The effects of metformin on inflammation and apoptosis in rats with preeclampsia.

BACKGROUND: Defined clinically by elevated blood pressure along with either proteinuria and/or maternal organ dysfunction, representing a major cause of morbidity and mortality pregnant women and newborns. Metformin (MET), an oral antidiabetic medication, has been shown to prevent preeclampsia (PE) through various mechanisms, including reducing inflammation, improving endothelial dysfunction, improving mitochondrial function, and altering cellular homeostasis and energy metabolism. Herein, we explored the role of MET in PE and its underlying molecular mechanisms using in in vivo experiments. METHODS: RT-qPCR, Western blot (WB), and immunohistochemistry (IHC) were conducted to assess the mRNA or protein expression of genes related to mitochondrial apoptosis. Additionally, ELISA was conducted to quantify the expression of mitochondrial apoptosis and inflammation-related genes, as well as PE biomarkers. RESULTS: Treatment with MET in PE rats ameliorated hypertension and proteinuria, altered the expression of PE biomarkers, and significantly inhibited L-NAME-induced inflammation and cell apoptosis. MET modulated the levels of inflammatory cytokines tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and IL-10, mitigating inflammation in PE rats. Furthermore, MET regulated mitochondrial outer membrane permeability (MOMP), thereby reducing cell apoptosis occurring in the mitochondrial pathway of PE rats. CONCLUSIONS: This study demonstrates that MET alleviates inflammation and cell apoptosis in PE rats by modulating the expression of inflammatory factors and MOMP. Our results indicate that MET has huge therapeutic potential against PE.

The involvement of aquaporin 5 in the inflammatory response of primary Sjogren's syndrome dry eye: potential therapeutic targets exploration.

Sjogren's syndrome (SS) is a chronic autoimmune disease. Mainly due to the infiltration of lymphoplasmic cells into the exocrine glands, especially the salivary glands and lacrimal glands, resulting in reduced tear and saliva secretion. Reduced tear flow can trigger Sjogren's syndrome dry eye (SSDE). Although the pathophysiology of SSDE xerosis remains incompletely understood, recent advances have identified aquaporin-5 (AQP5) as a critical factor in dysregulation of the exocrine gland and epithelium, influencing the clinical presentation of SSDE through modulation of inflammatory microenvironment and tear secretion processes. This review aims to explore AQP5 regulatory mechanisms in SSDE and analyze its potential as a therapeutic target, providing new directions for SSDE treatment.

Microbiome and Microbial Pure Culture Study Reveal Commensal Microorganisms Alleviate Salmonella enterica Serovar Pullorum Infection in Chickens.

Pullorum disease, an intestinal disease in chickens caused by Salmonella enterica serovar pullorum (S. Pullorum), is a significant threat to the poultry industry and results in substantial economic losses. The bacteria's transmission, both vertical and horizontal, makes it difficult to completely eliminate it. Control strategies for pullorum disease primarily involve stringent eradication programs that cull infected birds and employ antibiotics for treatment. However, eradication programs are costly, and antibiotic use is restricted. Therefore, developing alternative control strategies is essential. Increasingly, studies are focusing on modulating the gut microbiota to control intestinal diseases. Modulating the chicken gut microbiota may offer a novel strategy for preventing and controlling pullorum disease in poultry. However, the impact of S. Pullorum on the chicken gut microbiota has not been well established, prompting our exploration of the relationship between S. Pullorum and the chicken gut microbiota in this study. In this study, we initially analyzed the dynamic distribution of the gut microbiota in chickens infected with S. Pullorum. Alpha diversity analysis revealed a decrease in observed OTUs and the Shannon diversity index in the infected group, suggesting a reduction in the richness of the chicken gut microbiota due to S. Pullorum infection. Principal coordinate analysis (PCoA) showed distinct clusters between the gut microbiota of infected and uninfected groups, indicating S. Pullorum infection changed the chicken gut microbiota structure. Specifically, S. Pullorum infection enriched the relative abundance of the genera Escherichia-Shigella (65% in infected vs. 40.6% in uninfected groups) and Enterococcus (10.8% vs. 3.7%) while reducing the abundance of Lactobacillus (9.9% vs. 32%) in the chicken microbiota. Additionally, based on the observed changes in the chicken gut microbiota, we isolated microorganisms, including Bifidobacterium pseudolongum, Streptococcus equi and Lacticaseibacillus paracasei (L. paracasei), which were decreased by S. Pullorum infection. Notably, the L. paracasei Lp02 strain was found to effectively inhibit S. Pullorum proliferation in vitro and alleviate its infection in vivo. We found that S. Pullorum infection reduced the richness of the chicken gut microbiota and enriched the relative abundance of the genera Escherichia-Shigella and Enterococcus while decreasing the abundance of the anaerobic genus Lactobacillus. Furthermore, microbiota analysis enabled the isolation of several antimicrobial microorganisms from healthy chicken feces, with a L. paracasei strain notably inhibiting S. Pullorum proliferation in vitro and alleviating its infection in vivo. Overall, this research enhances our understanding of the interaction between gut microbiota and pathogen infection, as well as offers new perspectives and strategies for modulating the chicken gut microbiota to control pullorum disease.

Targeted anti-angiogenesis therapy for advanced osteosarcoma.

To date, despite extensive research, the prognosis of advanced osteosarcoma has not improved significantly. Thus, patients experience a reduced survival rate, suggesting that a reevaluation of current treatment strategies is required. Recently, in addition to routine surgery, chemotherapy and radiotherapy, researchers have explored more effective and safer treatments, including targeted therapy, immunotherapy, anti-angiogenesis therapy, metabolic targets therapy, and nanomedicine therapy. The tumorigenesis and development of osteosarcoma is closely related to angiogenesis. Thus, anti-angiogenesis therapy is crucial to treat osteosarcoma; however, recent clinical trials found that it has insufficient efficacy. To solve this problem, the causes of treatment failure and improve treatment strategies should be investigated. This review focuses on summarizing the pathophysiological mechanisms of angiogenesis in osteosarcoma and recent advances in anti-angiogenesis treatment of osteosarcoma. We also discuss some clinical studies, with the aim of providing new ideas to improve treatment strategies for osteosarcoma and the prognosis of patients.

Lipidomic profiling of amniotic fluid reveals aberrant fetal lung development and fetal growth disrupted by lipid disorders during gestational asthma.

This study aimed to investigate how maternal asthma during pregnancy disrupts fetal lung development by altering lipid metabolism in the amniotic fluid, which is crucial for fetal development. A pregnancy-induced asthma model was established in female rats using house dust mite (HDM) as a common allergen. The fetuses were divided into four groups based on whether the mother and fetus were exposed to the allergen: PBS+PBS, PBS+HDM, HDM+PBS, and HDM+HDM. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was employed to analyze changes in the lipid profile of the amniotic fluid and bronchoalveolar lavage fluid (BALF). Principal component analysis (PCA) and ChemRICH methods were used to explore the potential relationship between lipid metabolism abnormalities and impaired fetal lung development. The results indicate that maternal asthma exacerbates asthma-related inflammatory markers in fetuses, leading to pathological changes in the lungs and elevated levels of cytokines IL-5, IL-13, and IgE. Additionally, 18 differential lipids, primarily oxygenated lipids, were identified in the amniotic fluid after modeling, suggesting an enhanced oxidative stress environment for the fetus. This environment causes metabolic disturbances in various lipid groups in fetal lungs, with the HDM+HDM group showing significant abnormalities in lipids critical for lung development, including phosphatidylethanolamine (PE), phosphatidylglycerol (PG), and fatty acids (FA). In conclusion, gestational asthma can reshape the lipid profile in the amniotic fluid and BALF, significantly disrupting fetal growth and lung development. Restoring normal lipid metabolism in the amniotic fluid and fetal lungs may offer a potential therapeutic approach to managing aberrant fetal lung development in asthmatic mothers.

Spatial resolved transcriptomics reveals distinct cross-talk between cancer cells and tumor-associated macrophages in intrahepatic cholangiocarcinoma.

BACKGROUND: Multiple studies have shown that tumor-associated macrophages (TAMs) promote cancer initiation and progression. However, the reprogramming of macrophages in the tumor microenvironment (TME) and the cross-talk between TAMs and malignant subclones in intrahepatic cholangiocarcinoma (iCCA) has not been fully characterized, especially in a spatially resolved manner. Deciphering the spatial architecture of variable tissue cellular components in iCCA could contribute to the positional context of gene expression containing information pathological changes and cellular variability. METHODS: Here, we applied spatial transcriptomics (ST) and digital spatial profiler (DSP) technologies with tumor sections from patients with iCCA. RESULTS: The results reveal that spatial inter- and intra-tumor heterogeneities feature iCCA malignancy, and tumor subclones are mainly driven by physical proximity. Tumor cells with TME components shaped the intra-sectional heterogenetic spatial architecture. Macrophages are the most infiltrated TME component in iCCA. The protein trefoil factor 3 (TFF3) secreted by the malignant subclone can induce macrophages to reprogram to a tumor-promoting state, which in turn contributes to an immune-suppressive environment and boosts tumor progression. CONCLUSIONS: In conclusion, our description of the iCCA ecosystem in a spatially resolved manner provides novel insights into the spatial features and the immune suppressive landscapes of TME for iCCA.

Association analysis of BSA-seq, BSR-seq, and RNA-seq reveals key genes involved in purple leaf formation in a tea population (Camellia sinensis).

Purple tea, rich in anthocyanins, has a variety of health benefits and is attracting global interest. However, the regulation mechanism of anthocyanin in purple tea populations has not been extensively studied. In this experiment, RNA-seq, BSA-seq, and BSR-seq were performed using 30 individuals with extreme colors (dark-purple and green) in an F 1 population of 'Zijuan' and 'Jinxuan'. The results show that 459 genes were differentially expressed in purple and green leaves, among which genes involved in the anthocyanin synthesis and transport pathway, such as CHS, F3H, ANS, MYB75, GST, MATE, and ABCC, were highly expressed in purple leaves. Moreover, there were multiple SNP/InDel variation sites on chromosomes 2 and 14 of the tea plant, as identified by BSA-seq. The integrated analysis identified two highly expressed genes (CsANS and CsMYB75) with SNP/InDel site variations in the purple tea plants. By silencing leaves, we proved that CsMYB75 could positively regulate anthocyanin accumulation and expression of related structural genes in tea plants. A 181-bp InDel in the CsMYB75 promoter was also found to be co-segregating with leaf color. The results of this study provide a theoretical reference for the molecular mechanism of anthocyanin accumulation in purple tea plants and contribute to the creation of new tea cultivars with high anthocyanin content.

Inorganic carbon utilization strategies of plateau aquatic plants in response to native habitats.

Aquatic plants are a crucial component of the aquatic ecosystem in the Tibetan Plateau region. Researching the adaptability of plateau aquatic plants in photosynthesis to the plateau environment can enhance understanding of the operational mechanisms of plateau ecosystems, thereby providing a scientific basis for the protection and management of plateau aquatic ecosystems. This study presents an investigation of photosynthetic inorganic carbon utilization strategies and photosynthetic efficiency of 17 aquatic plants under natural growing conditions in Niyang River basin on the Tibetan Plateau. In pH-drift experiments, 10 of 17 species were able to utilize HCO3-, and environmental factors like water pH were shown to have a significant effect on the ability of the tested species to utilize HCO3-. Titratable acidity in the leaves of Stuckenia filiformis, Zannichellia palustris, Batrachium bungei, and Myriophyllum spicatum showed significant diurnal fluctuations at certain sampling sites, indicating the presence of CAM. In B. bungei, water pH positively correlated with CAM activity, while CO2 concentration negatively correlated with CAM activity. The chlorophyll fluorescence analysis revealed that aquatic plants inhabiting the Tibetan Plateau exhibited photosynthetic adaptations. In conclusion, the aquatic plants on the Tibetan Plateau employ diverse strategies for utilizing inorganic carbon during photosynthesis, exhibiting their flexible adaptability to the native high-altitude habitats of the Tibetan Plateau.

Association between timing of labor induction and neonatal and maternal outcomes: an observational study from China.

BACKGROUND: Growing evidence suggests that elective induction of labor at 39 weeks' gestation may lead to more favorable perinatal outcomes than expectant management, however, how to weigh the pros and cons of elective labor induction at 39 weeks, the expectation of spontaneous delivery at 40 or 41 weeks, or delayed labor induction at 40 or 41 weeks on neonatal and maternal outcomes remains a practical challenge in clinical decision-making. OBJECTIVE: We compared the neonatal and maternal outcomes between elective induction of labor at 39 weeks' gestation and expectant management in a real-world setting. We also divided the expectantly managed group and compared outcomes of the spontaneous delivery at 40 or 41 weeks' gestation group and the induced group at 40 or 41 weeks' gestation with those of the elective induction at 39 weeks' gestation group. STUDY DESIGN: This retrospective cohort study included 21,282 participants who delivered between January 1, 2019, and June 30, 2022. Participants were initially categorized into 3 groups at 39 weeks' gestation, namely elective induction of labor, spontaneous delivery, and expectant management, for the primary analysis in which elective induction was compared with expectant management. Subsequently, the expectant management group at 39 weeks' gestation was divided into 3 groups at 40 weeks, and participants who underwent expectant management at 40 weeks were then divided into 2 groups at 41 weeks' gestation, namely elective induction and spontaneous delivery. In total, 6 groups were compared in the secondary analysis with the elective induction at 39 weeks' gestation group serving as the reference group. RESULTS: At 39 weeks' gestational age, participants who underwent elective induction of labor had a significantly lower risk for the primary composite outcomes than participants who were managed expectantly (adjusted odds ratio, 0.72; 95% confidence interval, 0.55-0.95), and there was no significant difference in the risk for cesarean delivery between the 2 groups. After further dividing the expectantly managed group and comparing them with participants who underwent elective induction of labor at 39 weeks' gestation, those who underwent spontaneous delivery at 40 weeks' gestation had significantly lower risks for cesarean delivery (0.61; 0.52-0.71) and chorioamnionitis (0.78; 0.61-1.00) but a higher risk for fetal distress (1.39; 1.22-1.57); those with spontaneous delivery at 41 weeks' gestation had a significantly higher risk for fetal distress (1.44; 1.16-1.79), postpartum hemorrhage (1.83; 1.26-2.66), and prolonged or arrested labor (1.61; 1.02-2.54). Moreover, when compared with participants who underwent elective induction of labor at 39 weeks' gestation, participants who were induced later in gestation had significantly higher risks for adverse neonatal and maternal outcomes, especially at 40 weeks' gestation. CONCLUSION: Our findings indicate that elective induction of labor at 39 weeks' gestation was significantly associated with lower risks for adverse short-term neonatal and maternal outcomes when compared with expectant management. Moreover, our study highlights the nuanced trade-offs in risks and benefits between elective induction at 39 weeks' gestation and waiting for spontaneous labor or delayed induction at 40 or 41 weeks' gestation, thus providing valuable insights for clinical decision-making in practice.

Prognosis poor, immune infiltration of colon adenocarcinoma associated with low expression levels of calcium-activated chloride channel.

The calcium-activated chloride channel (CLCA4) in colon adenocarcinoma (COAD) and immunological infiltration have not been extensively studied. This work thoroughly employed several datasets to assess the expression, prognosis, and association between immune infiltration and clinicopathological characteristics of CLCA4 in cancer, as well as look into potential signalling pathways. The human protein atlas (HPA), TIMER, UALCAN, TISIDB, GSCA, SangerBox, GeneMANIA, and LinkedOmics were among the datasets that were used. The findings demonstrated that, in comparison to normal tissues, COAD tissues had lower levels of CLCA4 expression. The prognosis was worse for those whose levels of CLCA4 expression were lower. For validation, immunohistochemistry (HPA) was used. Positive correlations between CLCA4 mRNA expression and its copy number variation (CNV) were observed, and CLCA4 CNV was linked to immunological infiltration. Subsequent investigation demonstrated the association between immune cell markers, immune checkpoint genes, and immunological infiltration with CLCA4. The overall survival and disease-free survival of M0 patients were considerably better than those of M1 patients, and the groups with tumour stages M0 and M1 had notably different levels of CLCA4 expression. Its substantial enrichment in ion channel activity, transmembrane transporter activity, digestion, and other biological processes was revealed by gene ontology analysis. Oxidative phosphorylation, pancreatic secretion, Parkinson's and Alzheimer's diseases, renin secretion, and other signalling pathways were the primary associations found for CLCA4. It is evident that the immunological microenvironment and functions like ion transport, metabolism, and intestinal digestion are all impacted by CLCA4 expression.

A randomised controlled clinical study of standard triple therapy, bismuth-based quadruple therapy and sequential therapy for Helicobacter pylori infection in children.

BACKGROUND AND AIM: Bismuth and non-bismuth quadruple therapy are the guideline-recommended first-line therapy in children with Helicobacter pylori infection in areas with high antibiotic resistance. However, their efficacy in children is uncertain and there are few well-designed studies. Here, we evaluated the eradication rates of standard triple therapy, bismuth-based quadruple therapy and sequential therapy in children with H. pylori infection. METHODS: A randomised controlled trial was conducted in children infected with H. pylori in West China Second Hospital. They were randomly assigned to 14-day standard triple therapy (omeprazole + amoxicillin + clarithromycin), 14-day bismuth quadruple therapy (bismuth + omeprazole + amoxicillin + clarithromycin) and 10-day sequential therapy (omeprazole + amoxicillin for 5 days followed by omeprazole + clarithromycin + metronidazole for 5 days). The eradication rate was assessed by a 13C-urea breath test 4 to 6 weeks after therapy completion. Symptom improvement and adverse events were compared among the groups. RESULTS: In total, 132 patients were enrolled. The eradication rates of 14-day standard triple therapy, 14-day bismuth quadruple therapy and 10-day sequential therapy were 70.0%, 78.9% and 50.0% in per-protocol analysis and 63.6%, 68.2% and 43.2% in intention-to-treat analysis, respectively. Symptom improvement and adverse drug event rates were similar in the three groups. CONCLUSION: The three therapeutic regimens evaluated in this study are equally not recommendable for H. pylori infection treatment due to unsatisfactory eradication rates. The high prevalence of clarithromycin resistance makes the use of clarithromycin-based quadruple therapy not advisable, even in combination with amoxicillin and bismuth salts.

One-Step Genetic Modification by Embryonic Doral Aorta Injection of Adenoviral CRISPR/Cas9 Vector in Chicken.

In the avian species, genetic modification by cell nuclear transfer is infeasible due to its unique reproductive system. The in vitro primordial germ cell modification approach is difficult and cumbersome, although it is the main method of genetic modification in chickens. In the present study, the adenoviral CRISPR/Cas9 vector was directly microinjected into the dorsal aorta of chicken embryos to achieve in vivo genetic modification. The results demonstrated that keratin 75-like 4 (KRT75L4), a candidate gene crucial for feather development, was widely knocked out, and an 8bp deletion was the predominant mutation that occurred in multiple tissues in chimeras, particularly in the gonad (2.63-11.57%). As we expected, significant modification was detected in the sperm of G0 (0.16-4.85%), confirming the potential to generate homozygous chickens and establishing this vector as a simple and effective method for genetic modification in avian species.

A Soft-Fiber Bioelectronic Device with Axon-Like Architecture Enables Reliable Neural Recording In Vivo under Vigorous Activities.

Implantable neural devices that record neurons in various states, including static states, light activities such as walking, and vigorous activities such as running, offer opportunities for understanding brain functions and dysfunctions. However, recording neurons under vigorous activities remains a long-standing challenge because it leads to intense brain deformation. Thus, three key requirements are needed simultaneously for neural devices, that is, low modulus, low specific interfacial impedance, and high electrical conductivity, to realize stable device/brain interfaces and high-quality transmission of neural signals. However, they always contradict each other in current material strategies. Here, a soft fiber neural device capable of stably tracking individual neurons in the deep brain of medium-sized animals under vigorous activity is reported. Inspired by the axon architecture, this fiber neural device is constructed with a conductive gel fiber possessing a network-in-liquid structure using conjugated polymers and liquid matrices and then insulated with soft fluorine rubber. This strategy reconciles the contradictions and simultaneously confers the fiber neural device with low modulus (300 kPa), low specific impedance (579 kΩ µm2), and high electrical conductivity (32 700 S m-1) - ≈1-3 times higher than hydrogels. Stable single-unit spike tracking in running cats, which promises new opportunities for neuroscience is demonstrated.

Preparation of bovine serum albumin-arabinoxylan cold-set gels by glucono-δ-lactone and salt ions double induction.

In order to investigate the effect of glucono-δ-lactone (GDL) and different salt ions (Na+ and Ca2+) induction on the cold-set gels of bovine serum albumin (BSA)-arabinoxylan (AX), the gel properties and structure of BSA-AX cold-set gels were evaluated by analyzing the gel strength, water-holding capacity, thermal properties, and Fourier Transform Infrared (FTIR) spectra. It was shown that the best gel strength (109.15 g) was obtained when the ratio of BSA to AX was 15:1. The addition of 1 % GDL significantly improved the water-holding capacity, gel strength and thermal stability of the cold-set gels (p < 0.05), and the microstructure was smoother. Low concentrations of Na+ (3 mM) and Ca2+ (6 mM) significantly enhanced the hydrophobic interaction and hydrogen bonding between BSA and AX after acid induction, and the Na+-induced formation of a denser microstructure with a higher water-holding capacity (75.51 %). However, the excess salt ions disrupted the stable network structure of the cold-set gels and reduced their thermal stability and crystalline structure. The results of this study contribute to the understanding of the interactions between BSA and AX induced by GDL and salt ions, and provide a basis for designing hydrogels with different properties.

Enhanced fatty acid biosynthesis by Sigma28 in stringent responses contributes to multidrug resistance and biofilm formation in Helicobacter pylori.

The metabolic state of bacteria significantly contributes to their resistance to antibiotics; however, the specific metabolic mechanisms conferring antimicrobial resistance in Helicobacter pylori remain largely understudied. Employing transcriptomic and non-targeted metabolomics, we characterized the metabolic reprogramming of H. pylori when challenged with antibiotic agents. We observed a notable increase in both genetic and key proteomic components involved in fatty acid biosynthesis. Inhibition of this pathway significantly enhanced the antibiotic susceptibility of the sensitive and multidrug-resistant H. pylori strains while also disrupting their biofilm-forming capacities. Further analysis revealed that antibiotic treatment induced a stringent response, triggering the expression of the hp0560-hp0557 operon regulated by Sigma28 (σ28). This activation in turn stimulated the fatty acid biosynthetic pathway, thereby enhancing the antibiotic tolerance of H. pylori. Our findings reveal a novel adaptive strategy employed by H. pylori to withstand antibiotic stress.

Pentavalent Rotavirus Vaccine Coverage and Trends in Rotavirus Detection Before and After This Vaccination in Chengdu, China.

Pentavalent rotavirus vaccine (RV5) coverage and changes in rotavirus detection in the prevaccine and postvaccine era in Chengdu were investigated. The results showed that the coverage of RV5 had been increasing but still relatively low. Nevertheless, the dramatical decline in the rotavirus detection was observed after the introduction of RV5. Efforts to improve the coverage of rotavirus vaccination should continue to maximize the public health benefits.

A Biodegradable Fiber Calcium Ion Sensor by Covalently Bonding Ionophores on Bioinert Nanoparticles.

Implantable sensors, especially ion sensors, facilitate the progress of scientific research and personalized healthcare. However, the permanent retention of implants induces health risks after sensors fulfill their mission of chronic sensing. Biodegradation is highly anticipated; while; biodegradable chemical sensors are rare due to concerns about the leakage of harmful active molecules after degradation, such as ionophores. Here, a novel biodegradable fiber calcium ion sensor is introduced, wherein ionophores are covalently bonded with bioinert nanoparticles to replace the classical ion-selective membrane. The fiber sensor demonstrates comparable sensing performance to classical ion sensors and good flexibility. It can monitor the fluctuations of Ca2+ in a 4-day lifespan in vivo and biodegrade in 4 weeks. Benefiting from the stable bonding between ionophores and nanoparticles, the biodegradable sensor exhibits a good biocompatibility after degradation. Moreover, this approach of bonding active molecules on bioinert nanoparticles can serve as an effective methodology for minimizing health concerns about biodegradable chemical sensors.

Tenecteplase for Ischemic Stroke at 4.5 to 24 Hours without Thrombectomy.

BACKGROUND: Tenecteplase is an effective thrombolytic agent for eligible patients with stroke who are treated within 4.5 hours after the onset of stroke. However, data regarding the effectiveness of tenecteplase beyond 4.5 hours are limited. METHODS: In a trial conducted in China, we randomly assigned patients with large-vessel occlusion of the middle cerebral artery or internal carotid artery who had salvageable brain tissue as identified on perfusion imaging and who did not have access to endovascular thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or standard medical treatment 4.5 to 24 hours after the time that the patient was last known to be well (including after stroke on awakening and unwitnessed stroke). The primary outcome was the absence of disability, which was defined as a score of 0 or 1 on the modified Rankin scale (range, 0 to 6, with higher scores indicating greater disability), at day 90. The key safety outcomes were symptomatic intracranial hemorrhage and death. RESULTS: A total of 516 patients were enrolled; 264 were randomly assigned to receive tenecteplase and 252 to receive standard medical treatment. Less than 2% of the patients (4 in the tenecteplase group and 5 in the standard-treatment group) underwent rescue endovascular thrombectomy. Treatment with tenecteplase resulted in a higher percentage of patients with a modified Rankin scale score of 0 or 1 at 90 days than standard medical treatment (33.0% vs. 24.2%; relative rate, 1.37; 95% confidence interval, 1.04 to 1.81; P = 0.03). Mortality at 90 days was 13.3% with tenecteplase and 13.1% with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage within 36 hours after treatment was 3.0% and 0.8%, respectively. CONCLUSIONS: In this trial involving Chinese patients with ischemic stroke due to large-vessel occlusion, most of whom did not undergo endovascular thrombectomy, treatment with tenecteplase administered 4.5 to 24 hours after stroke onset resulted in less disability and similar survival as compared with standard medical treatment, and the incidence of symptomatic intracranial hemorrhage appeared to be higher. (Funded by the National Natural Science Foundation of China and others; TRACE-III ClinicalTrials.gov number, NCT05141305.).