Metformin has been demonstrated to attenuate hyperglycaemia by modulating the gut microbiota. However, the mechanisms through which the microbiome mediates metformin monotherapy failure (MMF) are unclear. Herein, in a prospective clinical cohort study of newly diagnosed type 2 diabetes mellitus (T2DM) patients treated with metformin monotherapy, metagenomic sequencing of faecal samples revealed that Phocaeicola vulgatus abundance was approximately 12 times higher in nonresponders than in responders. P. vulgatus rapidly hydrolysed taurine-conjugated bile acids, leading to ceramide accumulation and reversing the improvements in glucose intolerance conferred by metformin in high-fat diet-fed mice. Interestingly, C22:0 ceramide bound to mitochondrial fission factor to induce mitochondrial fragmentation and impair hepatic oxidative phosphorylation in P. vulgatus-colonized hyperglycaemic mice, which could be exacerbated by metformin. This work suggests that metformin may be unsuitable for P. vulgatus-rich T2DM patients and that clinicians should be aware of metformin toxicity to mitochondria. Suppressing P. vulgatus growth with cefaclor or improving mitochondrial function using adenosylcobalamin may represent simple, safe, effective therapeutic strategies for addressing MMF.

Autism Spectrum Disorders (ASDs) are reported as a group of neurodevelopmental disorders. The structural changes of brain regions including the hippocampus were widely reported in autistic patients and mouse models with dysfunction of ASD risk genes, but the underlying mechanisms are not fully understood. Here, we report that deletion of Trio, a high-susceptibility gene of ASDs, causes a postnatal dentate gyrus (DG) hypoplasia with a zigzagged suprapyramidal blade, and the Trio-deficient mice display autism-like behaviors. The impaired morphogenesis of DG is mainly caused by disturbing the postnatal distribution of postmitotic granule cells (GCs), which further results in a migration deficit of neural progenitors. Furthermore, we reveal that Trio plays different roles in various excitatory neural cells by spatial transcriptomic sequencing, especially the role of regulating the migration of postmitotic GCs. In summary, our findings provide evidence of cellular mechanisms that Trio is involved in postnatal DG morphogenesis.
Animals ; Dentate Gyrus/metabolism* ; Mice ; Morphogenesis/physiology* ; Neurons/pathology* ; Cell Movement ; Mice, Inbred C57BL ; Autism Spectrum Disorder/pathology* ; Mice, Knockout ; Neural Stem Cells ; Male ; Neurogenesis ; Autistic Disorder/genetics*

Accurate prediction of drug-target interactions (DTIs) plays a pivotal role in drug discovery, facilitating optimization of lead compounds, drug repurposing and elucidation of drug side effects. However, traditional DTI prediction methods are often limited by incomplete biological data and insufficient representation of protein features. In this study, we proposed KG-CNNDTI, a novel knowledge graph-enhanced framework for DTI prediction, which integrates heterogeneous biological information to improve model generalizability and predictive performance. The proposed model utilized protein embeddings derived from a biomedical knowledge graph via the Node2Vec algorithm, which were further enriched with contextualized sequence representations obtained from ProteinBERT. For compound representation, multiple molecular fingerprint schemes alongside the Uni-Mol pre-trained model were evaluated. The fused representations served as inputs to both classical machine learning models and a convolutional neural network-based predictor. Experimental evaluations across benchmark datasets demonstrated that KG-CNNDTI achieved superior performance compared to state-of-the-art methods, particularly in terms of Precision, Recall, F1-Score and area under the precision-recall curve (AUPR). Ablation analysis highlighted the substantial contribution of knowledge graph-derived features. Moreover, KG-CNNDTI was employed for virtual screening of natural products against Alzheimer's disease, resulting in 40 candidate compounds. 5 were supported by literature evidence, among which 3 were further validated in vitro assays.
Alzheimer Disease/drug therapy* ; Biological Products/therapeutic use* ; Humans ; Neural Networks, Computer ; Machine Learning ; Drug Discovery/methods* ; Algorithms ; Drug Evaluation, Preclinical/methods*

Objective To investigate the relationship of miRNA gene polymorphisms with blood pressure(BP)responses to the sodium and potassium diet intervention.Methods In 2004,we recruited 514 participants from 124 families in seven villages of Baoji,Shaanxi Province,China.All subjects were given a three-day normal diet,followed by a seven-day low-salt diet,a seven-day high-salt diet,and finally a seven-day high-salt and potassium supplementation.A total of 19 miRNA single nucleotide polymorphisms(SNPs)were selected for analysis.Results Throughout the sodium-potassium dietary intervention,the BP of the subjects fluctuated across all phases,showing a decrease during the low-salt period and an increase during the high-salt period,followed by a reduction in BP subsequent to potassium supplementation during the high-salt diet.MiR-210-3p SNP rs 12364149 was significantly associated with systolic BP(SBP),diastolic BP(DBP)and mean arterial pressure(MAP)responses to low-salt diet.MiR-4638-3p SNP rs6601178 was significantly associated with SBP while miR-26b-3p SNP rs115254818 was significantly associated with MAP responses to low-salt intervention.In addition,miR-26b-3p SNP rs115254818 was significantly correlated with SBP,DBP and MAP responses to high-salt intervention.MiR-1307-5p SNPs rs1 1191676 and rs2292807 were associated with SBP and MAP responses to high-salt diet.MiR-4638-3p SNP rs6601178,miR-210-3p SNP rs12364149,miR-382-5p SNP rs4906032 and rs4143957 were significantly associated with SBP response to high-salt diet.In addition,miR-26b-3p SNP rs115254818 was significantly associated with SBP,DBP and MAP responses to potassium supplementation.MiR-1307-5p SNPs rs11191676,rs2292807,and miR-19a-3p SNP rs4284505 were significantly associated with SBP responses to high-salt and potassium supplementation.Conclusion miRNA gene polymorphisms are associated with BP response to sodium and potassium,suggesting that miRNA genes may be involved in the pathophysiological process of salt sensitivity and potassium sensitivity.

Objective:To explore the related factors of non-suicidal self-injury behaviors among sexual and gender minorities.Methods:The database of CNKI,CBM,PubMed,Web of Science,Embase,PsycINFO and CI-NAHLwere retrieved.Software RevMan 5.3 was applied to perform Meta-analysis.Results:A total of 10 articles were included,with a total of 18 520 subjects.Seven factors were included in the meta-analysis.Among them,at-tempted suicide,depression,general victimization and victimization because of sexual and gender minority were riskfactors for non-suicidal self-injury behaviors among sexual and gender minorities(OR=6.50,3.67,1.50,1.48).Care of non-parent adult,parental contact and safe campus environment were protective factors for non-sui-cidal self-injury behaviors among sexual and gender minorities(OR=0.91,0.87,0.75).Conclusion:Sexual and gender minorities who are attempted suicide,with depression,with general victimization and with victimization be-cause of sexual and gender minority identity are more likely to bring about non-suicidal self-injury,and care of non-parent adult,parental contact and safe campus environment can reduce non-suicidal self-injury behaviors among sex-ual and gender minorities.

Objective:To systematically review the adverse events and relatedfactors ofmindfulness-based stress reduction therapy(MBSR)and mindfulness-based cognitive therapy(MBCT).Methods:By searching the randomized controlled trails of adverse events and adverse effects of MBSR and MBCT from PubMed,CINAHL,Embase,Web of Science,Scopus,Proquest,ScienceDirect,PsycINFO databases and unpublished studies and grey literature,and traces the references and related journals of the included studies.The databases were searched from inception to June 1,2022.Meta analysis was performed by using RevMan 5.4 softwareto calculate combined odds radio(OR)and 95％CI.Results:Fifteen literatures with a total of 2 841 subjects were included in the study.The results of meta-analysis showed that there were statistically significant differences in the incidence of adverse events or adverse reactions between theMBSR and MBCT group and the control group(OR=2.48,95％CI:1.09-1.61,P＜0.05).The mindfulness-based intervention methods(only MBSR,OR=9.04,95％CI:5.34-15.30),the un-derlying diseases of the participants(complicated with mental disorders,OR=1.49,95％CI:1.12-1.97;compli-cated with physical diseases,OR=8.65,95％CI:5.17-14.45),exercise intensity(once a week for 8 weeks,each time more than 2 hours,OR=1.43,95％CI:1.04-1.96)and the level of mindfulness therapists(did not underg-one standardized training,OR=1.96,95％CI:1.20-3.23)were factors that may affect the occurrence of adverse events or adverse reactions in the process of MBSR and MBCT.Conclusion:During the MBSR and MBCT thera-py,there may be occur adverse events or adverse effects.

Objective:To systematically evaluate the effectiveness and feasibility of aerobic exercise intervention in schizophrenia patients.Methods:Randomized controlled trials on exercise interventions for patients with schizophrenia were searched in eight databases from built up to March 2023, including China National Knowledge Infrastructure (CNKI), VIP Database for Chinese Technical Periodicals (VIP), WanFang Data, China Biomedical Literature Database, PubMed, Cochrane Library, EMBASE and Web of Science. The positive and negative symptom scale (PANSS) and its sub-scales were used as primary outcome indicators, and the negative symptom scale (SANS) and body mass index (BMI) were used as secondary indicators, and Meta-analysis was performed using R 4.1.0 and Stata 14.0.Results:Forty-seven studies including 3 139 patients with schizophrenia were included. Results of a network Meta-analysis based on 24 studies showed that aerobic exercise may be the most effective measure for reducing total PANSS scores in patients with schizophrenia. Compared to conventional treatment, combining aerobic exercise intervention improved patients' PANSS total score (MD= -5.09, 95% CI: -5.90~-4.28), SANS (MD= -12.17, 95% CI: -14.25~-10.10), and BMI (MD=-1.59, 95% CI: -1.93~-1.25). Meanwhile, subgroup analysis showed that 2 months of intervention was more appropriate (MD=-6.12, 95% CI: -7.22~-5.02) and the weekly total exercise time for 140-260 min was more appropriate (MD=-8.59, 95% CI: -12.93~-4.25) in terms of total PANSS score. The adherence rates between the trial and control groups showed no significant difference between the aerobic exercise intervention combined with conventional treatment and conventional treatment alone( P>0.05). Conclusion:Aerobic exercise intervention is an effective measure to relieve the symptoms of schizophrenia patients and has good compliance among inpatients.

Objective To construct a domain knowledge graph of dementia care,so as to provide the foundation and guarantee for the next intelligent application based on the knowledge graph.Methods A top-down approach was adopted to construct a domain knowledge graph of dementia care.Firstly,the ontology concept is constructed from the top level,namely the schema layer of knowledge graph.Then,instances are filled,and knowledge extraction is carried out from the existing data sources,and the extracted entities and relationships are filled into the pattern layer ontology database to complete the data layer construction of the knowledge graph.Finally,the"entity relationship entity"triplet data was input into the Neo4j graph database for storage.Results In this study,the personalized care plan set of 1 012 dementia cases was used as the corpus to construct a domain knowledge graph of dementia care.The knowledge graph takes people with dementia as the core,and unfolds,one by one,around basic characteristics,care problems,and care plans in a standardized"entity-relationship-entity"triplet format,forming a large knowledge network,which contains a total of 1 522 specific dementia care knowledge entities and 8 kinds of inter-entity relationships.Conclusion The domain knowledge graph of dementia care constructed in this study clearly and intuitively shows the global pedigree and logical path of knowledge,which provides an efficient and intelligent basic guarantee for the browsing,retrieval and application of dementia care knowledge,so as to realize personalized and intelligent management of people with dementia,break through the bottleneck of lack of professionals,improve the health outcomes of people with dementia,promote the implementation of inclusive pension services,and promote healthy aging.

Objective To study the invasive histopathological features of papillary thyroid carcinoma(PTC)with tall cell variant(TCV).Methods A retrospective analysis of 19 170 cases of PTC in Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from January 2018 to May 2023 was performed to analyze and the clinicopathological features between TCV-PTC group and classic PTC(cPTC)group.Results Pathological results showed 1 380 cases in TCV-PTC group and 15 578 cases in cPTC group.TCV-PTC had higher proportion and(or)mean value in patients'age,extraglandular invasion,nerve invasion,vascular invasion,maximum diameter of cancer focus,multifocality,lymph node metastasis and BRAF mutation,but the proportion of patients with coexistent Hashimoto's thyroiditis was lower than cPTC,and all results had significant difference(P<0.05).Conclusions Compared with the cPTC,TCV-PTC has stronger local invasive characteristics and lymph node metastasis rate,which provides the basis for the subsequent clinical treatment.