SBT using low-level pressure support ventilation. LUS and TTE were performed prospectively before and 30 min after starting the SBT, and diaphragm ultrasound was only performed 30 min after starting the SBT. Weaning failure was defined as failure of SBT, re-intubation, or non-invasive ventilation within 48 h. Results Fifty-one patients were included, of whom 15 experienced weaning failure. During the SBT, the global, anterior, and antero-lateral LUS scores were higher in the failed group than in the successful group. Receiver operating characteristic curve analysis showed that the areas under the curves for diaphragm thickening fraction (DTF) and global and antero-lateral LUS scores during the SBT to predict weaning failure were 0.678, 0.719, and 0.721, respectively. There was no correlation between the LUS scores and the average E/e’ ratio during the SBT. Multivariate analysis identified antero-lateral LUS score > 7 and DTF 7 and DTF

Abstract Background Depression is widely recognized as a common non‐motor symptom of Parkinson's disease (PD). Across different studies, the reported prevalence of depression in PD varies widely, ranging from 2.7% to 90%, but it is unclear whether this association is due to genetic or acquired factors. Whether there is a causal relationship remains unknown. The aim of this study was to use a two‐sample Mendelian randomization (MR) approach to investigate the causal effect of PD on depression. Methods Analyses were conducted separately for individuals of European and East Asian ancestry using publicly available summary data from genome‐wide association studies. Depression was divided into two categories: ever depressed for a whole week and major depressive disorder (MDD). PD data were used as the exposure and were obtained from the International Parkinson's Disease Genomics Consortium and the BioBank Japan PheWeb, while depression data were used as the outcome and were obtained from the ntegrative Epidemiology Unit (IEU) Open GWAS Project(A public GWAS database） and the Psychiatric Genomics Consortium. The influence of PD on depression was assessed using inverse variance weighted (IVW), weighted median, MR‐Egger, and weighted mode methods. Heterogeneity and pleiotropy were tested, and the results were validated using FinnGen GWAS data from version R9. Results In individuals of European ancestry, there was a causal relationship between PD and ever depressed for a whole week (IVW method, odds ratio [OR] = 0.990; 95% CI, 0.984–0.996; p = .002), but no causal relationship was observed between PD and MDD (IVW method, OR = 0.974; 95% CI, 0.942–1.009; p = .141). In individuals of East Asian ancestry, no causal relationship was observed between PD and ever depressed for a whole week (IVW method, OR = 1.001; 95% CI, 0.829–1.209; p = .990) and between PD and MDD (IVW method, OR = 1.017; 95% CI, 0.982–1.052; p = .342). The results of the three additional analysis methods were similar to those of the IVW method, and there was no heterogeneity according to Cochran's Q‐test. There was no evidence of pleiotropy based on MR‐Egger intercept test and MR‐PRESSO. The FinnGen validation dataset supported these findings. The results are stable and reliable. Conclusion The observed increase in depression among PD patients could potentially be attributed to modifiable acquired factors. Consequently, there is an urgent need to strengthen the management of PD patients in order to prevent the development of depression in the future.

The clinical application of 5-fluorouracil (5-Fu), a potent chemotherapeutic agent, is often hindered by its well-documented cardiotoxic effects. Nevertheless, natural polyphenolic compounds like resveratrol (RES), known for their dual anti-tumor and cardioprotective properties, are potential adjunct therapeutic agents. In this investigation, we examined the combined utilization of RES and 5-Fu for the inhibition of gastric cancer using both in vitro and in vivo models, as well as their combined impact on cardiac cytotoxicity. Our study revealed that the co-administration of RES and 5-Fu effectively suppressed MFC cell viability, migration, and invasion, while also reducing tumor weight and volume. Mechanistically, the combined treatment prompted p53-mediated apoptosis and autophagy, leading to a considerable anti-tumor effect. Notably, RES mitigated the heightened oxidative stress induced by 5-Fu in cardiomyocytes, suppressed p53 and Bax expression, and elevated Bcl-2 levels. This favorable influence enhanced primary cardiomyocyte viability, decreased apoptosis and autophagy, and mitigated 5-Fu-induced cardiotoxicity. In summary, our findings suggested that RES holds promise as an adjunct therapy to enhance the efficacy of gastric cancer treatment in combination with 5-Fu, while simultaneously mitigating cardiotoxicity.

BackgroundObservational studies have suggested that plasma lipidome play a pivotal role in the occurrence of Parkinson’s disease (PD). However, it remains unknown which lipids among plasma lipidome affect PD and how they exert their influence. Clarity is lacking regarding the causal relationship between plasma lipidome and PD, as well as whether circulating inflammatory proteins serve as mediators.MethodsSingle nucleotide polymorphisms (SNPs) significantly associated with 179 plasma lipidome were selected as instrumental variables to assess their causal impact on PD. PD data, serving as the outcome, were sourced from the International Parkinson’s Disease Genomics Consortium, which boasts the largest sample size to date. The inverse variance weighted (IVW), Weighted median method, MR-Egger method, Simple mode method, Weighted mode method and MR-PRESSO were employed to evaluate the influence of the 179 plasma lipidome on PD. Heterogeneity, pleiotropy tests, and reverse causality analyses were conducted accordingly. Additionally, we analyzed the causal relationship between 91 circulating inflammatory proteins and PD, exploring whether these proteins serve as mediators in the pathway from plasma lipidome to PD.ResultsAmong the 179 plasma lipidome, three were found to be associated with a reduced risk of PD: Phosphatidylcholine (14:0_18:2) (IVW, OR = 0.877; 95%CI, 0.787–0.978; p = 0.018), Phosphatidylcholine (16:0_16:1) levels (IVW, OR = 0.835; 95%CI, 0.717–0.973; p = 0.021), and Phosphatidylcholine (O-17:0_17:1) levels (IVW, OR = 0.854; 95%CI, 0.779–0.936; p = 0.001). Meanwhile, Sphingomyelin (d38:1) was linked to an increased risk of PD (IVW, OR = 1.095; 95%CI, 1.027–1.166; p = 0.005). Among the 91 circulating inflammatory proteins, three were associated with a lower PD risk: Fibroblast growth factor 21 levels (IVW, OR = 0.817; 95%CI, 0.674–0.990; p = 0.039), Transforming growth factor-alpha levels (IVW, OR = 0.825; 95%CI, 0.683–0.998; p = 0.048), and Tumor necrosis factor receptor superfamily member 9 levels (IVW, OR = 0.846; 95%CI, 0.744–0.963; p = 0.011). Two were associated with a higher risk of PD: Interleukin-17A levels (IVW, OR = 1.285; 95%CI, 1.051–1.571; p = 0.014) and TNF-beta levels (IVW, OR = 1.088; 95%CI, 1.010–1.171; p = 0.026). Additionally, a positive correlation was observed between Phosphatidylcholine (14:0_18:2) levels and Fibroblast growth factor 21 levels (IVW, OR = 1.125; 95%CI, 1.006–1.257; p = 0.038), suggesting that Fibroblast growth factor 21 levels may serve as a mediating factor in the pathway between Phosphatidylcholine (14.0_18.2) levels and PD. The mediation effect was estimated to be −0.024, accounting for approximately 18% of the total effect.ConclusionBoth plasma lipidome and circulating inflammatory proteins demonstrate a causal relationship with PD. Additionally, circulating inflammatory proteins may serve as mediators in the pathway from plasma lipidome to PD. These findings may contribute to the prediction and diagnosis of PD and potentially pave the way for targeted therapies in the future.

Recent studies suggest that plant disease identification via machine learning approach is vital for preventing the spread of diseases. Identifying multiple diseases simultaneous on a single leaf is one of the most irritating issues in agricultural production. However, the existing approaches are difficult to meet the requirements of production practice in accuracy or interpretability. Here, we present residual attention based multi-label learning framework (RAMDI), a method for predicting apple leaf diseases in natural environment. Built upon an attention based multi-label learning framework, the channel and spatial attention mechanisms are investigated and embedded in residual network for multi-label disease prediction, which takes advantage of channel-wise and spatial-wise attention weights. Experimental results indicate that the RAMDI achieves 0.976 accuracy, 0.986 F-score, and 0.979 mAPs, outperforms the existing state-of-the-art apple leaf disease identification models. RAMDI not only predicts multi-disease on a single leaf simultaneously, but also reveals the interpretability among positive predictions that contribute most to identify the key features that are significant for the leaf diseases. This method achieves the following two achievements. Firstly, it provides a solution for detecting multiple diseases on a single leaf. Secondly, this approach gains an interpretable understanding for apple leaf disease identification.

Abstract Cirsium japonicum contains a variety of medicinal components with good clinical efficacy. With the rapid changes in global climate, it is increasingly important to study the distribution of species habitats and the factors influencing their adaptability. Utilizing the MaxEnt model, we forecasted the present and future distribution regions of suitable habitats for C. japonicum under various climate scenarios. The outcome showed that under the current climate, the total suitable area of C. japonicum is 2,303,624 km2 and the highly suitable area is 79,117 km2. The distribution of C. japonicum is significantly influenced by key environmental factors such as temperature annual range, precipitation of the driest month, and precipitation of the wettest month. In light of future climate change, the suitable habitat for C. japonicum is anticipated to progressively relocate toward the western and northern regions, leading to an expansion in the total suitable area. These findings offer valuable insights into the conservation, sustainable utilization, and standardized cultivation of wild C. japonicum resources.

With the advancement of medical care and the continuous improvement of organ support technologies, some critically ill patients survive the acute phase of their illness but still experience persistent organ dysfunction, necessitating long-term reliance on intensive care and organ support, known as chronic critical illness. Chronic critical illness is characterized by prolonged hospital stays, high mortality rates, and significant resource consumption. Patients with chronic critical illness often suffer from malnutrition, compromised immune function, and poor baseline health, which, combined with factors like shock or trauma, can lead to intestinal mucosal damage. Therefore, effective nutritional intervention for patients with chronic critical illness remains a key research focus. Nutritional therapy has emerged as one of the essential components of the overall treatment strategy for chronic critical illness. This paper aims to provide a comprehensive review of the latest research progress in nutritional support therapy for patients with chronic critical illness.

Leaf color mutants in higher plants are considered to be ideal materials for studying the chlorophyll biosynthesis, photosynthesis mechanism and chloroplast development. Herein, we identified a spontaneous mutant, yc412, in cultivated cucumber that exhibited yellow cotyledons. The yellow-lethal mutant was diagnosed with an abnormal chloroplast ultrastructure, and reduced photosynthetic capacity and pigment content. Through bulked segregant analysis-based whole-genome sequencing and fine genetic mapping, we narrowed the yellow cotyledons (yc) locus to a 96.8 kb interval on chromosome 3. By resequencing and molecular cloning, we showed that Csyc is a potential candidate gene, which encodes a yellow stripe-like (YSL) transporter. The T to C mutation in the promoter region of Csyc caused the yellow cotyledon phenotype in yc412. Compared to YZU027A (WT), the expression of Csyc was significantly downregulated in the cotyledons of yc412. Silencing of Csyc in cucumber via virus-induced gene silencing resulted in chlorotic leaves, mainly by suppressing the chlorophyll content. Furthermore, a comparative transcriptome analysis revealed that chloroplast-related genes and chlorophyll biosynthesis genes were significantly downregulated in yc412 cotyledons. Our results provide new insights into the molecular function of the YSL transporter in plant chloroplast development and chlorophyll synthesis.

Abstract Over the years, the research of backward stochastic differential equations (BSDEs) has come a long way. As a extension of the BSDEs, the BSDEs with time delay have played a major role in the stochastic optimal control, financial risk, insurance management, pricing, and hedging. In this paper, we study a class of BSDEs with time-delay generators driven by Caputo fractional derivatives. In contrast to conventional BSDEs, in this class of equations, the generator is also affected by the past values of solutions. Under the Lipschitz condition and some new assumptions, we present a theorem on the existence and uniqueness of solutions.

Abstract Single-cell and spatial transcriptome sequencing, two recently optimized transcriptome sequencing methods, are increasingly used to study cancer and related diseases. Cell annotation, particularly for malignant cell annotation, is essential and crucial for in-depth analyses in these studies. However, current algorithms lack accuracy and generalization, making it difficult to consistently and rapidly infer malignant cells from pan-cancer data. To address this issue, we present Cancer-Finder, a domain generalization-based deep-learning algorithm that can rapidly identify malignant cells in single-cell data with an average accuracy of 95.16%. More importantly, by replacing the single-cell training data with spatial transcriptomic datasets, Cancer-Finder can accurately identify malignant spots on spatial slides. Applying Cancer-Finder to 5 clear cell renal cell carcinoma spatial transcriptomic samples, Cancer-Finder demonstrates a good ability to identify malignant spots and identifies a gene signature consisting of 10 genes that are significantly co-localized and enriched at the tumor-normal interface and have a strong correlation with the prognosis of clear cell renal cell carcinoma patients. In conclusion, Cancer-Finder is an efficient and extensible tool for malignant cell annotation.

With the introduction of the principles of the "3R" and the "Toxicology Testing in the 21st Century: Vision and Strategy", the focus of toxicological evaluation has shifted from in vivo testing to the application of in vitro models, thereby promoting the development of in vitro alternative models and attracting increasing attention from scholars. The liver is an important site for the metabolism of exogenous chemicals, and some exogenous chemicals metabolized by the liver can cause liver damage characterized by inflammation, oxidative stress, and necrosis. Therefore, it is crucial to use hepatotoxicity alternative models to detect the hepatotoxicity of exogenous chemicals. This article focused on the research of the in vitro alternative models of 2D hepatocytes, liver slices, and 3D liver for the evaluation of hepatotoxicity, and also provided a systematic description of the biomarkers of drug-induced liver injury (DILI), diagnostic methods for DILI, and emerging technologies related to DILI.

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder with extensive involvement of motor symptoms, imposing a heavy economic burden on patients and society. B lymphocytes, a group of immune cells associated with humoral immunity, have been shown to be involved in the pathogenesis of PD. However, the causal relationship and potential pathogenic effects of B cell in PD remain unclear. Based on the three core hypotheses of the Mendelian randomization (MR) study, we explored causal associations between 190 B-cell immunological traits and 482,730 European individuals (Ncase = 33,674, Ncontrol = 449,056) from genome wide association studies by means of the two-sample bidirectional MR method. The inverse‑variance weighted method was selected as the main approach when conducting MR analysis. Finally, the results were verified by the heterogeneity and horizontal pleiotropy analyses. Five B-cell immunological phenotypes were nominally associated with PD at the significance threshold of P

Abstract Understanding how plants alter their development and architecture in response to ambient temperature is crucial for breeding resilient crops. Here, we identify the quantitative trait locus qMULTIPLE INFLORESCENCE BRANCH 2 (qMIB2), which modulates inflorescence branching in response to high ambient temperature in tomato (Solanum lycopersicum). The non-functional mib2 allele may have been selected in large-fruited varieties to ensure larger and more uniform fruits under varying temperatures. MIB2 gene encodes a homolog of the Arabidopsis thaliana transcription factor SPATULA; its expression is induced in meristems at high temperature. MIB2 directly binds to the promoter of its downstream gene CONSTANS-Like1 (SlCOL1) by recognizing the conserved G-box motif to activate SlCOL1 expression in reproductive meristems. Overexpressing SlCOL1 rescue the reduced inflorescence branching of mib2, suggesting how the MIB2–SlCOL1 module helps tomato inflorescences adapt to high temperature. Our findings reveal the molecular mechanism underlying inflorescence thermomorphogenesis and provide a target for breeding climate-resilient crops.

Abstract Auxins and their analogs are widely used to promote root growth, flower and fruit development, and yield in crops. The action characteristics and application scope of various auxins are different. To overcome the limitations of existing auxins, expand the scope of applications, and reduce side effects, it is necessary to screen new auxin analogs. Here, we identified 3,4-dichlorophenylacetic acid (Dcaa) as having auxin-like activity and acting through the auxin signaling pathway in plants. At the physiological level, Dcaa promotes the elongation of oat coleoptile segments, the generation of adventitious roots, and the growth of crop roots. At the molecular level, Dcaa induces the expression of auxin-responsive genes and acts through auxin receptors. Molecular docking results showed that Dcaa can bind to auxin receptors, among which TIR1 has the highest binding activity. Application of Dcaa at the root tip of the DR5:GUS auxin-responsive reporter induces GUS expression in the root hair zone, which requires the PIN2 auxin efflux carrier. Dcaa also inhibits the endocytosis of PIN proteins like other auxins. These results provide a basis for the application of Dcaa in agricultural practices.

Abstract Purpose Prolonged exposure to plasma free fatty acids (FFAs) leads to impaired glucose tolerance (IGT) which can progress to type 2 diabetes (T2D) in the absence of timely and effective interventions. High-fat diet (HFD) leads to chronic inflammation and oxidative stress, impairing pancreatic beta cell (PBC) function. While Didymin, a flavonoid glycoside derived from citrus fruits, has beneficial effects on inflammation dysfunction, its specific role in HFD-induced IGT remains yet to be elucidated. Hence, this study aims to investigate the protective effects of Didymin on PBCs. Methods HFD-induced IGT mice and INS-1 cells were used to explore the effect and mechanism of Didymin in alleviating IGT. Serum glucose and insulin levels were measured during the glucose tolerance and insulin tolerance tests to evaluate PBC function and insulin resistance. Next, RNA-seq analysis was performed to identify the pathways potentially influenced by Didymin in PBCs. Furthermore, we validated the effects of Didymin both in vitro and in vivo. Mitochondrial electron transport inhibitor (Rotenone) was used to further confirm that Didymin exerts its ameliorative effect by enhancing mitochondria function. Results Didymin reduces postprandial glycemia and enhances 30-minute postprandial insulin levels in IGT mice. Moreover, Didymin was found to enhance mitochondria biogenesis and function, regulate insulin secretion, and alleviate inflammation and apoptosis. However, these effects were abrogated with the treatment of Rotenone, indicating that Didymin exerts its ameliorative effect by enhancing mitochondria function. Conclusions Didymin exhibits therapeutic potential in the treatment of HFD-induced IGT. This beneficial effect is attributed to the amelioration of PBC dysfunction through improved mitochondrial function.

The BeiDou Navigation Satellite System (BDS-3) has officially provided services worldwide since July 2020. BDS-3 has added new signals for B1C, B2a and B2b based on old BDS-2 B1I and B3I signals, which brings opportunities for achieving high-precision time transfer. In this research, the BDS-3/BDS-2 combined penta-frequency common-view (CV) single-differenced (SD) precise time transfer model is established with B1I, B3I, B2I, B1C, B2a and B2b signals, including dual-, triple-, quad- and penta-frequency (abbreviated as DF, TF, QF and PF) ionosphere-free (IF) combination CV SD models. Taking four long baseline time links (from 637.6 km to 1331.6 km) as examples, the accuracy and frequency stability of the BDS-3/BDS-2 combined DF, TF, QF and PF SD time transfer models were evaluated. The experimental results show that the frequency stability of the TF, QF and PF SD models were improved by 2.5%, 5.3% and 8.5%, on average, over the DF SD model. Compared with the traditional DF (B1I/B3I IF combination) SD model, the standard deviation (STD) of the multi-frequency SD model was reduced by 5.9%, on average, and the frequency stability was improved by 4.0% on average, which had the most apparent effect on the improvement of short-term frequency stability. Specifically, the DF1 (B1C and B2a DF IF combination), TF1 (B1C, B2a and B2b TF IF combination), QF1 (B1C, B1I, B2a and B2b QF IF combination) and PF4 (B1C, B1I, B2a, B2b and B3I PF IF combination) SD models had better performance in timing, and the PF4 SD model had the best performance. Considering that the PF4 (one PF signal IF combination) SD model does not require an estimated inter-frequency bias and that its noise factor is minor compared with the PF1 (four DF signal IF combination), PF2 (three TF signal IF combination) and PF3 (two QF signal IF combination) SD models, we recommend the PF4 SD model for multi-frequency time transfer and the use of the PF2, PF2 or PF3 SD model to supplement the PF4 SD model in cases of penta-frequency observation loss.

Reporting coulombic efficiency (CE) is the common way to assess the performance of electrochemical carbon dioxide (CO2) reduction reaction (eCO2RR) in literature, whereas its carbon conversion efficiency (CCE) is frequently neglected. Herein, the importance of reporting both efficiencies when evaluating the eCO2RR is discussed, using Sn‐based gas diffusion electrodes (GDEs) as model electrodes. It is shown that CCE can vary remarkably at a constant CE with minor operational changes. Over 120 min experiments with operational conditions being representative of numerous previous studies, the CCE is increased from ≈20% to 41% (being only 9% below the theoretical maximum). This was achieved by simply adjusting the inlet CO2 flow rate from ≈35 to 16 mL min−1, while CE was identical at both CO2 flow rates (≈85%, 7%, and 4% for production of formate/formic acid, CO, and H2, respectively at both conditions). Thus, it is advocated that reporting of both efficiencies, for electrons and carbon, is required for meaningfully assessing the performance of an eCO2RR system.

Triggering receptor expressed on myeloid cells 1 (TREM1) is a cell surface receptor expressed on neutrophils, monocytes and some tissue macrophages, where it functions as an immunoregulator that controls myeloid cell responses. The activation of TREM1 is suggested to be an upregulation-based, ligands-induced and structural multimerization-mediated process, in which damage- and pathogen-associated molecular patterns play important roles. Activated TREM1 initiates an array of downstream signaling pathways that ultimately result in the production of pro-inflammatory cytokines and chemokines, whereby it functions as an amplifier of inflammation and is implicated in the pathogenesis of many inflammation-associated diseases. Over the past decade, there has been growing evidence for the involvement of TREM1 overactivation in tumor stroma inflammation and cancer progression. Indeed, it was shown that TREM1 promotes tumor progression, immunosuppression, and resistance to therapy by activating tumor-infiltrating myeloid cells. TREM1-deficiency or blockade provide protection against tumors and reverse the resistance to anti-PD-1/PD-L1 therapy and arginine-deprivation therapy in preclinical models. Here, we first review the structure, activation modes and signaling pathways of TREM1 and emphasize the role of soluble TREM1 as a biomarker of infection and cancer. We then focus on the role of TREM1 in cancer and systematically summarize its expression patterns, upregulation mechanisms and functions in tumor development and progression. Lastly, we discuss the therapeutic prospects of TREM1 inhibition, via effective pharmacological inhibitors, in treating cancer and other diseases.

MicroRNAs have been studied extensively in neurodegenerative diseases. In a previous study, miR-153 promoted neural differentiation and projection formation in mouse hippocampal HT-22 cells. However, the pathways and molecular mechanism underlying miR-153-induced neural differentiation remain unclear. To explore the molecular mechanism of miR-153 on neural differentiation, we performed RNA sequencing on miR-153-overexpressed HT-22 cells. Based on RNA sequencing, differentially expressed genes (DEGs) and pathways in miR-153-overexpressed cells were identified. The Database for Annotation, Visualization and Integrated Discovery and Gene Set Enrichment Analysis were used to perform functional annotation and enrichment analysis of DEGs. Targetscan predicted the targets of miR-153. The Search Tool for the Retrieval of Interacting Genes and Cytoscape, were used to construct protein-protein interaction networks and identify hub genes. Q-PCR was used to detect mRNA expression of the identified genes. The expression profiles of the identified genes were compared between embryonic days 9.5 (E9.5) and E11.5 in the embryotic mouse brain of the GDS3442 dataset. Cell Counting Kit-8 assay was used to determine cell proliferation and cellular susceptibility to amyloid β-protein (Aβ) toxicity in miR-153-overexpressed cells. The results indicated that miR-153 increased cell adhesion/Ca2+ (Cdh5, Nrcam, and P2rx4) and Bdnf/Ntrk2 neurotrophic signaling pathway, and decreased ion channel activity (Kcnc3, Kcna4, Clcn5, and Scn5a). The changes in the expression of the identified genes in miR-153-overexpressed cells were consistent with the expression profile of GDS3442 during neural differentiation. In addition, miR-153 overexpression decreased cellular susceptibility to Aβ toxicity in HT-22 cells. In conclusion, miR-153 overexpression may promote neural differentiation by inducing cell adhesion and the Bdnf/Ntrk2 pathway, and regulating electrophysiological maturity by targeting ion channels. MiR-153 may play an important role in neural differentiation; the findings provide a useful therapeutic direction for neurodegenerative diseases.

Abstract Currently available guided bone regeneration (GBR) films lack active immunomodulation and sufficient osteogenic ability‐ in the treatment of periodontitis, leading to unsatisfactory treatment outcomes. Challenges remain in developing simple, rapid, and programmable manufacturing methods for constructing bioactive GBR films with tailored biofunctional compositions and microstructures. Herein, the controlled electroassembly of collagen under the salt effect is reported, which enables the construction of porous films with precisely tunable porous structures (i.e., porosity and pore size). In particular, bioactive salt species such as the anti‐inflammatory drug diclofenac sodium (DS) can induce and customize porous structures while enabling the loading of bioactive salts and their gradual release. Sequential electro‐assembly under pre‐programmed salt conditions enables the manufacture of a Janus composite film with a dense and DS‐containing porous layer capable of multiple functions in periodontitis treatment, which provides mechanical support, guides fibrous tissue growth, and acts as a barrier preventing its penetration into bone defects. The DS‐containing porous layer delivers dual bio‐signals through its morphology and the released DS, inhibiting inflammation and promoting osteogenesis. Overall, this study demonstrates the potential of electrofabrication as a customized manufacturing platform for the programmable assembly of collagen for tailored functions to adapt to specific needs in regenerative medicine.

Summary: Background: The burden of psychiatric symptoms in Parkinson's disease includes depression, anxiety, apathy, psychosis, and impulse control disorders. However, the relationship between psychiatric comorbidities and subsequent prognosis and neurological outcomes is not yet well understood. In this systematic review and meta-analysis, in individuals with Parkinson's disease, we aimed to characterise the association between specific psychiatric comorbidities and subsequent prognosis and neurological outcomes: cognitive impairment, death, disability, disease progression, falls or fractures and care home admission. Methods: We searched MEDLINE, Embase, PsycINFO and AMED up to 13th November 2023 for longitudinal observational studies which measured disease outcomes in people with Parkinson's disease, with and without specific psychiatric comorbidities, and a minimum of two authors extracted summary data. Studies of individuals with other parkinsonian conditions and those with outcome measures that had high overlap with psychiatric symptoms were excluded to ensure face validity. For each exposure-outcome pair, a random-effects meta-analysis was conducted based on standardised mean difference, using adjusted effect sizes–where available–in preference to unadjusted effect sizes. Study quality was assessed using the Newcastle–Ottawa Scale. Between-study heterogeneity was assessed using the I2 statistic and publication bias was assessed using funnel plots. PROSPERO Study registration number: CRD42022373072. Findings: There were 55 eligible studies for inclusion in meta-analysis (n = 165,828). Data on participants’ sex was available for 164,514, of whom 99,182 (60.3%) were male and 65,460 (39.7%) female. Study quality was mostly high (84%). Significant positive associations were found between psychosis and cognitive impairment (standardised mean difference [SMD] 0.44, [95% confidence interval [CI] 0.23–0.66], I2 30.9), psychosis and disease progression (SMD 0.46, [95% CI 0.12–0.80], I2 70.3%), depression and cognitive impairment (SMD 0.37 [95% CI 0.10–0.65], I2 27.1%), depression and disease progression (SMD 0.46 [95% CI 0.18–0.74], I2 52.2), depression and disability (SMD 0.42 [95% CI 0.25–0.60], I2 7.9%), and apathy and cognitive impairment (SMD 0.60 [95% CI 0.02–1.19], I2 27.9%). Between-study heterogeneity was moderately high. Interpretation: Psychosis, depression, and apathy in Parkinson's disease are all associated with at least one adverse outcome, including cognitive impairment, disease progression and disability. Whether this relationship is causal is not clear, but the mechanisms underlying these associations require exploration. Clinicians should consider these psychiatric comorbidities to be markers of a poorer prognosis in people with Parkinson's disease. Future studies should investigate the underlying mechanisms and which treatments for these comorbidities may affect Parkinson's disease outcomes. Funding: Wellcome Trust, UK National Institute for Health Research (NIHR), National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at South London and Maudsley NHS Foundation Trust and King's College London, National Institute for Health Research (NIHR) Biomedical Research Centre (BRC) at University College London Hospitals NHS Foundation Trust, National Brain Appeal.

The Pseudomonas promysalinigenes strain RL-WG26, which was previously isolated from the rhizosphere of Sea Rice 86 (SR86), could promote the plant growth and alleviate the plant salt stress of SR86 by regulating the ion concentration in plants, increasing the dry weight and chlorophyll content of plants, and reducing the proline and malondialdehyde content in roots. Here, we report the complete genome sequence of Pseudomonas promysalinigenes strain RL-WG26 to lay a foundation for deciphering the molecular mechanisms of strain RL-WG26-mediated plant salt tolerance and to further the application potential of this strain. [Figure: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.

Abstract Background Research has indicated that long-term sleep deprivation can lead to immune dysfunction and participate in the occurance and progression of tumors. However, the relationship between sleep deprivation and colon cancer remains unclear. This study explored the specific mechanism through which sleep deprivation promotes the proliferation and migration of colon cancer, with a focus on the neurotransmitter GABA. Methods Chronic sleep deprivation mice model were used to investigate the effect of sleep disorder on tumors. We detected neurotransmitter levels in the peripheral blood of mice using ELISA. CCK-8 assay, colony formation assay, wound healing assay, and transwell assay were performed to investigate the effect of GABA on colon cancer cells, while immunofluorescence showed the distribution of macrophages in lung metastatic tissues. We isolated exosomes from a GABA-induced culture medium to explore the effects of GABA-induced colon cancer cells on macrophages. Gain- and loss-of-function experiments, luciferase report analysis, immunohistochemistry, and cytokine detection were performed to reveal the crosstalk between colon cancer cells and macrophages. Results Sleep deprivation promote peripheral blood GABA level and colon cancer cell proliferation and migration. Immunofluorescence analysis revealed that GABA-induced colon cancer metastasis is associated with enhanced recruitment of macrophages in the lungs. The co-culture results showed that GABA intensified M2 polarization of macrophage induced by colon cancer cells. This effect is due to the activation of the macrophage MAPK pathway by tumor-derived exosomal miR-223-3p. Furthermore, M2-like macrophages promote tumor proliferation and migration by secreting IL-17. We also identified an endogenous miR-223-3p downregulation of the E3 ligase CBLB, which enhances the stability of cMYC protein and augments colon cancer cells proliferation and migration ability. Notably, cMYC acts as a transcription factor and can also regulate the expression of miR-223-3p. Conclusion Our results suggest that sleep deprivation can promote the expression of miR-223-3p in colon cancer cells through GABA, leading to downregulation of the E3 ligase CBLB and inhibition of cMYC ubiquitination. Simultaneously, extracellular miR-223-3p promotes M2-like macrophage polarization, which leads to the secretion of IL-17, further enhancing the proliferation and migration of colon cancer cells.