Learning-associated functional plasticity at hippocampal synapses remains largely unexplored. Here, in a single session of reward-based trace conditioning, we examine learning-induced synaptic plasticity in the dorsal CA1 hippocampus (dCA1). Local field-potential recording combined with selective optogenetic inhibition first revealed an increase of dCA1 synaptic responses to the conditioned stimulus (CS) induced during conditioning at both Schaffer collaterals to the stratum radiatum (Rad) and temporoammonic input to the lacunosum moleculare (LMol). At these dCA1 inputs, synaptic potentiation of CS-responding excitatory synapses was further demonstrated by locally blocking NMDA receptors during conditioning and whole-cell recording sensory-evoked synaptic responses in dCA1 neurons from naive animals. An overall similar time course of the induction of synaptic potentiation was found in the Rad and LMol by multiple-site recording; this emerged later and saturated earlier than conditioned behavioral responses. Our experiments demonstrate a cued memory-associated dCA1 synaptic plasticity induced at both Schaffer collaterals and temporoammonic pathways.
Animals ; CA1 Region, Hippocampal/physiology* ; Male ; Association Learning/physiology* ; Neuronal Plasticity/physiology* ; Cues ; Memory/physiology* ; Synapses/physiology* ; Conditioning, Classical/physiology* ; Excitatory Postsynaptic Potentials/physiology* ; Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors* ; Rats ; Optogenetics

Smoking is a well-established risk factor for periodontitis, yet the precise mechanisms by which smoking contributes to periodontal disease remain poorly understood. Recent advances in spatial transcriptomics have enabled a deeper exploration of the periodontal tissue microenvironment at single-cell resolution, offering new opportunities to investigate these mechanisms. In this study, we utilized Visium HD single-cell spatial transcriptomics to profile gingival tissues from 12 individuals, including those with periodontitis, those with smoking-associated periodontitis, and healthy controls. Our analysis revealed that smoking disrupts the epithelial barrier integrity, induces fibroblast alterations, and dysregulates fibroblast-epithelial cell communication, thereby exacerbating periodontitis. The spatial analysis showed that endothelial cells and macrophages are in close proximity and interact, which further promotes the progression of smoking-induced periodontal disease. Importantly, we found that targeting the endothelial CXCL12 signalling pathway in smoking-associated periodontitis reduced the proinflammatory macrophage phenotype, alleviated epithelial inflammation, and reduced alveolar bone resorption. These findings provide novel insights into the pathogenesis of smoking-associated periodontitis and highlight the potential of targeting the endothelial-macrophage interaction as a therapeutic strategy. Furthermore, this study establishes an essential information resource for investigating the effects of smoking on periodontitis, providing a foundation for future research and therapeutic development for this prevalent and debilitating disease.
Humans ; Gingiva/cytology* ; Smoking/adverse effects* ; Male ; Periodontitis/pathology* ; Single-Cell Analysis ; Female ; Adult ; Middle Aged ; Macrophages ; Fibroblasts ; Endothelial Cells ; Case-Control Studies ; Chemokine CXCL12/metabolism*

The cooccurrence of NPM1, FLT3-ITD, and DNMT3A mutations (i.e., triple mutation) is related to dismal prognosis in patients with acute myeloid leukemia (AML) receiving chemotherapy alone. In this multicenter retrospective cohort study, we aimed to identify whether allogeneic hematopoietic stem cell transplantation (allo-HSCT) could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut AML across four transplant centers in China. Fifty-three patients with triple-mutated AML receiving allo-HSCT in complete remission were enrolled. The 1.5-year probabilities of relapse, leukemia-free survival, and overall survival after allo-HSCT were 11.9%, 80.3%, and 81.8%, respectively. Multivariate analysis revealed that more than one course of induction chemotherapy and allo-HSCT beyond CR1 were associated with poor survival. To our knowledge, this work is the largest study to explore the up-to-date undefined role of allo-HSCT in patients with triple-mutated AML. Our real-world data suggest that allo-HSCT could overcome the poor prognosis of DNMT3A^mutNPM1^mutFLT3-ITD^mut in AML.
Humans ; Nucleophosmin ; Leukemia, Myeloid, Acute/mortality* ; Hematopoietic Stem Cell Transplantation/methods* ; Male ; Female ; DNA Methyltransferase 3A ; Adult ; China ; Retrospective Studies ; DNA (Cytosine-5-)-Methyltransferases/genetics* ; Middle Aged ; Prognosis ; fms-Like Tyrosine Kinase 3/genetics* ; Mutation ; Young Adult ; Transplantation, Homologous ; Nuclear Proteins/genetics* ; Adolescent ; Aged

Luteolin is a natural flavonoid compound exists in various fruits and vegetables. Recent studies have indicated that luteolin has variety pharmacological effects, including a wide range of antidepressant properties. Here, we systematically review the preclinical studies and limited clinical evidence on the antidepressant and neuroprotective effects of luteolin to fully explore its antidepressant power. Network pharmacology and molecular docking analyses contribute to a better understanding of the preclinical models of depression and antidepressant properties of luteolin. Seventeen preclinical studies were included that combined network pharmacology and molecular docking analyses to clarify the antidepressant mechanism of luteolin and its antidepressant targets. The antidepressant effects of luteolin may involve promoting intracellular noradrenaline (NE) uptake; inhibiting 5-hydroxytryptamine (5-HT) reuptake; upregulating the expression of synaptophysin, postsynaptic density protein 95, brain-derived neurotrophic factor, B cell lymphoma protein-2, superoxide dismutase, and glutathione S-transferase; and decreasing the expression of malondialdehyde, caspase-3, and amyloid-beta peptides. The antidepressant effects of luteolin are mediated by various mechanisms, including anti-oxidative stress, anti-apoptosis, anti-inflammation, anti-endoplasmic reticulum stress, dopamine transport, synaptic protection, hypothalamic-pituitary-adrenal axis regulation, and 5-HT metabolism. Additionally, we identified insulin-like growth factor 1 receptor (IGF1R), AKT serine/threonine kinase 1 (AKT1), prostaglandin-endoperoxide synthase 2 (PTGS2), estrogen receptor alpha (ESR1), and epidermal growth factor receptor (EGFR) as potential targets, luteolin has an ideal affinity for these targets, suggesting that it may play a positive role in depression through multiple targets, mechanisms, and pathways. However, the clinical efficacy of luteolin and its potential direct targets must be confirmed in further multicenter clinical case-control and molecular targeting studies.

AIM: To investigate the mechanism of action of Qingxuan Runmu Yin(QRY)in the treatment of dry eye(DE)based on transcriptomics and network pharmacology, and to validate the efficacy and key targets of QRY through a animal model of DE.METHODS:RNA-sequencing(RNA-seq)technology was used to detect differentially expressed genes(DEGs)between mice in the DE group and mice in the normal control group, the active ingredients and potential targets of QRY were screened through database, and gene ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)enrichment analysis were carried out after overlapping the results and obtaining key targets. Additionally, “drug-component-target signaling pathways” network was built and the protein-protein interaction(PPI)was analyzed. Mice were examined for Schirmer I test(SⅠt), tear film breakup time(BUT), and corneal fluorescein staining(FL)every 7 d from the beginning of the animal experiments. Hematoxylin-eosin staining(HE)was performed to observe pathologic changes in mouse corneal tissues. Enzyme linked immunosorbent assay(ELISA), Western blot and quantitative real-time polymerase chain reaction(qRT-PCR)were performed to verify the mRNA and protein expression levels of the core targets in mouse corneal tissues.RESULTS:Totally 2 234 DEGs, 233 active ingredients and 457 related targets of QRY were collected, with a total of 64 key targets obtained. GO function and KEGG pathway results showed that QRY was closely related to inflammatory mediators, and 19 core targets such as interleukin-1β(IL-1β)were screened by PPI network construction; SⅠt, BUT and FL results in the QRY group were statistically significantly different compared with the model group(all P<0.05); HE staining showed that corneal epithelial cell stratification was disordered and the corneal morphology was changed in the model group. However, QRY treatment significantly improved corneal morphology and disordered stratification, with a close morphology to the blank group; ELISA, Western blot and qRT-PCR results showed that the protein expression and RNA levels of IL-1β, IL-6, and tumor necrosis factor(TNF-α)in the QRY group showed a decreasing trend compared with the model group.CONCLUSION: Through the combination of multiple components, multiple targets and multiple pathways, QRY regulated the targets such as IL-6, IL-1β and TNF through quercetin and other main components, thereby inhibiting AGE-RAGE/TNF/IL-17 and other signaling pathways, thus achieving the treatment on DE.

NAD(P)H: quinone oxidoreductase 1 (NQO1) is a flavin protease highly expressed in various cancer cells. NQO1 catalyzes a futile redox cycle in substrates, leading to substantial reactive oxygen species (ROS) production. This ROS generation results in extensive DNA damage and elevated poly (ADP-ribose) polymerase 1 (PARP1)-mediated consumption of nicotinamide adenine dinucleotide (NAD⁺), ultimately causing cell death. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the NAD⁺ salvage synthesis pathway, emerges as a critical target in cancer therapy. The concurrent inhibition of NQO1 and NAMPT triggers hyperactivation of PARP1 and intensive NAD⁺ depletion. In this study, we designed, synthesized, and assessed a novel series of proqodine A derivatives targeting both NQO1 and NAMPT. Among these, compound T8 demonstrated potent antitumor properties. Specifically, T8 selectively inhibited the proliferation of MCF-7 cells and induced apoptosis through mechanisms dependent on both NQO1 and NAMPT. This discovery offers a promising new molecular entity for advancing anticancer research.
Humans ; NAD/metabolism* ; Cell Line, Tumor ; Reactive Oxygen Species/metabolism* ; Nicotinamide Phosphoribosyltransferase/metabolism* ; Cytokines/metabolism* ; Quinones ; Oxidoreductases

【Objective】 To analyze the clinical efficacy of modified Devine surgery combined with scrotal flap transfer in the treatment of concealed penis (CP) in children and provide reference for the surgical treatment of CP in children. 【Methods】 The clinical data of 54 CP children who underwent surgery in the Department of Urology, Puren Hospital Affiliated to Wuhan University of Science and Technology during Jun.2019 and Sep.2022 were retrospectively analyzed, including 27 patients treated with traditional Devine surgery (control group), and 27 patients in the modified group treated with modified Devine surgery combined with scrotal flap transfer (double degloving). The perioperative indexes, incidence of postoperative complications, penile lengthening and satisfaction of postoperative appearance were recorded. 【Results】 The surgical time of the modified group was longer than the control group [(62.78±5.07) min vs. (55.93±4.83) min ](t=5.085, P<0.05). The exposed length and penile lengthening length with moderate and severe CP patients in the modified group at 1 and 6 months after surgery were higher than those in the control group (P<0.05).The duration of prepuce edema, and the satisfaction of family members of moderate and severe CP children were (6.93±1.54) d vs. (5.56±1.16) d, (2.44±0.62) vs. (2.83±0.38), and (2.44±0.73) vs. (3.00±0) between the control and modified groups (P<0.05). There were no statistically significant difference in intraoperative bleeding volume and incidence of complications between the two groups (P>0.05). 【Conclusion】 In the treatment of CP, modified Devine surgery combined with scrotal flap transfer can produce good effects and appearance, which is of high application value.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.

Objective:To explore the predictive value of pulmonary effective arterial elastance (Ea) in patients with heart failure (HF).Methods:This is a retrospective cohort study, which retrospectively included 284 patients with HF who underwent right heart catheterization at Heart Failure Center in Fuwai Hospital between September 2013 and February 2022. Data regarding baseline clinical characteristics, hemodynamic profiles, and prognosis were collected. Ea was calculated as mean pulmonary arterial pressure/stroke volume. Patients were divided into Ea<0.555 group and Ea≥0.555 group according to the median value of Ea (0.555 mmHg/ml, 1 mmHg=0.133 kPa). The primary outcome was the primary clinical event, set as the first occurrence of a series of composite events, including all-cause death, heart transplantation, left ventricular assist device implantation, and HF rehospitalization. Event-free survival was defined as the absence of primary clinical events. Spearman correlation analysis was used to calculate the correlation coefficient between Ea and parameters reflective of right heart function. The Kaplan-Meier analysis was used to compare the different groups for the estimation of outcomes with the log-rank test. We used Cox proportional-hazards regression models to estimate hazard ratios ( HR) for primary clinical event. Subgroup analysis was performed based on the age, gender, New York Heart Association (NYHA) functional class, left ventricular ejection fraction, presence of pulmonary hypertension, and serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) values. We used receiver operating characteristic (ROC) curve to calculate the area under the curve ( AUC) of Ea for predicting event-free survival in patients with HF. Results:The median age was 51 years, and 206 (72.5%) patients were male. Ea and pulmonary vascular resistance (PVR) were significantly correlated ( r=0.698, P<0.001). The correlation between Ea and pulmonary arterial elastance (PAC) were even more significant ( r=-0.888, P<0.001). Compared with Ea<0.555 group, Ea≥0.555 group presented with higher serum NT-proBNP values (4 443 (1 792, 8 554) ng/L vs. 1 721 (480, 4 528)ng/L, P<0.001), higher PVR (3.4 (2.5, 4.7) Wood vs. 1.4 (0.9, 2.2) Wood, P<0.001), lower cardiac output (3.0 (2.3, 3.9) L/min vs. 4.3 (3.8, 4.9) L/min, P<0.001), and lower PAC (1.6 (1.3, 2.0) ml/mmHg vs. 4.0 (3.0, 6.0) ml/mmHg, P<0.001). The median follow-up time was 392 (166, 811) days. The Kaplan-Meier survival curve demonstrated a lower event-free survival rate in the Ea≥0.555 group compared to the Ea<0.555 group ( Plog-rank<0.001). After multivariate adjustment, Ea ( HR=1.734, P<0.001) remained significantly associated with the primary outcome. Subgroup analysis indicated that Ea was associated with the primary outcome across all subgroups. The AUC was 0.724 ( P<0.001) for Ea to predict event-free survival calculated from ROC analysis. Conclusions:Ea is closely related to parameters reflective of right ventricular afterload. Increased Ea is an independent predictor of adverse outcomes in patients with HF.

Objective:To carry out a study on the cost analysis of the clinical use of Artificial Intelligence-assisted Diagnosis Technology for Coronary CT Angiography(CCTA-AI)to explore the cost differences and cost effects of Coronary CT Angiography(CCTA)examinations before and after the introduction of Artificial Intelligence(AI),and analyze the impact of the application of AI technology on the high-quality development of public hospitals.Methods:The operation cost method was used to measure the changes in the cost and efficiency of CCTA examinations before and after the application of AI technology in five sample hospitals in Beijing,and diagnostic accuracy was used as the effect value to calculate the cost effect of CCTA-AI diagnosis versus CCTA-manual diagnosis,and to analyze the main factors affecting the unit cost.Results:The average cost of examination in 5 sample hospitals after the application of AI-assisted diagnosis system was 1 074.90 yuan,and 1 266.61 yuan before the application,with a large difference between institutions.The cost-effectiveness analysis based on diagnostic accuracy showed that the AI group had an absolute advantage over the manual group,with a cost of 1 074 900 yuan for the AI group and an effectiveness of 855.05 persons,and a cost of 1 266 610 yuan for the physician group,with an effectiveness of 815.07 persons for the high-year-end physician group,and an effectiveness of 793.40 persons for the low-year-end physician group;0.46 man-hours could be saved for each patient examined;the unit cost of CCTA examination was affected by a number of factors,among which"the number of annual examinations"and"the number of CT units involved in CCTA examination"had the greatest influence on the unit cost of CCTA examination.Conclusion:The application of AI-assisted diagnostic technology can promote the improvement of quality and efficiency in public hospitals in a certain extent,and help optimize the overall distribution of medical resources at the system level.In the future,the cost analysis of AI technology should be further strengthened to comprehensively assess its actual contribution to the healthcare system.