ObjectiveRepetitive transcranial magnetic stimulation (rTMS) has demonstrated efficacy in enhancing neurocognitive performance in Alzheimer’s disease (AD), but the neurobiological mechanisms linking synaptic pathology, neural oscillatory dynamics, and brain network reorganization remain unclear. This investigation seeks to systematically evaluate the therapeutic potential of rTMS as a non-invasive neuromodulatory intervention through a multimodal framework integrating clinical assessments, molecular profiling, and neurophysiological monitoring. MethodsIn this prospective double-blind trial, 12 AD patients underwent a 14-day protocol of 20 Hz rTMS, with comprehensive multimodal assessments performed pre- and post-intervention. Cognitive functioning was quantified using the mini-mental state examination (MMSE) and Montreal cognitive assessment (MOCA), while daily living capacities and neuropsychiatric profiles were respectively evaluated through the activities of daily living (ADL) scale and combined neuropsychiatric inventory (NPI)-Hamilton depression rating scale (HAMD). Peripheral blood biomarkers, specifically Aβ1-40 and phosphorylated tau (p-tau181), were analyzed to investigate the effects of rTMS on molecular metabolism. Spectral power analysis was employed to investigate rTMS-induced modulations of neural rhythms in AD patients, while brain network analyses incorporating topological properties were conducted to examine stimulus-driven network reorganization. Furthermore, systematic assessment of correlations between cognitive scale scores, blood biomarkers, and network characteristics was performed to elucidate cross-modal therapeutic associations. ResultsClinically, MMSE and MOCA scores improved significantly (P<0.05). Biomarker showed that Aβ1-40 level increased (P<0.05), contrasting with p-tau181 reduction. Moreover, the levels of Aβ1-40 were positively correlated with MMSE and MOCA scores. Post-intervention analyses revealed significant modulations in oscillatory power, characterized by pronounced reductions in delta (P<0.05) and theta bands (P<0.05), while concurrent enhancements were observed in alpha, beta, and gamma band activities (all P<0.05). Network analysis revealed frequency-specific reorganization: clustering coefficients were significantly decreased in delta, theta, and alpha bands (P<0.05), while global efficiency improvement was exclusively detected in the delta band (P<0.05). The alpha band demonstrated concurrent increases in average nodal degree (P<0.05) and characteristic path length reduction (P<0.05). Further research findings indicate that the changes in the clinical scale HAMD scores before and after rTMS stimulation are negatively correlated with the changes in the blood biomarkers Aβ1-40 and p-tau181. Additionally, the changes in the clinical scales MMSE and MoCA scores were negatively correlated with the changes in the node degree of the alpha frequency band and negatively correlated with the clustering coefficient of the delta frequency band. However, the changes in MMSE scores are positively correlated with the changes in global efficiency of both the delta and alpha frequency bands. Conclusion20 Hz rTMS targeting dorsolateral prefrontal cortex (DLPFC) significantly improves cognitive function and enhances the metabolic clearance of β-amyloid and tau proteins in AD patients. This neurotherapeutic effect is mechanistically associated with rTMS-mediated frequency-selective neuromodulation, which enhances the connectivity of oscillatory networks through improved neuronal synchronization and optimized topological organization of functional brain networks. These findings not only support the efficacy of rTMS as an adjunctive therapy for AD but also underscore the importance of employing multiple assessment methods—including clinical scales, blood biomarkers, and EEG——in understanding and monitoring the progression of AD. This research provides a significant theoretical foundation and empirical evidence for further exploration of rTMS applications in AD treatment.

OBJECTIVE: To observe the clinical efficacy of auricular electroacupuncture for post-stroke dysphagia in the pharyngeal phase. METHODS: Eighty-two patients with post-stroke dysphagia in the pharyngeal phase were randomized into an auricular electroacupuncture group (41 cases) and a swallowing electrical stimulation group (41 cases, 1 case dropped out). In the auricular electroacupuncture group, electroacupuncture was applied at auricular points, i.e. Xin (CO₁₅) and Yanhou (TG₃), using disperse-dense wave, in frequency of 2 Hz/10 Hz, 30 min a time. In the swallowing electrical stimulation group, swallowing electrical stimulation was delivered for 30 min a time. Both groups were treated once daily for 4 weeks. The functional oral intake scale (FOIS) grade, as well as the hyolaryngeal complex displacement, the pharyngeal constriction rate (PCR) and the pharyngeal delay time (PDT) under video fluoroscopic study of swallowing (VFSS) were observed before and after treatment, and the clinical efficacy was evaluated in the two groups. RESULTS: Compared before treatment, the FOIS grade was improved (P<0.01), the forward and upward displacement amplitude of hyoid bone and thyroid cartilage was increased (P<0.05), and the PCR and PDT were decreased (P<0.05) after treatment in the two groups. After treatment, compared with the swallowing electrical stimulation group, the FOIS grade was superior (P<0.01), the upward displacement amplitude of hyoid bone and thyroid cartilage was larger (P<0.05) and the PCR and PDT were lower (P<0.05) in the auricular electroacupuncture group. The total effective rate was 85.4% (35/41) in the auricular electroacupuncture group, which was higher than 62.5% (25/40) in the swallowing electrical stimulation group (P<0.05). CONCLUSION Auricular electroacupuncture can effectively trigger pharyngeal initiation and improve post-stroke dysphagia in the pharyngeal phase.
Humans ; Electroacupuncture ; Male ; Deglutition Disorders/etiology* ; Female ; Middle Aged ; Aged ; Stroke/physiopathology* ; Pharynx/physiopathology* ; Acupuncture, Ear ; Acupuncture Points ; Deglutition ; Treatment Outcome ; Adult

This study aimed to characterize and identify the non-volatile components in aqueous and ethanolic extracts of the stems and leaves of Rhododendron tomentosum by using sensitive and efficient ultra-performance liquid chromatography-quadrupole-time of flight mass spectrometry(UHPLC-Q-TOF-MS) combined with a self-built information database. By comparing with reference compounds, analyzing fragment ion information, searching relevant literature, and using a self-built information database, 118 compounds were identified from the aqueous and ethanolic extracts of R. tomentosum, including 35 flavonoid glycosides, 15 phenolic glycosides, 12 flavonoids, 7 phenolic acids, 7 phenylethanol glycosides, 6 tannins, 6 phospholipids, 5 coumarins, 5 monoterpene glycosides, 6 triterpenes, 3 fatty acids, and 11 other types of compounds. Among them, 102 compounds were reported in R. tomentosum for the first time, and 36 compounds were identified by comparing them with reference compounds. The chemical components in the ethanolic and aqueous extracts of R. tomentosum leaves and stems showed slight differences, with 84 common chemical components accounting for 71.2% of the total 118 compounds. This study systematically characterized and identified the non-volatile chemical components in the ethanolic and aqueous extracts of R. tomentosum for the first time. The findings provide a reference for active ingredient research, quality control, and product development of R. tomentosum.
Rhododendron/chemistry* ; Chromatography, High Pressure Liquid/methods* ; Drugs, Chinese Herbal/chemistry* ; Mass Spectrometry/methods* ; Plant Leaves/chemistry*

BACKGROUND: Atrial fibrillation (AF) is a common cardiac arrhythmia in the elderly. This study aimed to evaluate urban-rural disparities in its prevalence and management in elderly Chinese. METHODS: Consecutive participants aged ≥ 65 years attending outpatient clinics were enrolled for AF screening using handheld single-lead electrocardiogram (ECG) from April 2017 to December 2022. Each ECG rhythm strip was reviewed from the research team. AF or uninterpretable single-lead ECGs were referred for 12-lead ECG. Primary study outcome comparison was between rural and urban areas for the prevalence of AF. The Student's t-test was used to compare mean values of clinical characteristics between rural and urban participants, while the Pearson's chi-square test was used to compare between-group proportions. Multivariate stepwise logistic regression analysis was performed to estimate the association between AF and various patient characteristics. RESULTS: The 29,166 study participants included 13,253 men (45.4%) and had a mean age of 72.2 years. The 7073 rural participants differed significantly (P ≤ 0.02) from the 22,093 urban participants in several major characteristics, such as older age, greater body mass index, and so on. The overall prevalence of AF was 4.6% (n = 1347). AF was more prevalent in 7073 rural participants than 22,093 urban participants (5.6% vs. 4.3%, P < 0.01), before and after adjustment for age, body mass index, blood pressure, pulse rate, cigarette smoking, alcohol consumption and prior medical history. Multivariate logistic regression analysis identified overweight/obesity (OR = 1.35, 95% CI: 1.17-1.54) in urban areas and cigarette smoking (OR = 1.62, 95% CI: 1.20-2.17) and alcohol consumption (OR = 1.42, 95% CI: 1.04-1.93) in rural areas as specific risk factors for prevalent AF. In patients with known AF in urban areas (n = 781) and rural areas (n = 338), 60.6% and 45.9%, respectively, received AF treatment (P < 0.01), and only 22.4% and 17.2%, respectively, received anticoagulation therapy (P = 0.05). CONCLUSIONS In China, there are urban-rural disparities in AF in the elderly, with a higher prevalence and worse management in rural areas than urban areas. Our study findings provide insight for health policymakers to consider urban-rural disparity in the prevention and treatment of AF.

[This corrects the article DOI: 10.11909/j.issn.1671-5411.2017.08.005.].

OBJECTIVE: To investigate the effect and mechanism of Shuangshi Tonglin Capsules (SSTL) in the treatment of prostate fibrosis (PF). METHODS: Human prostate stromal cells (WPMY-1) were used for in vitro experiments to establish PF cell models induced with estradiol (E₂). The cell proliferation, migration and clonogenic capacity were determined by cell counting kit-8, scratch assay, and crystal violet staining, respectively. Sprague-Dawley rats were used for in vivo experiments. The changes in histomorphology and organ index of rat prostate by SSTL were determined. Pathologic changes and collagen deposition changes in rat prostate were observed by haematoxylin and eosin (HE) and Masson staining. Enzyme-linked immunosorbent assay kits were used to determine changes in rat PF markers fibroblast growth factor-23 (FGF-23), E₂ and prostate specific antigen (PSA). Mechanistically, changes in oxidative stress indicators by SSTL were determined in WPMY-1 cells and PF rats. Then the expressions of nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) and transforming growth factor-β1 (TGF-β1)/Smad pathway-related proteins as well as Nrf2 and TGF-β1 mRNA were further detected by Western blot or quantitative real-time polymerase chain reaction both in vivo and in vitro. RESULTS: In the efficacy study, SSTL significantly reduced the proliferation, migration, and clonogenic ability of cells, improved the morphology of the glandular tissue, significantly reduced the prostate index, reduced glandular fibrous tissue and collagen deposition, and resulted in a significant decrease in the levels of FGF-23, E₂ and PSA (P<0.01 or P<0.05). In the mechanistic study, SSTL ameliorated oxidative stress by significantly increasing superoxide dismutase and glutathione peroxidase levels and decreasing malondialdehyde level in WPMY-1 cells and rats (P<0.01 or P<0.05). SSTL significantly elevated the expressions of Nrf2, HO-1, NAD(P)H quinone oxidoreductase 1 (NQO-1), and Smad7 proteins in both cells and rats, and significantly decreased the expressions of TGF-β1, collagen I, α-smooth muscle actin and Smad4 proteins (P<0.01 or P<0.05). SSTL also elevated the content of Nrf2 mRNA and decreased the content of TGF-β1 mRNA in cells and rats (P<0.01 or P<0.05). The Nrf2 inhibitor ML385 was added in in vitro experiments to further validate the pathway relevance. CONCLUSION SSTL was effective in improving PF in vivo and in vitro, and its mechanism of action may function through the Nrf2/TGF-β1 signaling pathway.
Male ; NF-E2-Related Factor 2/metabolism* ; Animals ; Drugs, Chinese Herbal/therapeutic use* ; Signal Transduction/drug effects* ; Transforming Growth Factor beta1/metabolism* ; Rats, Sprague-Dawley ; Humans ; Fibrosis ; Prostate/drug effects* ; Cell Proliferation/drug effects* ; Capsules ; Cell Movement/drug effects* ; Oxidative Stress/drug effects* ; Rats

Immunotherapy has emerged as a revolutionary approach to treat immune-related diseases. Dendritic cells (DCs) play a pivotal role in orchestrating immune responses, making them an attractive target for immunotherapeutic interventions. Modulation of gene expression in DCs using genome editing techniques, such as the CRISPR-Cas system, is important for regulating DC functions. However, the precise delivery of CRISPR-based therapies to DCs has posed a significant challenge. While lipid nanoparticles (LNPs) have been extensively studied for gene editing in tumor cells, their potential application in DCs has remained relatively unexplored. This study investigates the important role of cholesterol in regulating the efficiency of BAMEA-O16B lipid-assisted nanoparticles (BLANs) as carriers of CRISPR/Cas9 for gene editing in DCs. Remarkably, BLANs with low cholesterol density exhibit exceptional mRNA uptake, improved endosomal escape, and efficient single-guide RNA release capabilities. Administration of BLAN_mCas9/gPD-L1 results in substantial PD-L1 gene knockout in conventional dendritic cells (cDCs), accompanied by heightened cDC1 activation, T cell stimulation, and significant suppression of tumor growth. The study underscores the pivotal role of cholesterol density within LNPs, revealing potent influence on gene editing efficacy within DCs. This strategy holds immense promise for the field of cancer immunotherapy, offering a novel avenue for treating immune-related diseases.

Glioma is difficult to treat due to the unique tumor microenvironment and blood-brain barrier. (13aS)-3-Hydroxyl-6,7-dimethoxyphenanthro[9,10-b] indolizidine (PF403), a phenanthroindolizidine alkaloid, has been identified as a promising therapeutic agent for the treatment of glioma. However, the anti-glioma mechanism of PF403 in vivo has not been conclusively verified and must be further elucidated. Hence, a strategy without chemical modification was applied to identify the target of PF403. In this study, we identified nicotinamide phosphoribosyl transferase (NAMPT) as the target of PF403 by using thermal proteome profiling (TPP). Moreover, microscale thermophoresis (MST), surface plasmon resonance (SPR), and isothermal titration calorimetry (ITC) experiments confirmed that NAMPT exhibits good affinity for PF403. Direct and indirect enzyme activity assays revealed that PF403 inhibited the catalytic activity of NAMPT, leading to a decrease in the concentration of nicotinamide adenine dinucleotide (NAD⁺) in U87 cells. X-ray diffraction and amino acid spot mutation experiments revealed that PF403 primarily relies on the formation of pi-pi interactions with residue Tyr188 to maintain binding with NAMPT (PDB code 8Y55). After NAMPT was knocked down with lentivirus, PF403 lost or partially lost its antitumor activity at the cellular and animal levels. These findings suggest that PF403 exerts antitumor activity by directly targeting NAMPT.

Early correction of childhood malocclusion is timely managing morphological, structural, and functional abnormalities at different dentomaxillofacial developmental stages. The selection of appropriate imaging examination and comprehensive radiological diagnosis and analysis play an important role in early correction of childhood malocclusion. This expert consensus is a collaborative effort by multidisciplinary experts in dentistry across the nation based on the current clinical evidence, aiming to provide general guidance on appropriate imaging examination selection, comprehensive and accurate imaging assessment for early orthodontic treatment patients.
Humans ; Malocclusion/diagnostic imaging* ; Child ; Consensus