Search

Abstract Noncontact humidity sensor overcomes the limitations of its contact sensing counterparts, including mechanical wear and cross infection, which becomes a promising candidate in healthcare and human-machine interface application. However, current humidity sensors still suffer the ubiquitous issue of uncomfortable wear and skin irritation hindering the long-term use. In this study, we report a skin-conformal and breathable humidity sensor assembled by anchoring MXenes-based composite into electrospun elastomer nanofibers coated with a patterned electrode. This composite is highly sensitive to the water molecules due to its large specific surface area and abundant water-absorbing hydroxyl groups, while the elastomeric nanofibers provide an ultrathin, highly flexible, and permeable substrate to support the functional materials and electrodes. This sensor presents not only excellent air permeability (0.078 g cm−2 d−1), high sensitivity (S = 704), and fast response/recovery (0.9 s/0.9 s), but also high skin conformability and biocompatibility. Furthermore, this humidity sensor is confirmed to realize the recognition of motional states and emotional modes, which provides a way for the advanced noncontact human-machine interface.

PLATZ is a novel zinc finger DNA-binding protein that plays an important role in regulating plant growth and development and resisting abiotic stress. However, there has been very little research on the function of this family gene in tomatoes, which limits its application in germplasm resource improvement. Therefore, the PLATZ gene family was identified and analyzed in tomato, and its roles were predicted and verified to provide a basis for in-depth research on SlPLATZ gene function. In this study, the PLATZ family members of tomato were identified in the whole genome, and 19 SlPLATZ genes were obtained. Functional prediction was conducted based on gene and promoter structure analysis and RNA-seq-based expression pattern analysis. SlPLATZ genes that responded significantly under different abiotic stresses or were significantly differentially expressed among multiple tissues were screened as functional gene resources. SlPLATZ17 was selected for functional verification by experiment-based analysis. The results showed that the downregulation of SlPLATZ17 gene expression reduced the drought and salt tolerance of tomato plants. Tomato plants overexpressing SlPLATZ17 had larger flower sizes and long, thin petals, adjacent petals were not connected at the base, and the stamen circumference was smaller. This study contributes to understanding the functions of the SlPLATZ family in tomato and provides a reference for functional gene screening.

Abstract Background Gexia-Zhuyu Tang (GZT), a traditional Chinese medicine formula, is used to treat a variety of diseases. However, its roles in gastric cancer (GC) remain unclear. Objective The aim of this study was to explore the roles and underlying molecular mechanisms of modified GZT in GC. Methods The effects of modified GZT on GC were investigated by constructing mouse xenograft models with MFC cell line. The fecal samples from low-dose, high-dose, and without modified GZT treatment groups were collected for the 16S rRNA gene sequencing and fecal microbiota transplantation (FMT). Histopathological alterations of mice were evaluated using the hematoxylin–eosin (HE). Immunohistochemical (IHC) analysis with Ki67 and GSDMD was performed to measure tissue cell proliferation and pyroptosis, respectively. Proteins associated with pyroptosis, invasion, and metastasis were detected by Western blotting. Enzyme-linked immunosorbent assay (ELISA) was used to assess inflammation-related factors levels. Results Modified GZT inhibited GC tumor growth and reduced metastasis and invasion-related proteins expression levels, including CD147, VEGF, and MMP-9. Furthermore, it notably promoted caspase-1-dependent pyroptosis, as evidenced by a dose-dependent increase in TNF-α, IL-1β, IL-18, and LDH levels, along with elevated protein expression of NLRP3, ASC, and caspase-1. Additionally, modified GZT increased species abundance and diversity of the intestinal flora. FMT assay identified that modified GZT inhibited GC tumor progression through regulation of intestinal flora. Conclusions Modified GZT treatment may promote pyroptosis by modulating gut microbiota in GC. This study identifies a new potential approach for the GC clinical treatment.

Bacterial wilt triggered by the soil-borne pathogenic bacterium Ralstonia solanacearum is one of the most serious diseases in tomato plants, leading to huge economic losses worldwide. Biological control is considered an environmentally friendly and sustainable way to manage soil-borne diseases. In this study, Streptomyces sp. STD57 isolated from the rhizosphere of Adenophora stricta showed strong antibacterial activity against R. solanacearum. Pot experiments showed that strain STD57 exhibited a significant biocontrol effect (81.7%) on tomato bacterial wilt in the greenhouse environment. Furthermore, strain STD57 could inhibit the growth of weeds (Amaranthus retroflexus, Portulaca oleracea, and Echinochloa crusgalli) but promote the growth of crops (wheat, rice, and tomato). The plant growth-promoting substance was identified as indoleacetic acid (IAA) by high-pressure liquid chromatography–mass spectrometry and genome analysis. Coarse separation of the fermented extracts revealed that the antibacterial and herbicidal substances were mainly in the fermentation supernatant and belonged to different products. These findings suggested that strain STD57 may be a potential biocontrol and bioherbicide agent useful in agriculture.

Abstract The Prechtl General Movements Assessment (GMA) is increasingly recognized for its role in evaluating the integrity of the developing nervous system and predicting motor dysfunctions, particularly in conditions such as cerebral palsy (CP). However, the necessity for highly trained professionals has hindered the adoption of GMA as an early screening tool in some countries. In this study, we propose a deep learning-based motor assessment model (MAM) that combines infant videos and basic characteristics, with the aim of automating GMA at the fidgety movements (FMs) stage. MAM demonstrates strong performance, achieving an Area Under the Curve (AUC) of 0.967 during external validation. Importantly, it adheres closely to the principles of GMA and exhibits robust interpretability, as it can accurately identify FMs within videos, showing substantial agreement with expert assessments. Leveraging the predicted FMs frequency, a quantitative GMA method is introduced, which achieves an AUC of 0.956 and enhances the diagnostic accuracy of GMA beginners by 11.0%. The development of MAM holds the potential to significantly streamline early CP screening and revolutionize the field of video-based quantitative medical diagnostics.

Abstract Objectives To analyze the diagnostic value of the tonsil–oropharynx (T/O) ratio on lateral cephalograms for evaluating tonsillar hypertrophy (TH). Methods A cross-sectional study was performed on 185 consecutive children (101 males, 84 females; mean age 7.3 ± 1.4 years) seeking orthodontic treatment. The T/O ratios on lateral cephalograms were calculated following Baroni et al.’s method. Tonsil sizes were clinically determined according to the Brodsky grading scale. Spearman correlation coefficients between the T/O ratio and clinical tonsil size were calculated with the total sample and subgroups and then compared between subgroups. Diagnostic value was analyzed using the receiver operating characteristic (ROC) curve, sensitivity, specificity, positive and negative predictive values, and accuracy. Results There was a strong correlation between the T/O ratio and clinical tonsil size in children (ρ = 0.73; P

Abstract Emerging evidence indicates that SOX2 is an oncogene for esophageal squamous cell carcinoma (ESCC). However, direct targeting of SOX2 is not feasible given that this transcription factor plays important roles in the maintenance of tissues such as the brain. Here, we identified CDP (Homeobox protein cut-like 1 or CASP) as a unique SOX2 binding partner enriched in ESCC with Duolink proximity ligation assay, bimolecular fluorescence complementation (BiFc) and immunoprecipitation. We then screened a peptide aptamer library using BiFc and immunoprecipitation and identified several peptide aptamers, including P58, that blocked the CDP/SOX2 interaction, leading to the inhibition of ESCC progress in vitro and in vivo. Upon administration, synthetic peptide P58, containing the YGRKKRRQRRR cell-penetrating peptide and the fluorophore TAMRA, also blocked the growth and metastasis of ESCC in both mice and zebrafish. Therefore, targeting the SOX2 binding partner CDP with peptide P58 offers an alternative avenue to treat ESCC with increased SOX2 levels.

Cohesin is a multi-subunit protein that plays a pivotal role in holding sister chromatids together during cell division. Sister chromatid cohesion 3 (SCC3), constituents of cohesin complex, is highly conserved from yeast to mammals. Since the deletion of individual cohesin subunit always causes lethality, it is difficult to dissect its biological function in both mitosis and meiosis. Here, we obtained scc3 weak mutants using CRISPR-Cas9 system to explore its function during rice mitosis and meiosis. The scc3 weak mutants displayed obvious vegetative defects and complete sterility, underscoring the essential roles of SCC3 in both mitosis and meiosis. SCC3 is localized on chromatin from interphase to prometaphase in mitosis. However, in meiosis, SCC3 acts as an axial element during early prophase I and subsequently situates onto centromeric regions following the disassembly of the synaptonemal complex. The loading of SCC3 onto meiotic chromosomes depends on REC8. scc3 shows severe defects in homologous pairing and synapsis. Consequently, SCC3 functions as an axial element that is essential for maintaining homologous chromosome pairing and synapsis during meiosis.

Introduction: Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS), is a serious health disorder that affects patient moods. It is caused by cyclic psychological symptoms and its pathogenesis is still unclear. Abnormalities in the basolateral amygdala (BLA) orexin system, which are important causes of the development of depressive mood, have not been reported in PMDD, so exploring its intrinsic mechanisms is meaningful for enriching the pathomechanisms of PMDD.Methods: High performance liquid chromatography was used for the determination of the active ingredients of Jingqianshu granules. Developing a rat model of premenstrual depression using the forced swimming test (FST). The experiment consisted of two parts. In Part 1, the rats were divided into the control group, the model group, the model + Jingqianshu group, and the model + fluoxetine group. The FST, open field test, and elevated plus maze test, were used to assess the behavior of the rats as well as to evaluate the effect of drug intervention. Immunofluorescence and RT-qPCR were used to detect the expression of orexin and its receptors OX1R and OX2R genes and proteins. The expression of Toll-like receptor 4, nuclear factor kappa-B, tumor necrosis factor-α, interleukin 6, and interleukin-1β in the BLA brain region was detected by Western-Blot. In part 2, the rats were injected intracerebrally with orexin-A. Observe the behavioral activities of rats in the control group, model group, and model+orexin-A group. Immunofluorescence was used to detect microglia in the BLA area of rats, and the expression levels of the above inflammatory factors were detected by Western-Blot.Results: The five components of Jingqianshu granules are: paeoniflorin, erulic acid, liquiritin, hesperidin, and paeonol. During the estrous cycle, rats exhibited depressive-like behavior during the non-receptive phase of the behavioral test, which disappeared during the receptive phase. Immunofluorescence and RT-qPCR showed reduced gene and protein expression of orexin, OX1R, and OX2R in the BLA region of rats in the model group.WB showed elevated levels of inflammatory factors. All returned to control levels after drug treatment. In part 2, injection of orexin-A into the BLA brain region of model rats resulted in reduced immunoreactivity of microglia and decreased expression levels of inflammatory factors.Discussion: Jianqianshu granules can achieve the purpose of treating premenstrual depression by regulating orexin-mediated inflammatory factors, which provides a new idea for further research on the pathogenesis of PMDD. However, the current study is still preliminary and the pathogenesis of PMDD is complex. Therefore, more in-depth exploration is needed.

Introduction Orthodontic treatment using face mask protraction combined with an alternate rapid maxillary expansion and constriction/protraction face mask (Alt-RAMEC/PFM) protocol is effective in the early treatment of patients with class III malocclusion, but the stability of treatment outcomes represents a major concern. Previous studies have suggested that tonsillar hypertrophy can be a risk factor for class III malocclusion and tonsillectomy may prompt the normalisation of dentofacial growth. However, these studies had a low-to-moderate level of evidence. This study was designed to identify the impact of tonsillectomy before orthodontic treatment on the efficacy and stability of Alt-RAMEC/PFM protocols and the sleep quality and oral health in children with anterior crossbite and tonsillar hypertrophy.Methods and analysis This is a two-arm, parallel-group, superiority cluster randomised controlled trial, with four clinics randomly assigned to the surgery-first arm and the orthodontic-first arm in a 1:1 ratio. The Alt-RAMEC protocol involves alternate activation and deactivation of the expander’s jet screw over 6 weeks to stimulate maxillary suture distraction. Patients will be instructed to wear the PFM for a minimum of 14 hours per day. The primary outcomes are changes in Wits appraisal and the degree of maxillary advancement from baseline to the end of orthodontic treatment. Lateral cephalometric radiographs, polysomnography, Obstructive Sleep Apnoea-18 questionnaire and Oral Health Impact Profile-14 questionnaire will be traced, collected and measured. We will recruit 96 patients intofor the study. To assess differences, repeated multilevel linear mixed modelling analyses will be used.Ethics and dissemination This study has been granted ethical approval by the Ethics Committee of the School & Hospital of Stomatology, Wuhan University (approval No. 2023-D10). Written informed consent will be obtained from the participants and their guardians. The results of the trial will be disseminated through academic conferences and journal publications.Trial registration number ChiCTR2300078833.

Microplastics (MPs), which are prevalent and increasingly accumulating in aquatic environments. Other pollutants coexist with MPs in the water, such as pesticides, and may be carried or transferred to aquatic organisms, posing unpredictable ecological risks. This study sought to assess the adsorption of lambda-cyhalothrin (LCT) by virgin and aged polyethylene MPs (VPE and APE, respectively), and to examine their influence on LCT's toxicity in zebrafish, specifically regarding acute toxicity, oxidative stress, gut microbiota and immunity. The adsorption results showed that VPE and APE could adsorb LCT, with adsorption capacities of 34.4 mg∙g−1 and 39.0 mg∙g−1, respectively. Compared with LCT exposure alone, VPE and APE increased the acute toxicity of LCT to zebrafish. Additionally, exposure to LCT and PE-MPs alone can induce oxidative stress in the zebrafish gut, while combined exposure can exacerbate the oxidative stress response and intensify intestinal lipid peroxidation. Moreover, exposure to LCT or PE-MPs alone promotes inflammation, and combined exposure leads to downregulation of the myd88-nf-κb related gene expression, thus impacting intestinal immunity. Furthermore, exposure to APE increased LCT toxicity to zebrafish more than VPE. Meanwhile, exposure to PE-MPs and LCT alone or in combination has the potential to affect gut microbiota function and alter the abundance and diversity of the zebrafish gut flora. Collectively, the presence of PE-MPs may affect the toxicity of pesticides in zebrafish. The findings emphasize the importance of studying the interaction between MPs and pesticides in the aquatic environment.

Abstract Endotoxemia‐related acute liver injury has a poor prognosis and high mortality, and macrophage polarization plays a central role in the pathological process. Pregnane X receptor (PXR) serves as a nuclear receptor and xenosensor, safeguarding the liver from toxic stimuli. However, the effect and underlying mechanism of PXR activation on endotoxemic liver injury remain largely unknown. Here, the expression of PXR is reported in human and murine macrophages, and PXR activation modified immunotypes of macrophages. Moreover, PXR activation significantly attenuated endotoxemic liver injury and promoted macrophage M2 polarization. Macrophage depletion by GdCl3 confirmed the essential of macrophages in the beneficial effects observed with PXR activation. The role of PXR in macrophages is further validated using AAV8‐F4/80‐Pxr shRNA‐treated mice; the PXR‐mediated hepatoprotection is impaired, and M2 polarization enhancement is blunted. Additionally, treatment with PXR agonists inhibited lipopolysaccharide (LPS)‐induced M1 polarization and favored M2 polarization in BMDM, Raw264.7, and THP‐1 cells. Further analyses revealed an interaction between PXR and p‐STAT6 in vivo and in vitro. Moreover, blocking Pxr or Stat6 abolished the PXR‐induced polarization shift. Collectively, macrophage PXR activation attenuated endotoxin‐induced liver injury and regulated macrophage polarization through the STAT6 signaling pathway, which provided a potential therapeutic target for managing endotoxemic liver injury.

Objectives Risk prediction for patients with polymyositis/dermatomyositis-associated interstitial lung disease (PM/DM-ILD) is challenging due to heterogeneity in the disease course. We aimed to develop a mortality risk prediction model for PM/DM-ILD.Methods This prognostic study analysed patients with PM/DM-ILD admitted to Nanjing Drum Hospital from 2016 to 2021. The primary outcome was mortality within 1 year. We used a least absolute shrinkage and selection operator (LASSO) logistic regression model to identify predictive laboratory indicators. These indicators were used to create a laboratory risk score, and we developed a mortality risk prediction model by incorporating clinical factors. The evaluation of model performance encompassed discrimination, calibration, clinical utility and practical application for risk prediction and prognosis.Results Overall, 418 patients with PM/DM-ILD were enrolled and randomly divided into development (n=282) and validation (n=136) cohorts. LASSO logistic regression identified four optimal features in the development cohort, forming a laboratory risk score: C reactive protein, lactate dehydrogenase, CD3+CD4+ T cell counts and PO2/FiO2. The final prediction model integrated age, arthralgia, anti-melanoma differentiation-associated gene 5 antibody status, high-resolution CT pattern and the laboratory risk score. The prediction model exhibited robust discrimination (area under the receiver operating characteristic: 0.869, 95% CI 0.811 to 0.910), excellent calibration and valuable clinical utility. Patients were categorised into three risk groups with distinct mortality rates. The internal validation, sensitivity analyses and comparative assessments against previous models further confirmed the robustness of the prediction model.Conclusions We developed and validated an evidence-based mortality risk prediction model with simple, readily accessible clinical variables in patients with PM/DM-ILD, which may inform clinical decision-making.

Introduction Class II malocclusion with mandibular retrognathia is a common complication of paediatric obstructive sleep apnoea (OSA), often accompanied by transverse maxillary deficiency. In early orthodontic treatment, a twin block (TB) is a regular functional appliance for correcting this malocclusion. For paediatric OSA, the most common risk factor is adenotonsillar hypertrophy (AHT). Untreated AHT may lead to the persistence and worsening of obstructive sleep-disordered breathing traits, including habitual mouth breathing. Additionally, the clockwise mandibular rotation associated with AHT-induced pharyngeal crowding can undermine the effectiveness and stability of TB treatment. Adenotonsillectomy (T&A) is currently the first-line treatment for paediatric OSA. This proposed trial will investigate the impact of T&A surgery timing on the efficacy and stability of TB functional treatment in children with class II mandibular retrognathia and ATH.Methods and analysis This will be a single-centre, parallel-group, superiority randomised controlled trial with participants randomised to intervention (T&A followed by TB treatment) or control arms (TB treatment followed by T&A) in a 1:1 ratio. A total of 40 patients aged 8–14 years, diagnosed with class II mandibular retrognathia and co-existing ATH-induced OSA, and indicated for both T&A surgery and TB treatment, will be recruited at the School and Hospital of Stomatology, Wuhan University. The primary outcomes will be the changes in the apnoea-hypopnoea index and the point A-nasion-point B angle from baseline to postorthodontic treatment between the two groups. Secondary outcomes will include other dental, skeletal, upper airway and soft tissue changes, as well as subjective sleep-related and oral-related quality of life. Outcome changes within each group and between groups will be analysed.Ethics and dissemination This study is approved by the Ethics Committee of the School and Hospital of Stomatology, Wuhan University (no. 2022-D07). The research findings will be faithfully disseminated through scientific conferences or published articles.Trial registration number ChiCTR2200061703 (https://www.chictr.org.cn).

Abstract Background Peritoneal dialysis (PD) remains limited due to dialysis failure caused by peritoneal fibrosis. Tamoxifen (TAM), an inhibitor of estrogen receptor 1 (ESR1), has been reported to treat fibrosis, but the underlying mechanism remains unknown. In this study, we sought to explore whether tamoxifen played an anti-fibrotic role by affecting transcription factor ESR1. Methods ESR1 expression was detected in the human peritoneum. Mice were daily intraperitoneally injected with 4.25% glucose PD dialysate containing 40 mM methylglyoxal for 2 weeks to establish PD-induced peritoneal fibrosis. Tamoxifen was administrated by daily gavage, at the dose of 10 mg/kg. Chromatin immunoprecipitation (ChIP) and dual‐luciferase reporter assay were performed to validate ESR1 bound H19 promoter. Gain-of-function and loss-of-function experiments were performed to investigate the biological roles of H19 on the mesothelial-mesenchymal transition (MMT) of human peritoneal mesothelial cells (HPMCs). Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified small interfering RNA was applied to suppress H19 in the mouse peritoneum. RNA immunoprecipitation and RNA pull-down assays demonstrated binding between H19 and p300. Exfoliated peritoneal cells were obtained from peritoneal dialysis effluent to analyze the correlations between ESR1 (or H19) and peritoneal solute transfer rate (PSTR). Results ESR1 was increased significantly in the peritoneum after long-term exposure to PD dialysate. Tamoxifen treatment ameliorated high glucose-induced MMT of HPMCs, improved ultrafiltration rate, and decreased PSTR of mouse peritoneum. Tamoxifen reduced the H19 level by decreasing the ESR1 transcription of H19. Depletion of H19 reversed the pro-fibrotic effect of high glucose while ectopic expression of H19 exacerbated fibrotic pathological changes. Intraperitoneal injection of nanomaterial-wrapped 2′-O-Me-modified siRNAs targeting H19 mitigated PD-related fibrosis in mice. RNA immunoprecipitation (RIP) and RNA pull-down results delineated that H19 activated VEGFA expression by binding p300 to the VEGFA promoter and inducing histone acetylation of the VEGFA promoter. ESR1 and H19 were promising targets to predict peritoneal function. Conclusions High glucose-induced MMT of peritoneal mesothelial cells in peritoneal dialysis via activating ESR1. In peritoneal mesothelial cells, ESR1 transcribed the H19 and H19 binds to transcription cofactor p300 to activate the VEGFA. Targeting ESR1/H19/VEGFA pathway provided new hope for patients undergoing peritoneal dialysis. Graphic Abstract

Abstract Objective Interstitial lung disease (ILD) is a severe complication of connective tissue disease (CTD) that can significantly impact patients' prognosis and quality of life. However, the current diagnostic arena lacks reliable biomarkers for detecting and monitoring the progression and exacerbation of CTD-ILD. This study aimed to investigate the clinical value of 12 serum cytokines in the diagnosis of CTD-ILD and prediction of the risk of acute exacerbation (AE) in this disease. Methods This study was a cross-sectional investigation. Ninety-one hospitalized CTD patients were allocated into two groups: CTD-ILD group (n = 61) and CTD-non-ILD group (n = 30), and 30 sex-age matched healthy volunteers were enrolled as controls. The serum concentrations of interferon (IFN)-α, IFN-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12p70, IL-17A, and IL-1β were measured by Luminex suspension arrays. Logistic regression was employed to determine the significance of variables in the occurrence of AE-CTD-ILD. A nomogram was constructed to visualize the independent variables. Results Elevated levels of IL-6, IL-8, and TNF-α were observed and compared in the CTD-ILD group with CTD-non-ILD (all P

Objective: To investigate the effect of β-sitosterol on endometrial cells to understand the underlying mechanism.Materials and Methods: This is a laboratory-based experimental study conducted on animals and cells. Histologicalassays were performed to determine the effect of β-sitosterol on endometrial cells. The CCK-8 assay was used toassess the inhibitory effect of β-sitosterol on the proliferation of ectopic endometrial stromal cells (hEM15A). Flowcytometry was performed to evaluate the induction of apoptosis by β-sitosterol in hEM15A cells. The transwell invasionassay was conducted to measure the suppression of hEM15A cell migration by β-sitosterol. Western blot analyseswere performed to analyze the effect of β-sitosterol on the expression of Smad family member 7 (Smad7) and theactivity of transforming growth factor-β (TGF-β1), as well as the phosphorylation of Smad2 and Smad3.Results: Histological assays showed that β-sitosterol regulates histopathology and induces apoptosis of endometrialcells in vivo. The CCK-8 assay revealed that β-sitosterol could inhibit the proliferation of hEM15A in human endometriosispatients. Flow cytometry showed that apoptosis was triggered by β-sitosterol in hEM15A. The transwell invasion assayindicated that the hEM15A migration under the β-sitosterol treatment group was suppressed. Western blot analysessuggested that β-sitosterol increased the expression of Smad7, decreased the activity of TGF-β1, and reduced thephosphorylation of Smad2 and Smad3. The effect of β-sitosterol was weakened by the silence of Smad7.Conclusion: The results suggest that β-sitosterol can inhibit the proliferation of endometrial cells and relieveendometriosis by inhibiting TGF-β-induced phosphorylation of Smads through regulation of Smad7.

Abstract Nitrogen is a key factor in various physiological and metabolic processes in plants. Providing an adequate supply of nitrogen is essential for improving the total yield and quality of the medicinal plant Artemisia argyi (A. argyi), but the underlying mechanisms of how this nutrient alters the crop remains unclear. In this study, we conducted a series of pot experiments to investigate the agronomic traits and active components in the leaves of A. argyi plants under low and high nitrogen stress. Additionally, we used transcriptome analysis and RT-qPCR to explore the molecular pathways associated with nitrogen stress. Our results demonstrate a dramatic increase in the accumulation of phenolic acids and flavonoids in the low nitrogen (LN) stress group compared to the control (CK), with increases of 40.00% and 79.49%, respectively. Interestingly, plants in the high nitrogen (HN) stress group exhibited enhanced plant growth with larger leaves, thicker stems, and a 3% increase in volatile oil content compared to the CK. Moreover, A. argyi in the HN group displayed a 66% increase in volatile oil concentration compared to the LN group. Our combined transcriptome and q-PCR results indicate that LN stress promotes the expression of genes involved in flavonoid synthesis, while HN stress promotes the expression of genes related to terpene skeleton production and photosynthesis. Taken together, these findings suggest that different gene expression levels under LN and HN stress contribute to the photosynthesis capacity and the accumulation of active ingredients in A. argyi leaves. Our results elucidate the physiological and molecular mechanisms of nitrogen stress on A. argyi secondary metabolites and guide fertilization strategies for plant cultivation.

Abstract Background To explore the effect of intervention programs constructed under the guidance of the comprehensive unit-based safety program (CUSP) model on chemotherapy-induced nausea and vomiting (CINV) in patients with ovarian cancer. Method According to the time of admission, 90 ovarian cancer chemotherapy patients in the first affiliated Hospital of Anhui Medical University from June 2019 to September 2020 were divided into an intervention group and a control group with 45 cases each. Both groups of patients received routine intervention, and the intervention group implemented the CUSP program on this basis. The intervention lasted 8 months. Before and after the intervention, the patients in the ward were used the Multinational Association of Supportive Care in Cancer (MASCC) Antiemesis Tool, the Functional Living Index-Emesis (FLIE), and the Hospital Anxiety and Depression Scale (HADS) for the effect evaluation. Results After the intervention, the degree of nausea and vomiting frequency in the intervention group were significantly lower than that in the control group, especially the degree of nausea in the delayed phase (P

Inflammatory bowel disease (IBD), encompassing ulcerative colitis (UC) and Crohn’s disease (CD), arises from intricate interactions involving genetics, environment, and pharmaceuticals with an ambiguous pathogenic mechanism. Recently, there has been an increasing utilization of lactic acid bacteria (LAB) in managing IBD, attributed to their ability to enhance intestinal barrier function, mitigate inflammatory responses, and modulate gut microbiota. This review initiates by elucidating the pathogenesis of IBD and its determinants, followed by an exploration of the mechanisms underlying LAB therapy in UC and CD. Special attention is directed towards their influence on intestinal barrier function and homeostasis regulated by gut microbiota. Furthermore, the review investigates the complex interplay among pivotal gut microbiota, metabolites, and pathways associated with inflammation. Moreover, it underscores the limitations of LAB in treating IBD, particularly in light of their varying roles in UC and CD. This comprehensive analysis endeavors to offer insights for the optimized application of LAB in IBD therapy.

A series of CO2-based thermoplastic polyurethanes (TPUs) were prepared using CO2-based poly(polycarbonate) diol (PPCDL), 4,4′-methylenebis (cyclohexyl isocyanate) (HMDI), and polypropylene glycol (PPG and 1,4-butanediol (BDO) as the raw materials. The mechanical, thermal, optical, and barrier properties shape memory behaviors, while biocompatibility and degradation behaviors of the CO2-based TPUs are also systematically investigated. All the synthesized TPUs are highly transparent amorphous polymers, with one glass transition temperature at ~15–45 °C varying with hard segment content and soft segment composition. When PPG is incorporated into the soft segments, the resultant TPUs exhibit excellent self-healing and shape memory performances with the average shape fixity ratio and shape recovery ratio as high as 98.9% and 88.3%, respectively. Furthermore, the CO2-based TPUs also show superior water vapor permeability resistance, good biocompatibility, and good biodegradation properties, demonstrating their pretty competitive potential in the polyurethane industry applications.

Currently, the clinical cure rate for primary liver cancer remains low. Effective screening and early diagnosis of hepatocellular carcinoma (HCC) remain clinical challenges. Exosomes are intimately associated with tumor development and their contents have the potential to serve as highly sensitive tumor-specific markers. A comprehensive untargeted metabolomics study was conducted using exosome samples extracted from the serum of 48 subjects (36 HCC patients and 12 healthy controls) via a commercial kit. An ultra-performance liquid chromatography-mass spectrometry (UPLC-MS) strategy was used to identify the metabolic compounds. A total of 18 differential metabolites were identified using the non-targeted metabolomics approach of UPLC-QTOF-MS/MS. Pathway analysis revealed significant alterations in the arachidonic acid metabolism, linoleic acid metabolism, and unsaturated fatty acid metabolism pathways. ROC analysis indicated that three metabolites with AUC values exceeding 0.900 were selected as potential biomarkers: caprylic acid and linoleic acid were upregulated in the HCC group, whereas pentadecanoic acid was downregulated. Linoleic acid, caprylic acid, and pentadecanoic acid are potential biomarkers for diagnosing HCC. The significant alterations in these three metabolic pathways offer new insights into the mechanisms underlying HCC formation and progression.

IntroductionThe emergence of SARS-CoV-2 Omicron subvariants has presented a significant challenge to global health, as these variants show resistance to most antibodies developed early in the pandemic. Therapeutic antibodies with potent efficacy to the Omicron variants are urgently demanded.MethodsUtilizing the rapid antibody discovery platform, Berkeley Lights Beacon, we isolated two monoclonal neutralizing antibodies, 2173-A6 and 3462-A4. These antibodies were isolated from individuals who recently recovered from Omicron infections.ResultsBoth antibodies, 2173-A6 and 3462-A4, demonstrated high affinity for the RBD and effectively neutralized pseudoviruses from various Omicron lineages, including BA.4/5, XBB.1.16, XBB.1.5, and EG.5.1. This neutralization was achieved through binding to identical or overlapping epitopes.DiscussionThe use of the Beacon platform enabled the rapid isolation and identification of effective neutralizing antibodies within less than 10 days. This process significantly accelerates the development of novel therapeutic antibodies, potentially reducing the time required to respond to unknown infectious diseases in the future.

IntroductionUnderstanding the response of cross-domain co-occurrence networks of soil microorganisms to phosphorus stability and the resulting impacts is critical in ecosystems, but the underlying mechanism is unclear in artificial grassland ecosystems.MethodsIn this study, the effects of four phosphorus concentrations, P0 (0 kg P ha−1), P1 (15.3 kg P ha−1), P2 (30.6 kg P ha−1), and P3 (45.9 kg P ha−1), on the cross-domain co-occurrence network of bacteria and fungi were investigated in an artificial Leymus chinensis grassland in an arid region.Results and discussionThe results of the present study showed that phosphorus addition significantly altered the stem number, biomass and plant height of the Leymus chinensis but had no significant effect on the soil bacterial or fungal alpha (ACE) diversity or beta diversity. The phosphorus treatments all increased the cross-domain co-occurrence network edge, node, proportion of positively correlated edges, edge density, average degree, proximity to centrality, and robustness and increased the complexity and stability of the bacterial-fungal cross-domain co-occurrence network after 3 years of continuous phosphorus addition. Among them, fungi (Ascomycota, Basidiomycota, Mortierellomycota and Glomeromycota) play important roles as keystone species in the co-occurrence network, and they are significantly associated with soil AN, AK and EC. Finally, the growth of Leymus chinensis was mainly due to the influence of the soil phosphorus content and AN. This study revealed the factors affecting the growth of Leymus chinense in artificial grasslands in arid areas and provided a theoretical basis for the construction of artificial grasslands.

Abstract Senescence‐associated microRNAs (SA‐miRNAs) are important molecules for aging regulation. While many aging‐promoting SA‐miRNAs have been identified, confirmed aging‐suppressive SA‐miRNAs are rare, that impeded our full understanding on aging regulation. In this study, we verified that miR‐708 expression is decreased in senescent cells and aged tissues and revealed that miR‐708 overexpression can alleviate cellular senescence and aging performance. About the molecular cascade carrying the aging suppressive action of miR‐708, we unraveled that miR‐708 directly targets the 3′UTR of the disabled 2 (Dab2) gene and inhibits the expression of DAB2. Interestingly, miR‐708‐caused DAB2 downregulation blocks the aberrant mammalian target of rapamycin complex 1 (mTORC1) activation, a driving metabolic event for senescence progression, and restores the impaired autophagy, a downstream event of aberrant mTORC1 activation. We also found that AMP‐activated protein kinase (AMPK) activation can upregulate miR‐708 via the elevation of DICER expression, and miR‐708 inhibitor is able to blunt the antiaging effect of AMPK. In summary, this study characterized miR‐708 as an aging‐suppressive SA‐miRNA for the first time and uncovered a new signaling cascade, in which miR‐708 links the DAB2/mTOR axis and AMPK/DICER axis together. These findings not only demonstrate the potential role of miR‐708 in aging regulation, but also expand the signaling network connecting AMPK and mTORC1.

Summary: The clinical utility of circulating tumor DNA (ctDNA) in hormone-sensitive prostate cancer (HSPC) remains inadequately elucidated. This study presents the largest real-world cohort to conduct a concordance analysis between ctDNA and tissue-based genomic profiling in HSPC patients. The findings reveal diminished ctDNA abundance in cases with low tumor burden and demonstrate an increased concordance rate between ctDNA and tissue along with the progression of disease burden. Notably, a substantial number of exclusive genomic alterations (GAs) were identified either in ctDNA or tissue in high-volume metastatic disease. Integrating tissue and ctDNA analysis identified specific gene alterations (BRCA1, BRCA2, CDK12, TP53, PTEN, or RB1) associated with a shorter time to the progression to castration-resistant prostate cancer (CRPC), with an escalated CRPC risk correlated with cumulative GAs. This multicenter, real-world investigation underscores the complementary role of ctDNA and tissue in detecting clinically pertinent GAs, highlighting their potential integration into clinical practice for advanced prostate cancer management.

A completely new poly(carbonate-ester) macrodiol (PPCP-mDL), derived from direct copolymerization of carbon dioxide (CO2), propylene oxide (PO), phthalic anhydride (PA) and 1, 4-butanediol (BDO) catalyzed by metal-free triethylborine (TEB)/1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) pairs has been developed. The molecular weight of PPCP-mDL produced varying from 1.1–2.3 kg mol−1 can be easily controlled through the regulation of reaction conditions. For the formulation of non-toxic, phthalate-free flexible PVC, novel and biodegradable ec-PPCP-mDL with high molecular weight may be obtained through end-capping the PPCP-mDL using benzoyl chloride. The ec-PPCP-mDL/PVC blends display better comprehensive plasticization performance than do comparable blends with commercial DEHP plasticizers. These blends exhibit high thermal stability, mechanical properies, plasticizer migration resistance and transmittance. The interaction between ec-PPCP-mDL and PVC has been characterized using FTIR spectroscopy. A possible mode of plasticization has been suggested. The rich ester groups in the structure of ec-PPCP-mDLs interact well with PVC via hydrogen bonding, resulting in excellent compatiblity with PVC. Overall, the novel ec-PPCP-mDL material, respects an attractive alternative to plasticizers as a green, non-toxic, biodegradable, partially sustainable for the preparation of flexible PVC formulations.

BackgroundAs a damage-associated molecular pattern protein, high mobility group box 1 (HMGB1) is associated with kidney and systemic inflammation. The predictive and therapeutic value of HMGB1 as a biomarker has been confirmed in various diseases. However, its value in diabetic kidney disease (DKD) remains unclear. Therefore, this study aimed to investigate the correlation between serum and urine HMGB1 levels and DKD progression.MethodsWe recruited 196 patients with type 2 diabetes mellitus (T2DM), including 109 with DKD and 87 T2DM patients without DKD. Additionally, 60 healthy participants without T2DM were also recruited as controls. Serum and urine samples were collected for HMGB1 analysis. Simultaneously, tumor necrosis factor receptor superfamily member 1A (TNFR-1) in serum and kidney injury molecule (KIM-1) in urine samples were evaluated for comparison.ResultsSerum and urine HMGB1 levels were significantly higher in patients with DKD than in patients with T2DM and healthy controls. Additionally, serum HMGB1 levels significantly and positively correlated with serum TNFR-1 (R2 = 0.567, p

ObjectiveCardiac surgery in Congenital Heart Disease-Heterotaxy (CHD-HTX) patients often leads to increased postoperative airway complications. Abnormal respiratory ciliary function, resembling primary ciliary dyskinesia, has been observed. We expanded the sample size by retrospectively reviewing Ciliary Dysfunction (CD) in CHD-HTX patients to verify the increased risk of post-surgical respiratory complications.MethodsWe conducted a retrospective review of 69 CHD-HTX patients undergoing cardiac surgery, assessing abnormal respiratory function using nasal nitric oxide (nNO) levels and nasal ciliary motion observed in video microscopy. Data collected included demographics, surgical details, postoperative complications, length of stay, ICU hours, salvage procedures, intubation duration, and mortality.ResultsThe CD and no-CD cohorts exhibited notable similarities in risk adjustment in Congenital Heart Surgery-1 (RACHS-1) risk categories, age at the time of surgery, and the duration of follow-up evaluations. We observed a trend toward an increased length of post-operative stay in the CD group (15.0 vs. 14.0; P = 0.0017). CHD-HTX patients with CD showed significantly higher rates of respiratory complications (70% vs. 44.4%; P = 0.008). There were no notable variances observed in postoperative hospitalization duration, mechanical ventilation period, or surgical mortality.ConclusionOur findings suggest that CHD-HTX patients with CD may face an elevated risk of respiratory complications. These results offer guidance for perioperative management and serve as a reference for further pathological studies.

Premenstrual syndrome (PMS) occurs recurrently during the luteal phase of a woman’s menstrual cycle and disappears after menstruation ends. It is characterized by abnormal changes in both the body and mood, and in certain cases, severe disruptions in daily life and even suicidal tendencies. Current drugs for treating PMS, such as selective serotonin reuptake inhibitors, do not yield satisfactory results. Orexin, a neuropeptide produced in the lateral hypothalamus, is garnering attention in the treatment of neurological disorders and is believed to modulate the symptoms of PMS. This paper reviews the advancements in research on sleep disturbances, mood changes, and cognitive impairment caused by PMS, and suggests potential pathways for orexin to address these symptoms. Furthermore, it delves into the role of orexin in the molecular mechanisms underlying PMS. Orexin regulates steroid hormones, and the cyclic fluctuations of estrogen and progesterone play a crucial role in the pathogenesis of PMS. Additionally, orexin also modulates the gamma-aminobutyric acid (GABA) system and the inflammatory response involved in coordinating the mechanism of PMS. Unraveling the role of orexin in the pathogenesis of PMS will not only aid in understanding the etiology of PMS but also hold implications for orexin as a novel target for treating PMS.

Peritoneal lymphomatosis is a rare presentation of lymphoma that can mimic peritoneal tuberculosis. The computed tomography findings in both conditions include omental caking, thickening, and nodularity. We report the case of a 41-year-old man who presented with intermittent abdominal pain and distension. Abdominal CT initially suggested peritoneal tuberculosis due to the thickening of the peritoneum and greater omentum with multiple nodules. However, 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) images showed diffuse metabolic activity increase in the thickened peritoneum, omentum, and mesentery. An omental biopsy was performed under ultrasonography guidance, and histopathological examination revealed a high-grade Burkitt lymphoma. It is crucial to distinguish peritoneal lymphomatosis from tuberculosis, as the prognosis and management of the two conditions are vastly different.

In response to the challenge of inefficient oblique-photography 3D modeling in emergency surveying and mapping support for the rapid investigation of geological disasters caused by the “8·8” Jiuzhaigou earthquake, this paper proposes an orthographic single-view oblique 3D modeling method based on the study of UAV oblique photogrammetry technology. By combining it with 3D scene construction technology and remote sensing interpretation technology, a comprehensive system for rapid geological disaster investigation using real-scene 3D technology in emergency situations was developed. This system was successfully applied during the rapid investigation of geological disasters after the "8·8" Jiuzhaigou earthquake, providing real 3D models and related information on disasters and damages within the critical 72-hour rescue period. It marked the first time in the history of emergency surveying and mapping support in Sichuan Province that a real-scene 3D model was provided, and it played a critical role in disaster assessment, emergency command and decision-making, as well as post-disaster recovery and reconstruction efforts by relevant authorities. Furthermore, based on the survey results, a series of suggestions for geological disaster prevention, mitigation, and relief were proposed, serving as a scientific basis for the comprehensive prevention and control of geological disasters in affected areas.

Abstract Anti-PD-1 therapy has shown promising outcomes in the treatment of different types of cancer. It is of fundamental interest to analyze the efficacy of anti-PD-1 therapy in cancer patients infected with hepatitis B virus (HBV) since the comorbidity of HBV and cancer is widely documented. We designed a multicenter retrospective study to evaluate the efficacy of anti-PD-1 therapy on non-liver cancer patients infected with HBV. We found anti-PD-1 therapy achieved much better outcomes in HBV+ non-liver cancer patients than their HBV– counterparts. We performed single-cell RNA sequencing (scRNA-seq) on peripheral blood mononuclear cells (PBMCs) from esophageal squamous cell carcinoma (ESCC) patients. We found both cytotoxicity score of T cells and MHC score of B cells significantly increased after anti-PD-1 therapy in HBV+ ESCC patients. We also identified CX3CR1high TEFF, a subset of CD8+ TEFF, associated with better clinical outcome in HBV+ ESCC patients. Lastly, we found CD8+ TEFF from HBV+ ESCC patients showing higher fraction of Exhaustionhi T than their HBV– counterpart. In summary, anti-PD-1 therapy on HBV+ non-liver cancer patients is safe and achieves better outcomes than that on HBV– non-liver cancer patients, potentially because HBV+ patients had higher fraction of Exhaustionhi T, which made them more efficiently respond to anti-PD-1 therapy.

The Yarlung Tsangpo-Brahmaputra River Basin (YBRB) has long been troubled by the competitive water development activities of India, China, and Bangladesh. While energy thirst and food security keep challenging the riparian States, climate-related changing monsoon pattern increases the potential for conflicts over scarce water. Based on a quantitative analysis of 400 water events spanning the years 1958–2020 of the basin, this research tries to provide a holistic understanding of the conflict and cooperation and explore the possibility of water war or ‘climate-based’ water war in the basin; and thus formulate more precise recommendations to help prevent and mitigate conflicts. The results of this quantitative research surprisingly reveal that, instead of being main causes of bilateral conflict in the basin, the ‘energy imperative’ and the ‘climate imperative’ have become two major catalysts for water cooperation in the basin, water war is therefore highly unlikely. However, current bilateral cooperation on climate change mainly involves ‘climate adaptation’; few efforts have yet been made cooperatively in the field of ‘climate mitigation’; while traditional disputes around food and energy persist, the imperative of ecological protection and the lack of attention to cooperative climate mitigation are set to intensify potential conflict in the YBRB. HIGHLIGHTS Four hundred water events focus on food–energy–environment–climate change.; Database about conflict and cooperation around water, food, energy, and climate change (floods and droughts) in the Yarlung Tsangpo Basin countries.; ‘Secondary states’ in balancing the interest between India and China.;

In this study, Ganoderma lingzhi mycelium powder was used as material to extract polysaccharides from Ganoderma lingzhi mycelium by water extraction and alcohol deposition method. On the basis of single factor experiment, response surface methodology was combined to optimize the extraction process of polysaccharides from Ganoderma lingzhi mycelium. Proteins and small molecules were removed by Sevage method and dialysis method, then, the preliminary purification of Ganoderma lingzhi mycelium polysaccharide (SGP) was obtained. Animal model: 60 mice were randomly divided into blank control group, model group, positive control group and low, medium and high administration groups (125, 250 and 500 mg/kg·bw). Except for blank group, each group was given 56° Beijing Red Star Erguotou by gavage at a dose of 0.1 mL/10 g·bw to establish a chronic alcohol liver injury model. Starting from the 15th day, 4 h after modeling, each administration group was given intragastric administration of silybin (200 mg/kg·bw) and different doses of SGP solution, respectively, and dissected after 2 consecutive weeks. The levels of aspartate amino transferase (AST), aspartate transaminase (ALT), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), total cholesterol (TC), triglyceride (TG), interleukin-6 (IL-6), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α) in serum and liver tissues of mice were determined by kit method, and the liver pathological sections of mice were observed. The results showed that the optimal extraction conditions of polysaccharides from Ganoderma lingzhi mycelium were 89 ℃, 2.5 h and liquid/solid ratio 85:1 mL/g. Under these conditions, the yield of polysaccharides was 3.44%. Animal experiment results showed that the liver index of mice in SGP medium and high dose groups was significantly decreased (P

Abstract Fibroblast activation protein (FAP) is higher expressed on cancer-associated fibroblasts (CAFs) in most malignant epithelial neoplasms, which is lower expressed in normal tissues. As a promising small molecular probe, FAP inhibitor (FAPI) shows the specific binding to FAP. This study aimed to explore a novel molecular probe [99mTc]Tc-HYNIC-FAPI targeting CAFs. The in vitro characteristics of the probe were also evaluated. The FAPI targeting FAP was designed, synthesized and conjugated with the chelator 6-hydrazinylnicotinic acid (HYNIC) for radiolabeling with 99mTc. The radiolabeling yield, radiochemical purity and stability were evaluated by Instant thin-layer chromatography (ITLC) and High performance liquid chromatography (HPLC). Lipophilicity was performed by the distribution coefficient test. The binding and migration ability of the probe was assessed using the FAP transfected tumor cell line. The radiolabeling yield of [99mTc]Tc-HYNIC-FAPI was (97.29 ± 0.46) %. The radiochemical purity was more than 90% and kept stable until 6 h. The radioligand was shown as lower lipophilicity, of which logD7.4 value was − 2.38 $$\pm$$ ± 0.13. In vitro experiments, the results indicated that the probe showed binding properties, and inhibited the migration of tumor cells. The novel [99mTc]Tc-HYNIC-FAPI probe was successfully radiosynthesized and exhibited good radiochemical purity, stability and in vitro binding ability to tumor cells. The [99mTc]Tc-HYNIC-FAPI will be a promising SPECT/CT imaging probe.

Abstract Background Diabetic nephropathy (DN) is a complex disease involving the upregulation of many inflammation-related proteins. Alternative polyadenylation (APA), a crucial post-transcriptional regulatory mechanism, has been proven to play vital roles in many inflammatory diseases. However, it is largely unknown whether and how APA exerts function in DN. Methods We performed transcriptomics and proteomics analysis of glomeruli samples isolated from 50 biopsy-proven DN patients and 25 control subjects. DaPars and QAPA algorithms were adopted to identify APA events from RNA-seq data. The qRT-PCR analysis was conducted to verify 3′UTR length alteration. Short and long 3ʹUTRs isoforms were also overexpressed in podocytes under hyperglycemia condition for examining protein expression. Results We detected transcriptome-wide 3′UTR APA events in DN, and found that APA-mediated 3ʹUTR lengthening of genes (APA genes) increased their expression at protein but not mRNA level. Increased protein level of 3′UTR lengthening gene was validated in podocytes under hyperglycemia condition. Pathway enrichment analysis showed that APA genes were enriched in inflammation-related biological processes including endoplasmic reticulum stress pathways, NF-κB signaling and autophagy. Further bioinformatics analysis demonstrated that 3′UTR APA of genes probably altered the binding sites for RNA-binding proteins, thus enhancing protein translation. Conclusion This study revealed for the first time that 3′UTR lengthening of APA genes contributed to the progression of DN by elevating the translation of corresponding proteins, providing new insight and a rich resource for investigating DN mechanisms.

Abstract Background Lung cancer (LC) is a fatal malignancy and often accompanied with converting normal fibroblasts to cancer‐associated fibroblasts (CAFs). Exosomal lncRNA AGAP2‐AS1 has been elucidated to be a potent prognostic factor for LC, while its role in activating CAFs is largely unknown. Methods We first extracted exosomes from LC patients and co‐cultured them with MRC5 cells to observe the state of MRC5 cells, detect AGAP2‐AS1 using real‐time quantitative polymerase chain reaction, and then analyze the interaction between EIF4A3 and AGAP2‐AS1 using RNA pull down experiments. CCK‐8 assay was used to detect cell proliferation. Transwell experiments demonstrated the regulation of MRC5 cells and, finally, the role of MyD88/NF‐κB in the downstream mechanism of EIF4A3/AGAP2‐AS1 was explored by RNA interference technology and pyrrolidinedithiocarbamic acid inhibition. Results We demonstrated that exosomes from the LC patients (cancer‐exo) notably increased the metastatic ability of MRC‐5 cells, promoting the expressions of the CAF biomarkers and lncRNA AGAP2‐AS1. Overexpression of lncRNA AGAP2‐AS1 prominently activated MRC‐5 cells. Moreover, EIF4A3 was upregulated in the cancer‐exo‐treated MRC‐5 cells, and EIF4A3 was verified to bind with lncRNA AGAP2‐AS1 to improve its stability. The MyD88/NF‐κB signaling pathway was subsequently proved to be positively regulated by lncRNA AGAP2‐AS1, and the promotive role of lncRNA AGAP2‐AS1 in LC and activating CAFs was confirmed in vivo. Conclusions The positive feedback of EIF4A3/AGAP2‐AS1/MyD88/NF‐κB signaling pathway contributed to the activation of CAFs and exacerbated LC in turn, revealing a novel regulatory axis underlying LC.

Abstract Background Blood–brain barrier (BBB) disruption is a major adverse event after ischemic stroke (IS). Caveolin-1 (Cav-1), a scaffolding protein, played multiple roles in BBB permeability after IS, while the pros and cons of Cav-1 on BBB permeability remain controversial. Numerous studies revealed that extracellular vesicles (EVs), especially stem cells derived EVs, exerted therapeutic efficacy on IS; however, the mechanisms of BBB permeability needed to be clearly illustrated. Herein, we compared the protective efficacy on BBB integrity between bone marrow mesenchymal stem cells derived extracellular vesicles (BMSC-EVs) and EVs from brain endothelial cells (BEC-EVs) after acute IS and investigated whether the mechanism was associated with EVs antagonizing Cav-1-dependent tight junction proteins endocytosis. Methods BMSC-EVs and BEC-EVs were isolated and characterized by nanoparticle tracking analysis, western blotting, and transmission electron microscope. Oxygen and glucose deprivation (OGD) treated b. End3 cells were utilized to evaluate brain endothelial cell leakage. CCK-8 and TRITC-dextran leakage assays were used to measure cell viability and transwell monolayer permeability. Permanent middle cerebral artery occlusion (pMCAo) model was established, and EVs were intravenously administered in rats. Animal neurological function tests were applied, and microvessels were isolated from the ischemic cortex. BBB leakage and tight junction proteins were analyzed by Evans Blue (EB) staining and western blotting, respectively. Co-IP assay and Cav-1 siRNA/pcDNA 3.1 vector transfection were employed to verify the endocytosis efficacy of Cav-1 on tight junction proteins. Results Both kinds of EVs exerted similar efficacies in reducing the cerebral infarction volume and BBB leakage and enhancing the expressions of ZO-1 and Claudin-5 after 24 h pMCAo in rats. At the same time, BMSC-EVs were outstanding in ameliorating neurological function. Simultaneously, both EVs treatments suppressed the highly expressed Cav-1 in OGD-exposed b. End3 cells and ischemic cerebral microvessels, and this efficacy was more prominent after BMSC-EVs administration. Cav-1 knockdown reduced OGD-treated b. End3 cells monolayer permeability and recovered ZO-1 and Claudin-5 expressions, whereas Cav-1 overexpression aggravated permeability and enhanced the colocalization of Cav-1 with ZO-1 and Claudin-5. Furthermore, Cav-1 overexpression partly reversed the lower cell leakage by BMSC-EVs and BEC-EVs administrations in OGD-treated b. End3 cells. Conclusions Our results demonstrated that Cav-1 aggravated BBB permeability in acute ischemic stroke, and BMSC-EVs exerted similar antagonistic efficacy to BEC-EVs on Cav-1-dependent ZO-1 and Claudin-5 endocytosis. BMSC-EVs treatment was superior in Cav-1 suppression and neurological function amelioration. Graphical Abstract

In this work, the authors report Cryo-EM structures of the signaling complexes of human GPR21, an orphan GPCR and a potential metabolic disease target, and reveal unique receptor activation conformation when bound to downstream signaling proteins in the absence of any ligand.

BackgroundDiabetic retinopathy-related (DR-related) diseases are posing an increasing threat to eye health as the number of patients with diabetes mellitus that are young increases significantly. The automatic diagnosis of DR-related diseases has benefited from the rapid development of image semantic segmentation and other deep learning technology.MethodsInspired by the architecture of U-Net family, a neighbored attention U-Net (NAU-Net) is designed to balance the identification performance and computational cost for DR fundus image segmentation. In the new network, only the neighboring high- and low-dimensional feature maps of the encoder and decoder are fused by using four attention gates. With the help of this improvement, the common target features in the high-dimensional feature maps of encoder are enhanced, and they are also fused with the low-dimensional feature map of decoder. Moreover, this network fuses only neighboring layers and does not include the inner layers commonly used in U-Net++. Consequently, the proposed network incurs a better identification performance with a lower computational cost.ResultsThe experimental results of three open datasets of DR fundus images, including DRIVE, HRF, and CHASEDB, indicate that the NAU-Net outperforms FCN, SegNet, attention U-Net, and U-Net++ in terms of Dice score, IoU, accuracy, and precision, while its computation cost is between attention U-Net and U-Net++.ConclusionThe proposed NAU-Net exhibits better performance at a relatively low computational cost and provides an efficient novel approach for DR fundus image segmentation and a new automatic tool for DR-related eye disease diagnosis.