The evolutionary arms race between life and pathogens drives diversification in immune system signaling mechanisms. Recent research has found that the TIR protein of the bacterial type II Thoeris defense system can produce a novel “hybrid” immune signaling molecule—histidine-ADP-ribose (His-ADPR). This molecule, formed by the direct linkage of an amino acid and a nucleotide, challenges the traditional view that TIR enzymes generate only pure nucleotide derivatives. This signal is specifically recognized by the Macro domain of an effector protein, triggering the transmembrane domain to disrupt the membrane for defense. The study further reveals that phages can evade immunity by expressing “signal sponge” proteins that bind and sequester His-ADPR. This offensive-defensive pressure drives TIR enzymes to continuously expand their “chemical arsenal” of signaling molecules. The discovery not only confirms the shared biochemical core of bacterial TIR signaling molecules (based on NAD⁺ modification), but also highlights their remarkable chemical plasticity and evolutionary innovative capacity. It provides a new perspective for understanding the origin and diversity of immune signaling.

Objective: To analyze the school tuberculosis (TB) outbreaks and preventive treatment in Hefei from 2022 to 2024, so as to provide reference for TB prevention and control in schools. Methods: Data were collected on all school based TB outbreaks occurring during 2022-2024 in Hefei, defined as ≥2 epidemiologically linked TB cases within the same school during a single semester. Statistical analyses were performed using the Chi square test. Results: Close contacts exhibited significantly higher TB incidence (2.88%) and latent mycobacterium tuberculosis infection (LTBI) rates (13.80%) in the school TB outbreaks, compared to non close contacts (0.12% and 2.63%, respectively). Among close contacts, secondary school students showed lower TB incidence (0.48%) and LTBI prevalence (3.42%) than both primary school or younger children (0.68%, 6.95%) and college students ( 0.78% , 6.50%), with statistically significant differences ( χ 2=360.91, 6.37; 791.71, 102.03, all P <0.05). The proportion of LTBI individuals recommended for preventive therapy was higher in primary school or younger groups (98.59%) than in secondary (95.25%) or college students (86.34%) ( χ 2=25.86, P <0.01). However, among those recommended, close contacts had higher uptake (85.82%) and completion rates (87.25%) of preventive therapy than non close contacts (69.63% and 70.57%); similarly, secondary school students demonstrated higher uptake (91.21%) and completion rates (86.45%) compared to primary school or younger (88.57%, 83.87%) and college students (57.28%, 64.08%) ( χ 2=30.52, 26.72; 125.17, 38.84, all P <0.01). Subsequent TB incidence among LTBI close contacts (13.30%) and among those who did not complete preventive therapy (22.73%) were significantly higher than among non close contacts (2.80%, 2.41%), respectively ( χ 2=32.19, 13.87, both P <0.05). Conclusions In school TB outbreaks, close contacts face higher LTBI prevalence and subsequent TB risk than non close contacts. College students show notably low adherence to preventive therapy. It is necessary to take targeted measures to improve the compliance of preventive measures among students.

Objective To clarify the metabolic phenotypic changes in the serum and placenta of pre-eclampsia(PE)patients and their potential impact on fetal serum,and to identify and explore potential predic-tive biomarkers related to PE by using non-targeted metabolomics technology,thereby providing a reference for clinical diagnosis and disease monitoring.Methods Based on non-targeted metabolomics using liquid chro-matography-mass spectrometry(LC-MS),metabolomic analyses were performed on serum,placenta and um-bilical cord blood samples from 6 PE patients(PE group)and 6 healthy pregnant women in the late trimester(control group).Differential endogenous metabolites in each sample were screened using multivariate and uni-variate statistical methods.Metabolic pathways involved in the differential metabolites were enriched using MetaboAnalyst software.Additionally,potential biomarkers for predicting PE were identified based on binary logistic regression models.Results Compared with the control group,significant differences in the metabolic profiles of serum,placenta,and fetal serum were observed in the PE group.In the serum of PE patients,major metabolic abnormalities included α-linolenic acid metabolism,taurine metabolism,glycine,serine and threonine metabolism.In the placenta,abnormalities in linoleic acid metabolism,taurine metabolism,α-linolenic acid me-tabolism,and unsaturated fatty acid biosynthesis were detected.In the fetus of PE patients,metabolic abnor-malities were found in glutamine and glutamate metabolism,α-linolenic acid metabolism,and alanine,aspar-tate,and glutamate metabolism,involving polyunsaturated fatty acids and amino acids.The receiver operating characteristic(ROC)curves of differential metabolites were plotted using binary logistic regression models,and 4 serum metabolites with an area under the curve(AUC)＞0.9 were identified,mainly polyunsaturated fatty acid metabolites.The AUC of α-linolenic acid,a common differential metabolite in all three samples,was 0.806,with a sensitivity of 66.67％and specificity of 100.00％,indicating high diagnostic value.Conclusion The serum,placenta,and fetal serum metabolic profiles of PE patients and healthy pregnant women in the late trimester are significantly different and affect the metabolic phenotypes of offspring,providing insights into the pathogenesis of PE.

Objective To investigate the efficacy of varying doses of methylprednisolone(MP)on mice with acute exacerbations of chronic obstructive pulmonary disease(AECOPD)induced with influenza A virus(IAV).Methods Mouse model of COPD was established using LPS combined with smoking for 12 weeks,and then these COPD mice were treated with administration of 40 μL IAV via nasal drip to establish a AECOPD model.A total of 15 AECOPD mice were randomly divided into low-,medium-and high-dose MP groups,oseltamivir group and blank group.The body weight and survival time were monitored within 10 d after IAV infection.On days 1,3,and 5 post-treatment,lung function was assessed using whole-body plethysmography(WBP),inflammatory factors in bronchoalveolar lavage fluid(BALF)were quantified with ELISA,viral titers in BALF were determined using plaque assays,and colony-forming units were evaluated with blood agar plates.Immunofluorescence analysis:① Pulmonary immunofluorescence assay:Mice were randomly categorized into(n=4):LPS 1-day group,LPS 3-day group,and LPS+MP treatment group.All groups received an initial dose of LPS via atomization;subsequently,the LPS+MP treatment group received a single gavage dose of MP.Lung tissues were harvested from the 1-day LPS group on 1 d post-treatment,and from the 3-day LPS and LPS+MP groups on 3 d for immunofluorescence staining.② Cellular immunofluorescence assay:Mouse bone marrow neutrophils were classified into blank control(no intervention),LPS stimulation(LPS group),MP intervention with LPS stimulation(LPS+MP group),and MP intervention alone(MP group).The above cells were collected in 4 h after corresponding interventions for subsequent cellular immunofluorescence analysis.Results ①The medium-dose MP group demonstrated the most significant improvement in survival rate,weight recovery,and lung function when compared to other groups(P＜0.05).② Treatment of medium-dose MP obviously reduced the levels of IL-6 and neutrophil extracellular traps(NETs)(P＜0.05),while,elevated inflammatory factors and NETs were observed in the high-dose MP group on day 5 post-treatment.③ Notable decline in the lung injury score was found in the medium-dose MP group than the other groups(P＜0.05).④The high-dose MP group exhibited substantial bacterial proliferation and delayed viral clearance since day 5 after treatment.Conclusion Medium-dose MP shows best efficacy in treatment of IAV-induced AECOPD,and the dose neither delays viral clearance nor increases the risk of bacterial infection following viral infection.

Objective:To investigate the effect of pre-stroke metformin (MET) use on early neurological improvement (ENI) and outcome after intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients with type 2 diabetes (T2DM).Methods:AIS patients with T2DM underwent IVT in the Department of Neurology, Yuncheng Central Hospital from January 2019 to February 2025 were included retrospectively. According to whether MET was used before onset, they were divided into MET group and non-MET group. Early neurological improvement (ENI) was defined as a decrease in the National Institutes of Health Stroke Scale (NIHSS) score ≥4 at 24 hours after IVT compared to admission, or the NIHSS score was 0-1. At 90 days after onset, the modified Rankin Scale was used for outcome assessment, and ≤2 was good outcome and >2 was poor outcome. Multivariate logistic regression analysis was used to determine the independent influencing factors of ENI and outcome. Results:A total of 115 AIS patients with T2DM were included in the study, with an age of 65.42±12.22 years. There were 83 males (72.2%). Fifty-four patients (47.0%) used MET, and 61 (53.0%) used other hypoglycemic drugs; 43 (37.4%) developed ENI, and 33 (28.7%) had poor outcome at 90 days. There were no significant difference in all baseline data between the MET group and the non-MET group, but the proportions of patients with ENI and good prognosis at 90 days in the MET group were significantly higher than those in the non-MET group (all P<0.05). The proportions of hypertensive patients and baseline NIHSS scores in the ENI group were significantly lower than those in the non-ENI group, while the proportions of patients using MET, antihypertensive drugs, statins, and patients with good outcome was significantly higher than that in the non-ENI group (all P<0.05). The body weight, high-density lipoprotein cholesterol, as well as the proportions of patients using antiplatelet drugs, MET, and patients with ENI in the good outcome group were significantly higher than those in the poor outcome group, while systolic blood pressure, fasting blood glucose, triglycerides, and the proportions of patients with hemorrhagic transformation, and symptomatic intracranial hemorrhage were significantly lower than those in the poor outcome group (all P<0.05). Multivariate logistic regression analysis showed that using statins (odds ratio [ OR] 5.291, 95% confidence interval [ CI] 1.599-17.514; P=0.006) and MET ( OR 3.018, 95% CI 1.125-8.092; P=0.006) were the independent influencing factors of ENI; using MET ( OR 0.014, 95% CI 0.001-0.246; P=0.004) and anterior circulation stroke ( OR 0.005, 95% CI 0.000-0.745; P=0.038) were significantly independently associated with good outcome, while high baseline NIHSS score ( OR 2.092, 95% CI 1.198-3.655; P=0.009) and serum homocysteine ( OR 1.202, 95% CI 1.024-1.411; P=0.024) were significantly independently associated with the poor outcome. Conclusion:The use of MET before stroke onset can help improve ENI and clinical outcome in AIS patients with T2DM after IVT.

BACKGROUND:Multiple studies have confirmed that mitogen-activated protein kinase(MAPK)signaling pathway is involved in cell proliferation,and microRNA(miR)is involved in the occurrence and development of hypertrophic scars.Therefore,the role of miR-27a-3p and MAPK signaling pathways in pathological scar formation has been further explored. OBJECTIVE:To explore the effect of miR-27a-3p on the proliferation of human hypertrophic scar fibroblasts through the MAPK signaling pathway. METHODS:The primary fibroblasts were isolated and collected from the skin samples.The primary fibroblasts were observed by inverted microscope and verified by immunofluorescence.The relative expression level of miR-27a-3p in tissues was detected by qRT-PCR.The target genes of hsa-miR-27a-3p were predicted using the database,and then the predicted target genes were enriched by gene ontology function analysis and biological pathway enrichment analysis of the Kyoto Encyclopedia of Genes and Genomes.There were seven groups:blank control,negative control,miR-27a-3p mimic,miR-27a-3p inhibitor,miR-27a-3p mimic+p38 MAPK inhibitor,miR-27a-3p mimic+extracellular regulated protein kinase inhibitor,miR-27a-3p mimic+c-Jun N-terminal kinase inhibitor.Western blot was used to detect the levels of extracellular regulated protein kinase,c-Jun N-terminal kinase inhibitor.and p38 kinase and their phosphorylation levels.Cell counting kit-8 and EdU were used to detect cell proliferation. RESULTS AND CONCLUSION:Compared with normal skin fibroblasts,hypertrophic scar fibroblasts had stronger proliferative activity(P<0.05)and faster proliferation level(P<0.001).Compared with normal skin,miR-27a-3p was highly expressed in hypertrophic scars(P<0.001).Compared with the negative control group,overexpression of miR-27a-3p could promote cell proliferation activity(P<0.001)and proliferation levels(P<0.001).Compared with the negative control group,knockdown of miR-27a-3p could inhibit the proliferation activity(P<0.05)and proliferation levels(P<0.001).Compared with the negative control group,overexpression of miR-27a-3p promoted the phosphorylated levels of extracellular regulated protein kinase,c-Jun N-terminal kinase,and p38 mitogen-activated protein kinase(P<0.05).Compared with the negative control group,knockdown of miR-27a-3p inhibited the phosphorylated levels of extracellular regulated protein kinase,c-Jun N-terminal kinase,and p38 MAPK(P<0.05).Compared with the miR-27a-3p mimic group,specific inhibitors of extracellular regulated protein kinase,c-Jun N-terminal kinase,and p38 MAPK reversed the effects of miR-27a-3p on the proliferative activity(P<0.01)and proliferation level(P<0.001)of fibroblasts.To conclude,these results suggest that miR-27a-3p promotes the proliferation of human hypertrophic scar fibroblasts by activating the MAPK signaling pathway.

OBJECTIVES: To investigate the risk factors for white matter damage (WMD) in preterm infants with necrotizing enterocolitis (NEC). METHODS: A retrospective analysis was conducted on the clinical data of 249 preterm infants with NEC admitted to Children's Hospital of Fudan University between January 2021 and December 2023. Based on brain magnetic resonance imaging (MRI) white matter scores, the infants were categorized into a WMD group (≥7 points) and a non-injury group (<7 points). A multivariable logistic regression analysis was performed to identify risk factors for WMD. RESULTS: Compared with the non-injury group, the WMD group had significantly higher rates of Gram-negative bacterial infection (43.1% vs 28.2%), surgical treatment (47.2% vs 23.2%), and moderate-to-severe abnormalities on video electroencephalography (VEEG) (51.4% vs 11.9%) (all P<0.05). The multivariable logistic regression analysis showed that surgical treatment (OR=1.822, 95%CI: 1.199-2.777), longer hospital stay (OR=1.041, 95%CI: 1.004-1.080), and moderate-to-severe VEEG abnormalities (OR=7.045, 95%CI: 3.349-14.855) were independent risk factors for WMD (all P<0.05). CONCLUSIONS Surgical treatment, prolonged hospitalization, and moderate-to-severe VEEG abnormalities are independent risk factors for WMD in preterm infants with NEC, providing a basis for early clinical identification and intervention to improve neurological outcomes.
Humans ; Enterocolitis, Necrotizing/complications* ; Infant, Newborn ; Male ; Female ; Risk Factors ; Retrospective Studies ; Infant, Premature ; White Matter/diagnostic imaging* ; Logistic Models ; Magnetic Resonance Imaging

BACKGROUND: The clinical impact of post-percutaneous coronary intervention (PCI) quantitative flow ratio (QFR) in patients treated with PCI for chronic total occlusion (CTO) was still undetermined. METHODS: All CTO vessels treated with successful anatomical PCI in patients from PANDA III trial were retrospectively measured for post-PCI QFR. The primary outcome was 2-year vessel-oriented composite endpoints (VOCEs, composite of target vessel-related cardiac death, target vessel-related myocardial infarction, and ischemia-driven target vessel revascularization). Receiver operator characteristic curve analysis was conducted to identify optimal cutoff value of post-PCI QFR for predicting the 2-year VOCEs, and all vessels were stratified by this optimal cutoff value. Cox proportional hazards models were employed to calculate the hazard ratio (HR) with 95% CI. RESULTS: Among 428 CTO vessels treated with PCI, 353 vessels (82.5%) were analyzable for post-PCI QFR. 31 VOCEs (8.7%) occurred at 2 years. Mean value of post-PCI QFR was 0.92 ± 0.13. Receiver operator characteristic curve analysis shown the optimal cutoff value of post-PCI QFR for predicting 2-year VOCEs was 0.91. The incidence of 2-year VOCEs in the vessel with post-PCI QFR < 0.91 (n = 91) was significantly higher compared with the vessels with post-PCI QFR ≥ 0.91 (n = 262) (22.0% vs. 4.2%, HR = 4.98, 95% CI: 2.32-10.70). CONCLUSIONS Higher post-PCI QFR values were associated with improved prognosis in the PCI practice for coronary CTO. Achieving functionally optimal PCI results (post-PCI QFR value ≥ 0.91) tends to get better prognosis for patients with CTO lesions.

Cemental tear is a rare and indetectable condition unless obvious clinical signs present with the involvement of surrounding periodontal and periapical tissues. Due to its clinical manifestations similar to common dental issues, such as vertical root fracture, primary endodontic diseases, and periodontal diseases, as well as the low awareness of cemental tear for clinicians, misdiagnosis often occurs. The critical principle for cemental tear treatment is to remove torn fragments, and overlooking fragments leads to futile therapy, which could deteriorate the conditions of the affected teeth. Therefore, accurate diagnosis and subsequent appropriate interventions are vital for managing cemental tear. Novel diagnostic tools, including cone-beam computed tomography (CBCT), microscopes, and enamel matrix derivatives, have improved early detection and management, enhancing tooth retention. The implementation of standardized diagnostic criteria and treatment protocols, combined with improved clinical awareness among dental professionals, serves to mitigate risks of diagnostic errors and suboptimal therapeutic interventions. This expert consensus reviewed the epidemiology, pathogenesis, potential predisposing factors, clinical manifestations, diagnosis, differential diagnosis, treatment, and prognosis of cemental tear, aiming to provide a clinical guideline and facilitate clinicians to have a better understanding of cemental tear.
Humans ; Dental Cementum/injuries* ; Consensus ; Diagnosis, Differential ; Cone-Beam Computed Tomography ; Tooth Fractures/therapy*

OBJECTIVE: Cancer remains a significant global health challenge, necessitating the development of effective treatment approaches. Developing synergistic therapy can provide a highly promising strategy for anti-cancer treatment through combining the benefits of various mechanisms. METHODS: In this study, we developed a synergistic strategy for chemo-photothermal therapy by constructing nanocomposites using gold nanorods (GNRs) and tetrahedral framework nucleic acids (tFNA) loaded with the anti-tumor drug doxorubicin (DOX). RESULTS: Our in vitro studies have systematically clarified the anti-cancer behaviors of tFNA-DOX@GNR nanocomposites, characterized by their enhanced cellular uptake and proficient lysosomal escape capabilities. It was found that the key role of tFNA-DOX@GNR nanocomposites in tumor ablation is primarily due to their capacity to induce cytotoxicity in tumor cells via a photothermal effect, which generates instantaneous high temperatures. This mechanism introduces various responses in tumor cells, facilitated by the thermal effect and the integrated chemotherapeutic action of DOX. These reactions include the induction of endoplasmic reticulum stress, characterized by elevated reactive oxygen species levels, the promotion of apoptotic cell death, and the suppression of tumor cell proliferation. CONCLUSION This work exhibits the potential of synergistic therapy utilizing nanocomposites for cancer treatment and offers a promising avenue for future therapeutic strategies.
Doxorubicin/chemistry* ; Gold/chemistry* ; Nanotubes/chemistry* ; Humans ; Nanocomposites/chemistry* ; Cell Line, Tumor ; Nucleic Acids/chemistry* ; Antibiotics, Antineoplastic/pharmacology* ; Antineoplastic Agents/administration & dosage*