The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated ion channel characterized by high Ca²⁺ permeability, rapid activation, and rapid desensitization. It is widely expressed in the nervous system and various non-neuronal cell types. α7 nAChR is involved in regulating neuronal excitability, synaptic transmission and plasticity, cognitive function, and inflammatory responses. These properties have made α7 nAChR a potential therapeutic target for neuropsychiatric and inflammatory diseases. In recent years, advances in cryo-electron microscopy have provided structural insights into α7 nAChR gating, ligand recognition, allosteric modulation, and allosteric activation. The receptor mainly undergoes transitions among resting, open, and desensitized states. Recent structural studies have further revealed asymmetric conformational changes and multiple intermediate states during receptor activation and recovery from desensitization. Conformational rearrangements in the extracellular domain-transmembrane domain coupling region and the pore-forming M2 helices are closely associated with channel opening and desensitization. However, structural characterization of the α7 nAChR gating cycle still largely depends on pharmacological stabilization. Open-state structures have been resolved in the presence of PNU-120596 or GAT107, whereas a high-resolution structure of the open state induced by acetylcholine alone remains to be determined. These physiological roles underpin the involvement of α7 nAChR in multiple disease processes. In the hippocampus, α7 nAChR regulates local neuronal circuits, theta oscillations, synaptic transmission, and synaptic plasticity, thereby contributing to learning, memory, attention, and other cognitive processes. In macrophages, microglia, and other immune-related cells, α7 nAChR activation regulates inflammatory responses and oxidative stress. These effects involve several signaling pathways, including Janus kinase 2 (JAK2)/STAT3, phosphoinositide 3-kinase (PI3K)/AKT, and NF-κB signaling, as well as regulation of the NLRP3 inflammasome and IL-1β production. Such anti-inflammatory effects may also contribute to α7 nAChR-mediated neuroprotection. Although several compounds targeting α7 nAChR have entered clinical studies, no α7 nAChR-selective drug has been approved for clinical use. Limited clinical translation may be related to rapid receptor desensitization, inconsistent efficacy across clinical studies, insufficient or variable target engagement, patient heterogeneity, and clinical endpoint selection. TC-5619 showed promising effects on cognitive impairment and negative symptoms in an early exploratory study of schizophrenia, but these effects were not confirmed in a subsequent, larger phase II trial. Encenicline (EVP-6124) also showed cognitive improvement in early studies, whereas two global phase III trials in schizophrenia failed to meet their co-primary cognitive and functional endpoints. Pharmacological strategies targeting α7 nAChR have expanded from orthosteric agonists to positive allosteric modulators (PAMs) and allosteric agonist-positive allosteric modulators (ago-PAMs). Orthosteric agonists directly activate the receptor by binding to the orthosteric site, but their effects are limited by rapid receptor desensitization. Type I PAMs mainly enhance agonist-evoked responses with relatively small effects on desensitization, whereas type II PAMs markedly potentiate receptor responses and reduce or delay desensitization. Ago-PAMs such as GAT107 can directly activate α7 nAChR through an allosteric mechanism while also potentiating responses to orthosteric agonists. Together, these findings have broadened the pharmacological approaches to α7 nAChR regulation. In summary, future drug development should focus on precise regulation of α7 nAChR according to receptor structure and disease mechanisms, rather than simply enhancing receptor activation. Further studies are needed to clarify how candidate ligands affect receptor gating, conformational transitions, recovery from desensitization, and downstream signaling. Pharmacological differences between neuronal and non-neuronal α7 nAChRs, between homomeric α7 and heteromeric α7β2 receptors, and between α7 nAChR and other nAChR subtypes also require further investigation. Integrating structure prediction, artificial intelligence-assisted virtual screening, molecular docking, molecular dynamics simulations, and electrophysiological validation may facilitate the discovery and optimization of new α7 nAChR modulators.

Objective:To study the incidence and epidemiological characteristics of tsutsugamushi disease in Ankang City, Shaanxi Province.Methods:From 2018 to 2023, data on tsutsugamushi disease cases reported by various medical institutions at all levels in Ankang City were collected through the China Disease Prevention and Control Information System. At the same time, individual epidemiological investigation of reported cases was carried out, and electronic medical records of patients were retrieved to verify their diagnosis. In 2023, the rodents and chigger mites were monitored in 3 townships with high incidence of tsutsugamushi disease in Ankang City by night clamping method, and the chigger mites rate and chigger mites index were calculated. Blood, liver, spleen and kidney samples of rodents were collected, DNA of blood and organ mixture was extracted, and quantitative real-time PCR was used to detect Orientia tsutsugamushi. Results:A total of 330 cases of tsutsugamushi disease were reported in Ankang City from 2018 to 2023, and the reported incidence rate increased from 0.56/100 000 in 2018 to 5.02/100 000 in 2023. Among them, 139 were males and 191 were females, with a sex ratio of 0.73∶1.00. The age was mainly 45 - 70 years old, accounting for 81.52% (269/330). The occupation was mainly farmers, accounting for 86.97% (287/330). The onset time was mainly concentrated from April to October, with a total of 317 cases, accounting for 96.06% (317/330). The main clinical manifestations were fever (93.20%, 274/294), ulcer or eschar (75.85%, 223/294), headache (44.56%, 131/294), and lymph node enlargement (44.22%, 130/294). The misdiagnosis rate at the first diagnosis was 73.81% (217/294). A total of 452 rodents were captured, of which 91 rodents carried chigger mites, and chigger mites rate was 20.13% (91/452). A total of 1 463 chigger mites were captured, and the chigger mites index was 3.24 (1 463/452). Quantitative real-time PCR was performed on blood and organ mixture samples collected from 452 rodents, and one of the organ mixture samples tested positive for Orientia tsutsugamushi. Conclusions:The incidence of tsutsugamushi disease in Ankang City is relatively high, and the overall incidence is on the rise. The cases are mainly female, middle-aged and elderly, and farmers, with a high misdiagnosis rate at the first diagnosis. There are chigger mites in rodents in townships with high incidence of tsutsugamushi disease.

OBJECTIVE: To investigate the relationship between physical activity and genetic risk and their combined effects on the risk of developing chronic obstructive pulmonary disease. METHODS: This prospective cohort study included 318,085 biobank participants from the UK. Physical activity was assessed using the short form of the International Physical Activity Questionnaire. The participants were stratified into low-, intermediate-, and high-genetic-risk groups based on their polygenic risk scores. Multivariate Cox regression models and multiplicative interaction analyses were used. RESULTS: During a median follow-up period of 13 years, 9,209 participants were diagnosed with chronic obstructive pulmonary disease. For low genetic risk, compared to low physical activity, the hazard ratios ( HRs) for moderate and high physical activity were 0.853 (95% confidence interval [ CI]: 0.748-0.972) and 0.831 (95% CI: 0.727-0.950), respectively. For intermediate genetic risk, the HRs were 0.829 (95% CI: 0.758-0.905) and 0.835 (95% CI: 0.764-0.914), respectively. For participants with high genetic risk, the HRs were 0.809 (95% CI: 0.746-0.877) and 0.818 (95% CI: 0.754-0.888), respectively. A significant interaction was observed between genetic risk and physical activity. CONCLUSION Moderate or high levels of physical activity were associated with a lower risk of developing chronic obstructive pulmonary disease across all genetic risk groups, highlighting the need to tailor activity interventions for genetically susceptible individuals.
Humans ; Pulmonary Disease, Chronic Obstructive/epidemiology* ; Exercise ; Male ; Female ; Middle Aged ; Prospective Studies ; Aged ; Genetic Predisposition to Disease ; Risk Factors ; United Kingdom/epidemiology* ; Incidence ; Adult

Objective To construct a cloud-based platform for healthcare-associated infection(HAI)management based on multi-source data fusion and data visualization,and evaluate its application effectiveness.Methods A ter-tiary first-class cancer hospital was selected as the research object.Aligned with graded hospital accreditation stan-dards and based on grid-based management and responsibility zone mode,a platform was constructed in 2023 with low-code technology,multi-source data fusion,and visualization function.The self-comparison method was adopted to compare occurrence of HAI before and after the operation of the platform.A questionnaire survey was adopted to assess the experience and workload reduction feelings of full-time and part-time infection surveillance and control profe-ssionals using the platform.Results 81.56％of the surveyed respondents believed that the platform could re-duce the workload of infection surveillance and control.Compared with before the trial operation,the hospital achieved an annual reduction of 11 200 yuan in paper costs,with associated labor savings of approximately 4 482.5 hours.The incidence of HAI cases in the whole hospital decreased from 0.67％to 0.45％.The pathogen detection rate before therapeutic use of antimicrobial agents increased from 51.26％to 71.54％.Differences were both statis-tically significant(both P＜0.05).The detection number and proportion of carbapenem-resistant Pseudomonas aeruginosa(CRPA)and extended-spectrum β-lactamase-producing Klebsiella pneumoniae(ESBL-KP)in HAI cases decreased(54.55％vs 36.47％and 51.14％vs 32.50％,respectively,both P＜0.05).Conclusion The construc-tion and application of smart HAI management cloud-based platform can reduce cost,improve management quality,and provide a theoretical basis and technical paradigm for the construction of smart HAI management system.

Objective:To study the incidence and epidemiological characteristics of tsutsugamushi disease in Ankang City, Shaanxi Province.Methods:From 2018 to 2023, data on tsutsugamushi disease cases reported by various medical institutions at all levels in Ankang City were collected through the China Disease Prevention and Control Information System. At the same time, individual epidemiological investigation of reported cases was carried out, and electronic medical records of patients were retrieved to verify their diagnosis. In 2023, the rodents and chigger mites were monitored in 3 townships with high incidence of tsutsugamushi disease in Ankang City by night clamping method, and the chigger mites rate and chigger mites index were calculated. Blood, liver, spleen and kidney samples of rodents were collected, DNA of blood and organ mixture was extracted, and quantitative real-time PCR was used to detect Orientia tsutsugamushi. Results:A total of 330 cases of tsutsugamushi disease were reported in Ankang City from 2018 to 2023, and the reported incidence rate increased from 0.56/100 000 in 2018 to 5.02/100 000 in 2023. Among them, 139 were males and 191 were females, with a sex ratio of 0.73∶1.00. The age was mainly 45 - 70 years old, accounting for 81.52% (269/330). The occupation was mainly farmers, accounting for 86.97% (287/330). The onset time was mainly concentrated from April to October, with a total of 317 cases, accounting for 96.06% (317/330). The main clinical manifestations were fever (93.20%, 274/294), ulcer or eschar (75.85%, 223/294), headache (44.56%, 131/294), and lymph node enlargement (44.22%, 130/294). The misdiagnosis rate at the first diagnosis was 73.81% (217/294). A total of 452 rodents were captured, of which 91 rodents carried chigger mites, and chigger mites rate was 20.13% (91/452). A total of 1 463 chigger mites were captured, and the chigger mites index was 3.24 (1 463/452). Quantitative real-time PCR was performed on blood and organ mixture samples collected from 452 rodents, and one of the organ mixture samples tested positive for Orientia tsutsugamushi. Conclusions:The incidence of tsutsugamushi disease in Ankang City is relatively high, and the overall incidence is on the rise. The cases are mainly female, middle-aged and elderly, and farmers, with a high misdiagnosis rate at the first diagnosis. There are chigger mites in rodents in townships with high incidence of tsutsugamushi disease.

Aim To explore the effect of Trichinella spiralis(Ts)proteins on lipopolysaccharide(LPS)-induced inflammatory response in macrophage RAW264.7 cells.Methods The inflammation model was constructed by LPSstimulating macrophages in vitro,which were divided intothe control group,Ts group(Ts 2 mg·L-1),LPSgroup(LPS 1 mg·L-1),and Ts+LPS group(Ts 2 mg·L-1+LPS 1 mg·L-1).qRT-PCR was used to detect the mRNA levels of molecular markers of macrophage polarization,inclu-ding iNOS and Arg1,and inflammatory factors,inclu-ding IL-1 β and IL-6.The protein levels of IL-1 β,IL-6 and BRD2 were detected by Western blot further.BRD2 localization was also validated by immunofluo-rescence.In order to explore whether Ts proteins played a role in inhibiting inflammation through BRD2,si-BRD2 were transfected into RAW 264.7 cells.Once a-gain,the expression levels of iNOS,Arg1,IL-1 β,and IL-6 were detected by qRT-PCR,and IL-1 β and IL-6 were also detected by Western blot.Results Com-pared with the control group,LPS promoted the expres-sion of iNOS,IL-1 β,IL-6,and BRD2,while Ts proteins intervention decreased the expression of iNOS,IL-1 β,IL-6,BRD2.After the knockdown of BRD2,Ts pro-teins further reduced the level of iNOS,while Arg1,IL-1 β and IL-6 levels were restored.Conclusion Ts pro-teins alleviate LPS-induced macrophage inflammation by regulating macrophage polarization and inhibiting BRD2.

Iron metabolism is a critical factor in tumorigenesis and development. Although TP53 mutations are prevalent in glioblastoma (GBM), the mechanisms by which TP53 regulates iron metabolism remain elusive. We reveal an imbalance iron homeostasis in GBM via TCGA database analysis. TP53 mutations disrupted iron homeostasis in GBM, characterized by elevated total iron levels and reduced ferritin (FTH). The gain-of-function effect triggered by TP53 mutations upregulates itchy E3 ubiquitin-protein ligase (ITCH) protein expression in astrocytes, leading to FTH degradation and an increase in free iron levels. TP53-mut astrocytes were more tolerant to the high iron environment induced by exogenous ferric ammonium citrate (FAC), but the increase in intracellular free iron made them more sensitive to Erastin-induced ferroptosis. Interestingly, we found that Erastin combined with FAC treatment significantly increased ferroptosis. These findings provide new insights for drug development and therapeutic modalities for GBM patients with TP53 mutations from iron metabolism perspectives.
Ferroptosis/drug effects* ; Humans ; Iron/metabolism* ; Glioblastoma/metabolism* ; Tumor Suppressor Protein p53/metabolism* ; Homeostasis/physiology* ; Ferritins/metabolism* ; Brain Neoplasms/genetics* ; Mutation ; Astrocytes/drug effects* ; Cell Line, Tumor ; Piperazines/pharmacology* ; Quaternary Ammonium Compounds/pharmacology* ; Ferric Compounds

Dental pulp-dentin complex defects remain a major unresolved problem in oral medicines. Clinical therapeutic methods including root canal therapy and vital pulp therapy are both considered as conservative strategies, which are incapable of repairing the pulp-dentin complex defects. Although biomaterial-based strategies show remarkable progress in antibacterial, anti-inflammatory, and pulp regeneration, the important modulatory effects of nerves within pulp cavity have been greatly overlooked, making it challenging to achieve functional pulp-dentin complex regeneration. In this study, we propose an injectable bioceramics-containing composite hydrogel in combination of Li-Ca-Si (LCS) bioceramics and gelatin methacrylate matrix with photo-crosslinking properties. Due to the sustained release of bioactive Li, Ca and Si ions from LCS, the composite hydrogels possess multiple functions of promoting the neurogenic differentiation of Schwann cells, odontogenic differentiation of dental pulp stem cells, and neurogenesis-odontogenesis couples in vitro. In addition, the in vivo results showed that LCS-containing composite hydrogel can significantly promote the pulp-dentin complex repair. More importantly, LCS bioceramics-containing composite hydrogel can induce the growth of nerve fibers, leading to the re-innervation of pulp tissues. Taken together, the study suggests that LCS bioceramics can induce the innervation of pulp-dentin complex repair, offering a referable strategy of designing multifunctional filling materials for functional periodontal tissue regeneration.
Dental Pulp/drug effects* ; Hydrogels/pharmacology* ; Animals ; Ceramics/pharmacology* ; Dentin/drug effects* ; Biocompatible Materials/pharmacology* ; Rats ; Gelatin ; Regeneration/drug effects* ; Cell Differentiation/drug effects* ; Injections ; Humans ; Odontogenesis/drug effects*

ObjectiveBased on the Huangdi Neijing，a traditional Chinese medicine（TCM）identification scale of five human qualities was constructed and applied in elderly people to evaluate its reliability and validity. MethodsBased on the original text of the Huangdi Neijing and a review of relevant ancient and modern literature， an identification scale of five human qualities was developed through Delphi expert interviews. Offline surveys were conducted to evaluate the feasibility，reliability，and validity of its application in elderly people，and the scale was evaluated and revised. ResultsThe scale of five human qualities is divided into five subscales：wood，fire，earth，metal，and water. Each subscale is divided into four dimensions：morphological structure，psychological characteristics，tolerance，and physiological characteristics，with a total of 75 items. The survey results in elderly people show that：（1） The recovery rate and completion rate are 100%，and the average filling time is 23.3 min. 85.5% of the samples are completed within the preset time. （2） Reliability analysis results：The homogeneity reliability of each subscale，Chronbach's α，ranges from 0.702 to 0.793. The scores of each subscale in the split-half reliability range from 0.758 to 0.841， indicating that the internal consistency of the scale is good. （3） Validity analysis results. Content validity：During the development stage of the scale，the item pool，dimensions，and structure of the scale are designed reasonably， and the content is complete. The evaluation of content validity shows that the item-level content validity index （I-CVI） ranges from 0.83 to 1.00， and the scale-level content validity index for universal agreement （S-CVI/UA） is 0.92，indicating good content validity of the scale. Construct validity extracts 22 common factors based on an eigenvalue of 1，with a contribution rate of 62.333% to the overall system. The number of common factors in the five subscales is 4，5，4，5，and 4，respectively，with contribution rates of 52.64%，53.376%，51.445%，51.359%，and 50.714%，respectively，indicating the required structure for physical fitness measurement in elderly people. ConclusionThe scale constructed in this study has high reliability and validity，and it is suitable for evaluating the physical condition of elderly people in TCM.

BACKGROUND: Disease-modifying therapies have been approved for the treatment of relapsing multiple sclerosis (RMS). The present study aims to examine the safety of teriflunomide in Chinese patients with RMS. METHODS: This non-randomized, multi-center, 24-week, prospective study enrolled RMS patients with variant (c.421C>A) or wild type ABCG2 who received once-daily oral teriflunomide 14 mg. The primary endpoint was the relationship between ABCG2 polymorphisms and teriflunomide exposure over 24 weeks. Safety was assessed over the 24-week treatment with teriflunomide. RESULTS: Eighty-two patients were assigned to variant ( n  = 42) and wild type groups ( n  = 40), respectively. Geometric mean and geometric standard deviation (SD) of pre-dose concentration (variant, 54.9 [38.0] μg/mL; wild type, 49.1 [32.0] μg/mL) and area under plasma concentration-time curve over a dosing interval (AUC tau ) (variant, 1731.3 [769.0] μg∙h/mL; wild type, 1564.5 [1053.0] μg∙h/mL) values at steady state were approximately similar between the two groups. Safety profile was similar and well tolerated across variant and wild type groups in terms of rates of treatment emergent adverse events (TEAE), treatment-related TEAE, grade ≥3 TEAE, and serious adverse events (AEs). No new specific safety concerns or deaths were reported in the study. CONCLUSION: ABCG2 polymorphisms did not affect the steady-state exposure of teriflunomide, suggesting a similar efficacy and safety profile between variant and wild type RMS patients. REGISTRATION NCT04410965, https://clinicaltrials.gov .
Humans ; Crotonates/adverse effects* ; Toluidines/adverse effects* ; Nitriles ; Hydroxybutyrates ; Female ; Male ; Adult ; ATP Binding Cassette Transporter, Subfamily G, Member 2/genetics* ; Middle Aged ; Multiple Sclerosis, Relapsing-Remitting/genetics* ; Prospective Studies ; Young Adult ; Neoplasm Proteins/genetics* ; East Asian People