OBJECTIVE To investigate the ameliorative effect and mechanism of short-acting exenatide on diabetic cognitive dysfunction. METHODS Spontaneously diabetic db / db mice were randomly divided into model group （normal saline） and exenatide group （50 μg/kg）， with db / m mice as the normal control group （normal saline）， with 8 mice in each group. Mice in each group were subcutaneously injected with corresponding drugs or normal saline twice daily for 8 consecutive weeks. Body weight and fasting blood glucose were measured at a fixed time every week. Cognitive function was evaluated by Morris water maze test. The levels of oxidative st ress indicators [malondialdehyde （MDA）， superoxide dismutase （SOD）， glutathione （GSH） ] ， cyclic adenosine monophosphate （cAMP） and protein kinase A （PKA） were detected in hippocampus tissue of mice. The hippocampal neuronal HT22 cells of mice were divided into control group （25 mmol/L glucose）， high glucose group （125 mmol/L glucose）， high glucose+exenatide group （125 mmol/L glucose+20 nmol/L exenatide）， high glucose+exenatide+H89 （PKA inhibitor） group （125 mmol/L glucose+20 nmol/L exenatide+10 μmol/L H89）， and high glucose+H89 group （125 mmol/L glucose+10 μmol/L H89）. After 48 h of intervention with corresponding solutions/culture medium， the levels of oxidative stress indicators， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and the phosphorylation level of dynamin-related protein 1 （Drp1） were measured. RESULTS Animal experiments showed that compared with the normal control group， the model group exhibited significantly increased body weight， fasting blood glucose and MDA level in the hippocampus （ P ＜0.05）， as well as significantly prolonged escape latency （ P ＜0.05）； swimming speed significantly slowed down， the time spent in the target quadrant， the number of platform crossings， and the levels of SOD， GSH， cAMP and PKA in the hippocampus were significantly decreased （ P ＜0.05）. Compared with model group， all the above indicators （except for swimming speed） in the exenatide group were significantly reversed （ P ＜0.05）. Cell experiments showed that compared with high glucose group， the high glucose+exenatide group had significantly decreased MDA level （ P ＜0.05）， and significantly increased levels of SOD， GSH， cAMP and PKA， the activities of mitochondrial respiratory enzymes Ⅱ and Ⅳ， and phosphorylation level of Drp1 （ P ＜0.05）. Compared with high glucose+exenatide group， the above indicators in the high glucose+exenatide+H89 group were significantly reversed （ P ＜0.05）. CONCLUSIONS Short-acting exenatide can activate the cAMP/PKA pathway， promote Drp1 phosphorylation， and increase the activities of mitochondrial respiratory enzymes， thereby maintaining mitochondrial stability， reducing oxidative stress injury， and ultimately improving diabetic cognitive dysfunction.

ObjectiveMigraine is a leading neurological disorder and the fourth most common cause of years lived with disability worldwide, affecting nearly 116 million individuals. Although pharmacological treatments are available, their efficacy is often limited by side effects and variable response rates. Repetitive transcranial magnetic stimulation (rTMS) over the dorsolateral prefrontal cortex (DLPFC) offers a safe, non-invasive alternative for migraine management. However, the neurophysiological mechanisms, particularly how rTMS modulates local cortical excitability and distributed pain-related circuits, remain poorly understood. Elucidating these mechanisms is essential for optimizing treatment protocols and improving clinical outcomes. MethodsThis study employed concurrent transcranial magnetic stimulation and electroencephalography (TMS-EEG) to investigate neuroplastic and neurocircuitry mechanisms of DLPFC-rTMS in migraine. Study 1 compared 30 migraineurs and 28 healthy controls to identify abnormalities in TMS-evoked potentials (TEPs) and significant current density (SCD) within sensory-discriminative regions including the primary somatosensory cortex (S1) and posterior insula (pINS), cognitive-affective regions including the anterior insula (aINS) and midcingulate cortex (MCC), and a descending modulatory region, the periaqueductal gray (PAG). Study 2 used a single-blind, crossover, sham-controlled design in 34 healthy participants. Each participant received both active (10 Hz, 80% RMT, 1 500 pulses) and sham DLPFC-rTMS in counterbalanced order. TMS-EEG and cold pain tolerance were assessed before and after each session. ResultsIn Study 1, migraineurs showed a significantly less negative N120 amplitude compared to healthy controls (P=0.027, Cohen’s d=0.60), indicating local intracortical disinhibition. No group differences were observed for N40, P60, or P180 components. At the source level, migraineurs exhibited significantly higher SCD in the S1, pINS, aINS, and MCC (allQ<0.05), but not in the ventroposterior thalamus (vpTHAL), mediodorsal thalamus (mdTHAL), or PAG. In Study 2, active rTMS significantly reduced SCD from pre- to post-stimulation in the S1, aINS, and MCC (all Q<0.05). Sham stimulation also reduced SCD in the S1 (Q<0.05) but not in the aINS or MCC. Although no significant group-level analgesic effect was observed between active and sham conditions (P=0.107), correlation analyses revealed that greater SCD reductions in the S1 and MCC were significantly associated with higher post-rTMS pain tolerance (R=-0.487 and -0.495, both Q<0.01) and larger improvements in pain tolerance(R=-0.487 and -0.451, both Q<0.05). No such correlations were found following sham stimulation, suggesting that the behavioural relevance of neural changes is specific to active rTMS. ConclusionThis study provides novel evidence that migraineurs exhibit both local neuroplastic abnormalities (reduced N120 amplitude) and hyperactivity in key pain-processing regions (S1, pINS, aINS, MCC). A single session of DLPFC-rTMS reduced hyperactivity in the aINS, MCC, and S1. Notably, greater reductions in the S1 and MCC were associated with improved pain tolerance. These findings identify distinct cortical circuitries, particularly within the cognitive-affective pain network, that may serve as potential biomarkers for optimizing rTMS treatment in migraine and other chronic pain conditions. Future studies should validate these results in patient populations experiencing spontaneous migraine attacks and explore multi-session or accelerated rTMS protocols.

Objective:To explore the effect of Chaibei Zhixian Decoction on intestinal flora and T helper 17/regulatory T cell(Th17/Treg)immune balance in epileptic rats by regulating mammalian target of rapamycin/hypoxia-inducible factor-1α(mTOR/HIF-1α)pathway.Methods:Sixty rats were randomly divided into Sham group,Model group,low-dose Chaibei Zhixian Decoction group(CBZXD-Low)and high-dose Chaibei Zhixian Decoction group(CBZXD-High),with 15 rats in each group.Lateral ventricular injec-tion 1 μl kainic acid(1.5 μg/μl)was used to prepare epileptic rat model,Sham group was injected with an equal amount of physiological saline.CBZXD-Low group and CBZXD-High group were given Chaibei Zhixian Decoction by gavage daily(8.48 g/kg,16.96 g/kg),while Sham group and model group were given an equal amount of physiological saline by gavage.After continuous gavage for 4 weeks,HE staining and Nissl staining were used to detect pathological damage in hippocampal tissue;RT-qPCR was used to detect Th17/Treg related marker mRNA levels in spleen tissue and mTOR,HIF-1α mRNA levels in hippocampus tissue;flow cytometry was used to de-tect Th17/Treg cell ratio in spleen tissue;16S rRNA sequencing of feces in colon segment was performed;Western blot was used to de-tect mTOR and HIF-1α protein levels in hippocampal tissue.Results:Compared with Sham group,Model group rats suffered from spontaneous epilepsy,the arrangement of hippocampal neurons was disordered and severely lacking,intracellular Nissl bodies was de-creased,RORγt,IL-17A mRNA levels in spleen tissue were increased,Foxp3,CTLA-4 and GITR mRNA levels were decreased,the proportion of Th17 cells and Th17/Treg were increased,the proportion of Treg cell was decreased,intestinal flora α/β diversity were decreased,the proportion of harmful bacteria such as Cronobacter and Heliobacillus were increased,the proportion of beneficial bacte-ria such as Bacteroides,Lactobacillus,Prevotella and Akkermansia were decreased;mTOR and HIF-1α mRNA levels,p-mTOR/mTOR,HIF-1α protein levelsin hippocampal tissue were increased(P<0.05);compared with Model group,the seizures of rats in CBZXD-Low group and CBZXD-High group were significantly reduced,and the damage to hippocampal neurons was alleviated,RORγt,IL-17A mRNA levels in spleen tissue were decreased,Foxp3,CTLA-4 and GITR mRNA levels were increased,the propor-tion of Th17 cells and Th17/Treg were decreased,the proportion of Treg cell was increased,intestinal flora α/β diversity were in-creased,the proportion of harmful bacteria such as Cronobacter and Heliobacillus were decreased,the proportion of beneficial bacte-ria,such as Bacteroides,Lactobacillus,Prevotella,and Akkermansia were increased;mTOR and HIF-1α mRNA levels,p-mTOR/mTOR,HIF-1α protein levels in hippocampal tissue were decreased(P<0.05);and it showed a dose-dependent effect of Chaibei Zhixian Decoction(P<0.05).Conclusion:Chaibei Zhixian Decoction can restore intestinal flora and Th17/Treg cell immune balance in epileptic rats,it possibly plays a role by regulating mTOR/HIF-1α pathway.

Glycoengineering was carried out in the mammalian cell line CHO for the production of pro-tein-based drugs.Firstly,the genome sequence of the Rosa26 locus of CHO cells was determined,the gRNA sequences were designed,and the landing pad was integrated into the Rosa26 locus of CHO cells by CRISPR/Cas9 technology.Three targeting vectors co-expressed by glycosyltransferases,which are β-1,4 galactosyltransferase(B4GALT1),α-2,6-sialyltransferase 1(ST6GAL1)and N-acetaminoglycosyl-transferase Ⅲ(GnT Ⅲ),were constructed by overlapping PCR and seamless ligation technology,and the three glycosyltransferase genes were integrated into the CHO Rosa26 locus by Cre enzyme-mediated cassette exchange technology.PCR confirmed that three glycosyltransferases had been successfully site-directed integrated into the Rosa26 site.The mRNA expression levels of the three glycosyltransferases were more than 50 000-fold by qRT-PCR,and the protein expression levels of the three glycosyltrans-ferases were more than 4-fold via western blotting(P＜0.001).A CHO-engineered cell line with three glycosyltransferases integrated into Rosa26 site was successfully constructed.

With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.

Glycoengineering was carried out in the mammalian cell line CHO for the production of pro-tein-based drugs.Firstly,the genome sequence of the Rosa26 locus of CHO cells was determined,the gRNA sequences were designed,and the landing pad was integrated into the Rosa26 locus of CHO cells by CRISPR/Cas9 technology.Three targeting vectors co-expressed by glycosyltransferases,which are β-1,4 galactosyltransferase(B4GALT1),α-2,6-sialyltransferase 1(ST6GAL1)and N-acetaminoglycosyl-transferase Ⅲ(GnT Ⅲ),were constructed by overlapping PCR and seamless ligation technology,and the three glycosyltransferase genes were integrated into the CHO Rosa26 locus by Cre enzyme-mediated cassette exchange technology.PCR confirmed that three glycosyltransferases had been successfully site-directed integrated into the Rosa26 site.The mRNA expression levels of the three glycosyltransferases were more than 50 000-fold by qRT-PCR,and the protein expression levels of the three glycosyltrans-ferases were more than 4-fold via western blotting(P＜0.001).A CHO-engineered cell line with three glycosyltransferases integrated into Rosa26 site was successfully constructed.

With the rapid development of generative artificial intelligence(GAI)technologies,their widespread application in academic research and writing is continuously expanding the boundaries of sci-entific inquiry.However,this trend has also raised a series of ethical and regulatory challenges,inclu-ding issues related to authorship,content authenticity,citation accuracy,and accountability.In light of the growing involvement of AI in generating academic content,establishing an open,controllable,and trustworthy ethical governance framework has become a key task for safeguarding research integrity and maintaining trust within the academic community.This expert consensus outlines ethical requirements across key stages of AI-assisted academic writing-including topic selection,data management,citation practices,and authorship attribution.It aims to clarify the boundaries and ethical obligations surrounding AI use in academic writing,ensuring that technological tools enhance efficiency without compromising in-tegrity.The goal is to provide guidance and institutional support for building a responsible and sustainable research ecosystem.

Objective To investigate the clinical characteristics of patients with clinical and subclinical Cushing's syndrome caused by primary bilateral macronodular adrenal hyperplasia(PBMAH).Methods A retrospective analysis was performed on the clinical data of 198 patients with Cushing's syndrome caused by PBMAH diagnosed in the First Medical Center of Chinese PLA General Hospital from January 2004 to October 2024.According to clinical manifestations,the patients were classified into clinical type Cushing's syndrome(n=61)and subclinical type Cushing's syndrome(n=137),and the clinical characteristics of the two types were compared.Results The mean age at diagnosis of patients with PBMAH-induced Cushing's syndrome was(53.5±10.4)years,including 118 males and 80 females,with a male-to-female ratio of 1.475:1.Compared with the subclinical type,the clinical type had a higher proportion of females,higher levels of serum cortisol,24-hour urine free cortisol(24 h UFC),and inhibited serum cortisol after low-dose dexamethasone suppression.Additionally,the clinical type had lower plasma ACTH,larger adrenal nodules and a higher risk of surgery(P<0.05)compared with those in subclinical type.The incidences of hypertension,dyslipidemia,obesity,diabetes mellitus,hypokalemia,vitamin D deficiency,osteoporosis,coronary heart disease,and cerebrovascular disease in patients with Cushing's syndrome caused by PBMAH were 87.9%,50.5%,37.1%,36.9%,27.8%,25.9%,18.7%,18.7%and 12.1%,respectively.Among them,compared with subclinical type patients,clinical type patients had higher incidence of hypokalaemia,vitamin D deficiency and osteoporosis(P<0.05),while there were no statistically significant differences in the incidences of other comorbidities between the two types(P>0.05).The results of postoperative follow-up for PBMAH patients showed that the short-term biochemical remission rate of unilateral total adrenalectomy was 41.5%(22/53)and the long-term biochemical remission rate was 32.0%(8/25).The short-term biochemical remission rate of unilateral partial(or nodular)adrenalectomy was 52.9%(9/17),and the long-term biochemical remission rate was 14.3%(1/7).All patients who underwent unilateral total adrenalectomy plus contralateral partial resection developed adrenal insufficiency(3/3),and 1 patient(1/3)relapsed 3.4 years after surgery.Conclusion Clinical and subclinical types of Cushing's syndrome caused by PBMAH have their distinct clinical characteristics.Surgery is an effective treatment for PBMAH,but a certain proportion of patients fail to achieve biochemical remission after non-bilateral total adrenalectomy.

Objective To analyze the clinical characteristics,treatment,and prognosis of immune checkpoint inhibitor-related diabetes mellitus(ICI-DM).Methods The clinical characteristics,laboratory examinations,treatment regimens,and follow-up outcomes of 10 ICI-DM patients who were diagnosed and treated in the First Medical Center of Chinese PLA General Hospital between July 2019 and December 2024 were retrospectively analyzed.Relevant literatures were retrieved from domestic and foreign databases such as PubMed,CNKI,and VIP.The clinical characteristics of ICI-DM were summarized based on the literature results.Results All 10 patients were PD-1 inhibitor users,including 5 males and 5 females,with a median age of 54.5(51.3,64.0)years and a body mass index(BMI)of(22.0±2.15)kg/m2.Among them,9 cases(90.0%)were fulminant type 1 diabetes mellitus(FT1DM);9 cases(90.0%)had a severity of adverse events reaching grade 3-4 according to the Common Terminology Criteria for adverse events(CTCAE).The median time from PD-1 inhibitor treatment to the occurrence of the classic diabetes symptoms referred to as"three more and one less"(polyuria,polydipsia,polyphagia,and weight loss)in all patients was 145.5(110.5,204.8)days,and the medication duration was 6.0(4.3,7.8)cycles.The average blood glucose level of the 10 patients at the time of consultation was 25.3(10.0-41.4)mmol/L,and the glycated hemoglobin(HbA1c)level was 8.0%(6.6%-10.9%).Eight patients had fasting and 2-hour C-peptide levels<0.1 ng/ml(fasting C-peptide from<0.010 to 0.067 ng/ml,2-hour C-peptide from<0.010 to 0.077 ng/ml).Nine of the 10 patients were negative for diabetes autoantibodies,while 1 was not tested.All 10 patients were successfully treated with insulin and other therapies.During the follow-up after discharge,all patients still relied on insulin treatment,and no significant recovery of pancreatic islet β cell function was observed compared with that at discharge.Literature review revealed that ICI-DM was more common in PD-1 inhibitor users,with clinical mainly manifested as diabetic ketoacidosis(DKA)(65.4%)and diabetic ketosis(13.1%).Patients had severely impaired pancreatic islet function and required long-term insulin treatment,and some cases were complicated by thyroid or pituitary dysfunction.Conclusions ICI-DM typically presents as FT1DM,often manifesting with DKA or diabetic ketosis at onset.It is characterized by severe and irreversible loss of pancreatic islet function,necessitating lifelong insulin therapy.To enable early detection and prompt treatment,close monitoring of blood glucose is essential during ICI treatment.

Tauopathies, including Alzheimer's disease (AD), are a series of neurodegenerative diseases characterized by pathological accumulation of the microtubule-associated protein tau. Since the abnormal modification and deposition of tau in nerve cells are crucial for tauopathy etiology, methods for reducing tau levels, such as promoting tau degradation, may become effective strategies for disease treatment. Herein, we identified that sorafenib significantly reduced total tau and phosphorylated tau levels through screening FDA-approved drugs. We showed that sorafenib treatment attenuated cognitive deficits and tau pathologies in PS19 tauopathy model mice. Mechanistically, we found that sorafenib inhibited multiple kinases involved in tau phosphorylation and promoted autophagy. Importantly, we further demonstrated that sorafenib also promoted the expression of the E3 ubiquitin ligase FBXW7, which could bind tau and mediate tau degradation through the ubiquitin-proteasome pathway. Finally, we showed that FBXW7 expression decreased in the brains of AD patients and tauopathy model mice, and that overexpression of FBXW7 in the hippocampus attenuated cognitive deficits and tau pathologies in PS19 mice. These results suggest that sorafenib may be a promising treatment option for tauopathies by promoting tau degradation and reducing tau phosphorylation, and that targeting FBXW7 could also serve as an alternative therapeutic strategy for tauopathies.