1.Discussion on Construction of a Multi-Agent "Cross-scale" Collective Decision-making Model for Superior Disease Entities in Sichuan-style Traditional Chinese Medicine
Qiuping CHEN ; Hang ZHOU ; Dan ZHENG ; Baixue LI ; Chenhao LIU ; Ju CHEN ; Jibin LIU ; Quansheng FENG ; JIANGYUMING ; Cen JIANG
Chinese Journal of Experimental Traditional Medical Formulae 2026;32(14):1-13
At present, the systematic excavation of the clinical experience and academic thought of the Sichuan school of Chinese medicine vis-à-vis its dominant disease entities remains fragmentary, and replicable paradigms are scarce. Confronted with empirical fragmentation, data heterogeneity and decision-making subjectivity, the standardised distillation, inheritance and clinical translation of these distinctive experiences has become a critical bottleneck constraining the development of the Sichuan school. The integration of artificial-intelligence technologies in data processing, pattern recognition and intelligent decision-making has rendered deep mining of traditional Chinese medicine(TCM) clinical knowledge and patterns imperative. Constructing an intelligent modern TCM diagnostic-therapeutic-evaluative system is now the obligatory route for inheritance and innovation in Chinese medicine, and simultaneously provides a technological breakthrough for intelligent decision paradigms in the dominant diseases of the Sichuan school. Accordingly, this study adopts the regional academic school as its point of entry, focuses on the dominant diseases of the Sichuan school, and proposes an innovative pathway of "four-dimensional data-multi-modal fusion-multi-agent decision-making". Specifically, four data dimensions are defined and instantiated: (Ⅰ) knowledge from classical medical literature and historical case records. (Ⅱ) objective four-diagnosis phenotypic data. (Ⅲ) master physicians' prescribing regularities. (Ⅳ) characteristic mechanisms of renowned formulae. Leveraging multi-modal data fusion and generative artificial intelligence, the entire causal chain of Famous Physicians and Renowned Formulas is explicated to reconstruct the diagnostic-therapeutic cognitive logic of the regional school. Finally, a multi-agent collective-decision model is established and refined for the dominant diseases of the Sichuan school, capable of generating precise, individualised treatment regimens and thereby advancing an intelligent diagnostic-therapeutic paradigm that delivers more efficient and accurate clinical decision support.
2.Effects of Ningxin Shugan Decoction Combined with Antagonist Fixation Regimen on IVF-ET Outcomes and Serum Kisspeptin Expression in Infertility Patients with Polycystic Ovary Syndrome
Hua FENG ; Dan XU ; Xuelan HONG
Chinese Journal of Experimental Traditional Medical Formulae 2025;31(5):177-184
ObjectiveTo investigate the effects of Ningxin Shugan decoction combined with an antagonist fixation regimen on in vitro fertilization and embryo transfer (IVF-ET) outcomes and serum kisspeptin expression in infertility patients with polycystic ovary syndrome. MethodsA total of 96 infertile patients with polycystic ovary syndrome treated in Yancheng No.1 People's Hospital and Yancheng Affiliated Hospital of Nanjing University of Chinese Medicine were enrolled in this study and randomized into control and observation groups (n=48). The control group was treated with an antagonist fixation regimen, and the observation group was treated with Ningxin Shugan decoction on the basis of the treatment in the control group. The clinical efficacy was compared between the two groups. The total score and single scores of TCM symptoms, ovulation promotion status, and serum levels of reproductive hormones, miR-335-5p, miR-141-3p, and kisspeptin were determined before and after treatment. The IVF-ET outcome indicators and treatment safety were evaluated. Pearson test was conducted to analyze the correlations of serum levels of follicle-stimulating hormone (FSH), kisspeptin, miR-335-5p, and miR-141-3p with IVF-ET outcomes. ResultsThe total response rate in the observation group was 90.91%, which was higher than that (70.45%) in the control group (P<0.05). The total score and single scores of TCM symptoms and the testosterone, luteinizing hormone (LH), and LH/FSH levels declined after treatment (P<0.05), and they were lower in the observation group than in the control group (P<0.05). After treatment, the serum levels of FSH, kisspeptin, miR-335-5p, and miR-141-3p rose in both groups, being higher in the observation group than in the control group (P<0.05). The observation group showed higher ovulation number, number of MⅡ oocytes, embryo implantation rate, clinical pregnancy rate, and live birth rate than the control group (P<0.05, P<0.01). Serum levels of FSH, kisspeptin, miR-335-5p, and miR-141-3p were positively correlated with embryo implantation rate, clinical pregnancy rate, and live birth rate (P<0.01). ConclusionNingxin Shugan decoction combined with the antagonist fixation regimen can improve the IVF-ET outcome, promote the serum kisspeptin expression, and increase the ovulation rate and pregnancy rate in infertility patients with polycystic ovary syndrome.
3.Hepatitis E virus infection among blood donors in Ningbo
Mingxi PENG ; Yiyu LIU ; Huyan MAO ; Dan LIN ; Lu XIN ; Ning SHU ; Jianfeng HAN ; Feng DING
Chinese Journal of Blood Transfusion 2025;38(1):7-12
[Objective] To investigate the infection status and characteristics of HEV among voluntary blood donors in Ningbo, and to provide a basis for improving the blood screening strategy. [Methods] A total of 12 227 blood samples from voluntary blood donors in Ningbo from June 2022 to May 2023 were tested for HEV serology, enzymology, and nucleic acid testing. Furthermore, HEV gene sequencing was performed for genotyping analysis, and donors with reactive nucleic acid testing results were followed up to confirm their infection status. [Results] The reactivity rate of HEV Ag, anti-HEV IgM and anti-HEV IgG was 0.098%, 0.899% and 29.198%, respectively. There was no difference in the reactivity of anti-HEV IgM and anti-HEV IgG between genders, donation frequencies and donation types (P>0.05). The reactivity rate increased significantly with age (P<0.05). The rate of ALT disqualification (ALT>50U/L) was significantly higher than that in non-reactive samples (P<0.05). The HEV Ag reactivity rate (0.098%) was not correlated with gender, donation frequency, donation type or age. One HEV RNA positive case was found, with a positive rate of 0.008%(1/12 227). It was confirmed to be hepatitis E virus genotype 3 by sequencing analysis. Apart from HEV Ag reactivity, all other blood safety screening items were non-reactive, suggesting this case might be in the acute infection phase. The follow-up results showed that all indicators of the donor's previous blood donation were non-reactive. [Conclusion] Pre-donation ALT detection can reduce the risk of transfusion-transmitted HEV (TT-HEV) to a certain extent, and the effective way to prevent TT-HEV is to detect HEV RNA and serology of donor blood.
4.Current status and influencing factors of decision anxiety in guardians of children with acute appendicitis under ERAT background
Dan WEI ; Yali LI ; Tingting HE ; Xiaomin XIE ; Lei WANG ; Jiawei FENG ; Yan LIN ; Xun JIANG ; Bei FENG
Chinese Journal of Practical Nursing 2025;41(27):2134-2139
Objective:To investigate the current status and influencing factors of decision anxiety in guardians of children with acute appendicitis under Endoscopic retrograde appendicitis therapy (ERAT) background, and to provide reference for the development of targeted intervention programs for decision anxiety.Methods:Convenient sampling method was used to select 254 guardians of children with acute appendicitis treated in the Department of Pediatrics, Second Affiliated Hospital of PLA Air Force Medical University from February 2023 to April 2024. A cross-sectional survey was conducted using the General Data Questionnaire, the State-Trait Anxiety Inventory Form Y-State anxiety subscale and the Preparation for Decision Making Scale. Multiple linear regression was used to analyze the influencing factors in guardians of children with acute appendicitis.Results:Among the guardians of 254 children with acute appendicitis, 156 were males and 98 were females, aged (37.44 ± 3.63) years old. The decision anxiety score of guardians of children with acute appendicitis was (52.49 ± 6.54). The results of multiple linear regression showed that age of children, gender of guardian, education level of guardian, per capita monthly income of family, decision making tendency and decision preparation were the main influencing factors of decision anxiety in guardians of children with acute appendicitis ( t values were -7.07-3.58, all P<0.05), which could explain 64.4% of the total variation. Conclusions:The decision anxiety in guardians of children with acute appendicitis is at a high level. Medical staff should provide targeted decision guidance, improve decision assistance programs and provide more effective decision support for guardians of children with acute appendicitis.
5.Tiaojing Zhuyun formula combined with Dai meridian moxibustion method improves endometrial fibrosis in rats with uterine adhesion by regulating M2 type macrophage polarization
Dan CHOU ; Dan FENG ; Wenwen LIU ; Qian CHEN ; Ruyi XU ; Yuan QI ; Shuxiang HU ; Xinni WANG
Chinese Journal of Immunology 2025;41(10):2334-2340
Objective:To explore the improvement effect of Tiaojing Zhuyun formula combined with Dai meridian moxibustion on endometrial fibrosis in rats with intrauterine adhesions(IUA)by regulating M2 type macrophage polarization.Methods:SD rats were selected to establish an IUA model using a dual injury method of mechanical curettage and lipopolysaccharide infection,which were randomly separated into model group,Tiaojing Zhuyun formula group,Dai meridian moxibustion group,Tiaojing Zhuyun formula+Dai meridian moxibustion group and Bujiale group,with 10 rats in each group,another 10 rats were regarded as a sham operation(control)group,after grouping and treatment,the number of embryo implantation of rats in each group after cage closure was detected;HE staining was applied to detect pathological morphology of uterine tissue in rats in different groups,and their endometrial thickness and glandular number were compared;Masson staining was applied to detect endometrial fibrosis in rats of each group,and the collagen volume fraction(CVF)was compared;ELISA was applied to detect serum levels of profibrotic factor TGF-β1,pro-inflammatory factors IL-1β and IL-6,and levels of procollagen type Ⅰ carboxy-terminal peptide(PⅠNP)and procollagen Ⅲ N-terminal peptide(PⅢNP)of rats in each group;immunofluorescence staining was applied to detect expressions of M2 type macrophage markers CD163 and CD68 in endometrium of rats in each group.Results:Compared with control group,model group showed obvious pathological damage to uterine tissue,thickness of endometrium was thinner,the number of glands and embryo implantation were obviously reduced(P<0.05),endometrial CVF,levels of serum PⅠNP,P Ⅲ NP,TGF-β1,IL-1β and IL-6,and the number of CD163 and CD68 positive cells in endometrium were increased(P<0.05);compared with model group,pathological damage to uterine tissue of rats in Tiaojing Zhuyun formula group,Dai meridian moxibustion group,Tiaojing Zhuyun formula+Dai meridian moxibustion group and Bujiale group was reduced,thickness of endometrium,the number of glands and embryo implantation,and the numbers of CD163 and CD68 positive cells in endometrium were increased(P<0.05),endometrial CVF and levels of serum PⅠNP,P Ⅲ NP,TGF-β1,IL-1β and IL-6 were reduced(P<0.05);compared with Tiaojing Zhuyun formula group and Dai meridian moxibustion group,pathological damage to uterine tissue of rats in Tiaojing Zhuyun formula+Dai meridian moxibustion group and Bujiale group was alleviated,thickness of endometrium,the number of glands and embryo implantation,and the number of CD163 and CD68 positive cells in endometrium were increased(P<0.05),endometrial CVF and levels of serum PⅠNP,P Ⅲ NP,TGF-β1,IL-1β and IL-6 were reduced(P<0.05);there was no obvious change in all indicators between Tiaojing Zhuyun formula+Dai meridian moxibustion group and Bujiale group(P>0.05).Conclusion:Combination of Tiaojing Zhuyun formula and Dai meridian moxibustion can promote the polarization of M2 type macrophages,thereby inhibiting inflammation and endometrial fibrosis in IUA rats,and improving their symptoms of uterine adhesions.
6.Association of afterschool physical exercise and sleep quality among preschool children in Minhang district of Shanghai
Li-li ZHANG ; Yi-dan JIA ; Xue-qing MIAO ; Xiao-feng YIN ; Hui-jing SHI ; Yan-qi HU
Fudan University Journal of Medical Sciences 2025;52(5):657-663
Objective To observe the association between afterschool physical exercise and sleep quality among preschool children,and to explore the proper afterschool physical exercise model for better sleep quality.Methods A cross-sectional study was conducted.From Apr to Jun 2024,a total of 1 430 children from three public kindergartens in Minhang district were enrolled to participate in the survey.Parents were invited to complete the basic sociodemographic information,afterschool physical exercise information and the Children's Sleep Habits Questionnaire.One-way ANOVA and linear mixed effects models were used to explore the relationship between afterschool exercise and sleep quality.Results A total of 1 430 questionnaires were sent out and 1 384 were recovered with a recovery rate of 96.78%.Among them 1 366 were valid,with an effective rate of 95.52%.The average age of the children was(5.19±0.87)years old with gender ration of 1.07∶1(male:female).The prevalence of poor sleep quality was 80.60%(regarding a CSHQ total score>41 as cutoff).A one-way ANOVA indicated that time on afterschool physical exercise was significantly associated with sleep duration,Night waking,and sleep onset delay(P<0.05).After adjusting for age,gender,the only child or not,main caregiver,and parental education and occupation,linear mixed effects models showed that engaging in afterschool physical activity for at least 180 mins per week has a statistically significant predictive effect on sleep duration scores(β=-0.50,z=-4.52,95%CI:-0.72,-0.28,P<0.001),night waking scores(β=-0.16,z=-2.34,95%CI:-0.29,-0.02,P=0.020),and sleep onset delay scores(β=-0.14,z=-2.35,95%CI:-0.26,-0.02,P=0.019).Conclusion Afterschool exercise was significantly associated with sleep quality among preschool children in Minhang district of Shanghai.The time≥180 min on afterschool exercise per week in preschool children was significantly positively associated with maintaining sleep duration,reducing night wakings and shortening the latency to fall asleep.The habit of afterschool exercise and the time on afterschool exercise should be emphasized by parents and the society to improve sleep quality among preschool children.
7.Treatment and mechanism of chrysoeriol on pulmonary hypertension based on network pharmacology and experimental study
Ying-fang MA ; Meng CAI ; Dan FENG ; Yang GUO ; Yu-he TIAN ; Yun-hua ZHANG ; Li-li WEI ; Yang WANG ; Jun-qiang SI
Chinese Pharmacological Bulletin 2025;41(11):2167-2176
Aim To investigate the effect of chrysoeriol on pulmonary vascular remodeling in pulmonary hyper-tension by animal experiments combined with cell ex-periments,and to explore its potential therapeutic tar-gets by network pharmacology.Methods The target of chrysoeriol was collected in Targetnet,SEA and SwissTargetPrediction database.Pulmonary arterial hy-pertension(PAH)targets were collected in the Dis-GeNET and GeneCards databases,and PPI network map was drawn in the STRING database,and key tar-gets were screened.The GO and KEGG pathway en-richment analysis was carried out through DAVID data-base and Weishengxing platform.AutoDock software was used for molecular docking of key core targets.The PAH model of rats was constructed,and the pulmo-nary hemodynamics and vascular remodeling were de-tected by echocardiography,HE and Masson staining.Primary pulmonary smooth muscle cells were extracted,and the effects of drugs on pathway proteins were de-tected in vitro.Results The results of network phar-macology showed that chrysoeriol exerted therapeutic effects on pulmonary hypertension by affecting key tar-gets such as AKT1,SRC,EGFR,MMP9 and gsk3 β,and signaling pathways such as EGFR and PI3K-AKT.Molecular docking showed that chrysoeriol had good binding ability with 5 key target genes.Animal experi-ments showed that the pulmonary hemodynamic func-tion of PAH rats was significantly improved after ad-ministration of chrysoeriol.The remodeling of small pulmonary arteries was significantly reduced.Cell ex-periments showed that chrysoeriol could inhibit the ex-pression of proliferation,migration and phenotypic transformation genes.Conclusion Chrysoeriol may play a role in the treatment of pulmonary hypertension through multiple targets.
8.Multidisciplinary expert consensus on weight management for overweight and obese children and adolescents based on healthy lifestyle
HONG Ping, MA Yuguo, TAO Fangbiao, XU Yajun, ZHANG Qian, HU Liang, WEI Gaoxia, YANG Yuexin, QIAN Junwei, HOU Xiao, ZHANG Yimin, SUN Tingting, XI Bo, DONG Xiaosheng, MA Jun, SONG Yi, WANG Haijun, HE Gang, CHEN Runsen, LIU Jingmin, HUANG Zhijian, HU Guopeng, QIAN Jinghua, BAO Ke, LI Xuemei, ZHU Dan, FENG Junpeng, SHA Mo, Chinese Association for Student Nutrition & ; Health Promotion, Key Laboratory of Sports and Physical Fitness of the Ministry of Education,〖JZ〗 Engineering Research Center of Ministry of Education for Key Core Technical Integration System and Equipment,〖JZ〗 Key Laboratory of Exercise Rehabilitation Science of the Ministry of Education
Chinese Journal of School Health 2025;46(12):1673-1680
Abstract
In recent years, the prevalence of overweight and obesity among children and adolescents has risen rapidly, posing a serious threat to their physical and mental health. To provide scientific, systematic, and standardized weight management guidance for overweight and obese children and adolescents, the study focuses on the core concept of healthy lifestyle intervention, integrates multidisciplinary expert opinions and research findings,and proposes a comprehensive multidisciplinary intervention framework covering scientific exercise intervention, precise nutrition and diet, optimized sleep management, and standardized psychological support. It calls for the establishment of a multi agent collaborative management mechanism led by the government, implemented by families, fostered by schools, initiated by individuals, optimized by communities, reinforced by healthcare, and coordinated by multiple stakeholders. Emphasizing a child and adolescent centered approach, the consensus advocates for comprehensive, multi level, and personalized guidance strategies to promote the internalization and maintenance of a healthy lifestyle. It serves as a reference and provides recommendations for the effective prevention and control of overweight and obesity, and enhancing the health level of children and adolescents.
9.Inhibitory effect of safranal on proliferation,migration and phenotypic transformation of vascular smooth muscle cells of rats induced by high glucose in vitro
Yixuan GAO ; Peng WANG ; Silong ZHANG ; Ruijuan GAO ; Yingfang MA ; Keke ZHANG ; Dan FENG ; Zongqi HUANG ; Ketao MA ; Li LI ; Junqiang SI
Journal of Jilin University(Medicine Edition) 2025;51(4):948-957
Objective:To discuss whether safranal affects the proliferation,migration,and phenotypic transformation of the vascular smooth muscle cells(VSMCs)in a high-glucose environment and to clarify the function of safranal in the prevention and treatment of diabetic(DM)vascular complications.Methods:The SD rats were selected as experimental subjects;primary VSMCs were cultured from rat thoracic aortas and divided into control group,25 mmol·L-1 high glucose(HG)group,HG+20 μmol·L-1 safranal group,HG+40 μmol·L-1 safranal group,and HG+80 μmol·L-1 safranal group.The cells in control group received no treatment;the cells in 25 mmol·L-1 HG group were pretreated with 25 mmol·L-1 HG;the cells in HG+20,40,and 80 μmol·L-1 safranal groups were further treated with 20,40,and 80 μmol·L-1 safranal respectively for 48 h on the basis of 25 mmol·L-1 HG group.Cell counting kit-8(CCK-8)method was used to determine the appropriate concentration of safranal and detect the viabilities of the VSMCs in various groups;cell scratch healing assay was used to detect the scratch healing rates of the VSMCs in various groups;Transwell chamber assay was used to detect the numbers of the migration VSMCs in various groups;immunofluorescence method was used to detect the fluorescence intensities of alpha-smooth muscle actin(α-SMA)and rabbit anti-osteopontin(OPN)in the VSMCs in various groups;Western blotting method was used to detect the expression levels of OPN,α-SMA,and proliferating cell nuclear antigen(PCNA)in the VSMCs in various groups.Results:Under microscope,on the 4th day of in vitro culture,the spindle-shaped or triangular cells crawled out from the edge of the thoracic aorta tissue blocks,with long spindle being the most common morphology.On the 14th,the cells gradually covered the bottom of the dish;when cell density reached 80%-90%,the characteristic"hills and valleys"growth pattern appeared.Third-generation cells were taken for immunofluorescence identification;immunofluorescence staining with VSMC-specific marker α-SMA showed positive expression of α-SMA protein in the primarily cultured VSMCs.The CCK-8 assay results showed that compared with control group,the cell viability of the cells in 160 μmol·L-1 safranal group was significantly decreased(P<0.01),indicating toxic damage to the cells.Under the conditions of safranal concentrations at 20,40,and 80 μmol·L-1 respectively,after 48 h intervention on VSMCs,no significant adverse effect on cell viability was observed;considering both the effect and toxicity of safranal,these three concentrations were used in subsequent cell experiments.After 48 h intervention,compared with control group,the activity of the VSMCs in 25 mmol·L-1 HG group was increased(P<0.001);compared with 25 mmol·L-1 HG group,the activities of the VSMCs in HG+20,40,and 80 μmol·L-1 safranal groups were gradually decreased(P<0.05).The cell scratch healing assay and Transwell assay results showed that after 48 h intervention,the scratch healing rate of the VSMCs in 25 mmol·L-1 HG group was significantly higher than that in control group(P<0.01),and the number of transmembrane cells through the Transwell chamber was significantly increased(P<0.05);compared with 25 mmol·L-1 HG group,the scratch healing rates of the VSMCs in HG+20,40,and 80 μmol·L-1 safranal groups were gradually decreased(P<0.05),and the number of transmembrane cells was decreased(P<0.05).The immunofluorescence staining results showed that compared with control group,the fluorescence intensity of α-SMA protein in the VSMCs in 25 mmol·L-1 HG group was significantly weakened(P<0.001),while the fluorescence intensity of OPN protein was significantly enhanced(P<0.001);compared with 25 mmol·L-1 HG group,the fluorescence intensities of α-SMA protein in the VSMCs in HG+20,40,and 80 μmol·L-1 safranal groups were gradually increased(P<0.05),and the fluorescence intensities of OPN were gradually weakened(P<0.05).The Western blotting method results showed that compared with control group,the expression level of α-SMA protein in the VSMCs in 25 mmol·L-1 HG group was decreased(P<0.05),and the expression levels of PCNA and OPN proteins were increased(P<0.01);compared with 25 mmol·L-1 HG group,the expression level of α-SMA protein in the VSMCs in HG+20,40,and 80 μmol·L-1 safranal groups were increased(P<0.05),and the expression levels of PCNA and OPN proteins were decreased(P<0.05).Conclusion:Safranal can inhibit the proliferation,migration,and phenotypic transformation of the VSMCs induced by high glucose.
10.Potential pharmacodynamic substances and mechanism of Zhizi Houpu decoction in treating insomnia based on UHPLC-QTOF-MS and network pharmacology
Huifen WU ; Yanqiu GU ; Kunmiao FENG ; Dan JIA ; Yuanyuan DAI ; Xiaofei CHEN ; Ting HAN
Academic Journal of Naval Medical University 2025;46(10):1267-1277
Objective To establish an ultra-high performance liquid chromatography with quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS)method for identifying the active ingredients of Zhizi Houpu decoction,and to predict its material basis and mechanism of anti-insomnia effects using network pharmacology.Methods The chemical components of Zhizi Houpu decoction were identified according to UHPLC-QTOF-MS ion fragmentation rule combined with compound library and literature review.Components with oral bioavailability(OB)≥30%and drug-like properties(DL)≥0.18 were selected to construct the Zhizi Houpu decoction-active ingredients-target network.The STRING database and the Database for Annotation,Visualization,and Integrated Discovery(DAVID)were used to screen key target proteins.Subsequently,enrichment analysis was performed for biological processes,molecular functions,cellular components,and signaling pathways.Results A total of 107 chemical components were identified,including 35 compounds related to insomnia and 11 anti-insomnia targets such as AKT serine/threonine kinase 1,tumor protein 53,and prostaglandin-endoperoxide synthase 2.Gene Ontology functional enrichment analysis indicated that Zhizi Houpo decoction may exert its effects through cellular components such as the presynaptic membrane,dendrite,and plasma membrane,by participating in biological processes like chemical synaptic transmission,G protein signaling pathway,and neuron apoptosis,and by regulating molecular functions such as G protein-coupled serotonin receptor activity.Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis revealed that its anti-insomnia effects were mainly concentrated in pathways such as neuroactive ligand-receptor interaction,calcium signaling pathway,serotonergic synapse,and cyclic adenosine monophosphate signaling pathway.Conclusion The anti-insomnia effect of Zhizi Houpo decoction is the result of a synergistic action involving multiple components,multiple targets,and multiple pathways.Its material basis and mechanism of action are primarily related to regulating biological processes such as neurotransmitter metabolism,synaptic function,neuronal apoptosis,and inflammatory response.


Result Analysis
Print
Save
E-mail