Interfering hepatitis B virus (HBV) capsid assembly holds promise as a therapeutic approach for chronic hepatitis B (CHB). Novel anti-HBV agents are urgently needed to overcome drug resistance challenges, with targeted protein degradation (TPD) emerging as a hopeful strategy. Herein, we report the first degradation of HBV core protein (HBC), a multifunctional structural protein, using small-molecule degraders developed by hydrophobic tagging (HyT) technology. Structure-activity relationship (SAR) analysis identified compound HyT-S7, featuring an adamantyl group, exhibiting potent inhibitory activity (EC₅₀ = 0.46 μmol/L, HepAD38 cells) and degradation ability (DC₅₀ = 3.02 ± 0.54 μmol/L) in a dose- and time-dependent manner. Mechanistic studies demonstrated that the autophagy-lysosome pathway was a potential driver of HyT-S7-induced HBC degradation. Remarkably, HyT-S7 effectively degraded 11 drug-resistant mutants, including highly resistant strains P25G and T33N, to Phase III drug GLS4. Furthermore, cellular thermal shift assay, surface plasmon resonance assay, and molecular dynamics simulations revealed the precise mode of HyT-S7 binding to HBC with the adamantyl group potentially mimicking protein misfolding to facilitate HBC degradation. This first proof-of-concept study highlights the potential of HyT-mediated TPD in HBC as a promising avenue for discovering novel HBV and other antiviral agents with favorable drug resistance profiles.

Objective:Laboratory evaluation of the relationship between cerebrospinal fluid and plasma indicators and intrathecal immunoglobulin G(IgG) synthesis in patients with neurological diseases, and establishment of a new diagnostic method for intrathecal IgG synthesis.Methods:This study retrospectively analyzed the content of IgG in cerebrospinal fluid samples and blood albumin in blood samples, and other test results of 410 patients with neurological diseases who visited Beijing Tiantan Hospital from 2019 to 2022. According to the results of oligoclonal bands in cerebrospinal fluid, patients were divided into intrathecal IgG synthesis group and non-intrathecal IgG synthesis group. The Mann Whitney U test was used for inter group comparison, and a bilateral test with P<0.05 indicates a statistically significant difference. Include indicators with differences between groups in logistic regression analysis, construct a predictive model, and compare it with the established quantitative formula IgG index. Results:There were significant differences in 10 indicators, including cerebrospinal fluid leukocyte count and 24-hour intrathecal IgG synthesis rate, between the intrathecal IgG synthesis group and the non-intrathecal IgG synthesis group, with P<0.05. The area under the curve (AUC) of intrathecal IgG synthesis was higher than the IgG index (AUC=0.920, 0.809, Z=31.178, P<0.001), the sensitivity was higher than the IgG index (0.825, 0.618), and the specificity was lower than the IgG index (0.876, 0.908). Conclusion:The combination of 10 indicators such as cerebrospinal fluid white blood cell count and 24-hour intrathecal IgG synthesis rate can improve the diagnostic efficacy and sensitivity of intrathecal IgG synthesis.

Purpose To investigate the clinical,imaging,pathological,and genetic characteristics of neuroepithelial tumors with EWSR1 translocation.Methods The clinicopatho-logical data of 6 patients with EWSR1 translocation in neuroepi-thelial tumors were collected,routine HE and immunohistochem-ical staining were performed,the information of high-throughput sequencing was summarized,and the relevant literature was re-viewed.Results The median age of the 6 patients was 11.5 years(ranging from 1.9 to 17 years),including 1 male and 5 females.The tumors located in temporal lobe,frontal lobe,pari-etal lobe,suprasellar region,or lateral ventricle.The clinical manifestations mainly started with seizures.Brain MRI showed abnormal signal focus in the cerebral hemisphere near the cortex in 4 cases,and ventricle/periventricular regions in 2 cases,with an almost clear boundary in 5 cases.Microscopically,the histo-logical changes were diverse,including low-grade gliomas/gli-oneuronal tumors in 3 cases,high-grade gliomas in 2 cases,and glioneuronal tumor with high-grade feature in 1 case.Immuno-histochemically,tumor cells expressed GFAP,S-100,Syn,and Olig2 partially.2 cases exhibited slightly positive of NeuN and 1 case exhibited little dot-like staining of EMA.Next generation sequencing revealed EWSR1 rearrangement in all 6 cases,with chaperone genes including PATZ1 in 5 cases,and PLAGL1 in 1 case.3 cases were treated with chemotherapy after surgery,and no recurrence or progression was found during follow-up.Con-clusion The neuroepithelial tumors with the fusion of EWSR1 and non-ETS commonly occur in the cerebral hemisphere of teenagers and children.Most of the boundaries lesion are still clear,the histomorphological spectrum is diverse,and the bio-logical behavior is presented as a low to moderate malignancy,which provides the possibility for expanding the molecular classi-fication of CNS neuroepithelial tumor.

Objective To explore the value of quantitative chest CT in early diagnosis of chronic obstructive pulmonary disease(COPD).Methods The clinical data of 138 cases of COPD high-risk patients in Shanghai community and COPD high-risk respondents in outpatient clinic of Zhongshan Hospital,Fudan University from September 20,2013 to May 20,2014 were retrospectively analyzed.All high-risk participants underwent pulmonary function and chest CT examination at baseline and 1 year later.Chest CT images were imported into quantitative CT analysis software to collect quantitative CT data.These participants were divided into COPD group(n=40)and non-COPD group(n=98)based on their lung functions after 1 year.The differences in baseline lung function and quantitative CT measurements between the two groups were compared.Binary logistic regression was used to analyze the predictors of COPD in high-risk individuals after 1 year of follow-up,and the efficacy of the logistic regression model was evaluated by ROC curve.Results There were no significant differences in gender,body mass index(BMI),the percentage value of forced expiratory volume in 1 second predicted(FEV1%pred),airway wall area ratio(WA%),total airway count(TAC),and airway wall thickness(WT)between the two groups at baseline.Compared to the non-COPD group,the square root of the tracheal wall area at 10 mm from the inner circumference of the airway(Pi10),(3.43[3.30,3.54]vs 3.23[3.15,3.36],P＜0.001),and the percentage area of low attenuation regions below ﹣950 HU(LAA%﹣950),(2.06[0.32,6.29]vs 0.57[0.25,1.89],P=0.015)were significantly higher in the COPD group.The mean lung density(MLD)in the COPD group was lower than that in the non-COPD group([﹣799.89±35.62]vs[﹣783.60±43.52],P=0.038).Binary logistic regression analysis indicated that age and Pi10 were risk factors for COPD(P＜0.05),with an area under the ROC curve of 0.791(95%CI 0.714-0.868).Conclusions In the COPD high-risk population with normal lung function,patients with elevated Pi10 and LAA%﹣950 have a higher incidence of COPD one year later,suggesting that quantitative chest CT measurements such as Pi10 and LAA%﹣950 can assist clinicians in identifying early-stage COPD.

Objective To study on the traits,micro-traits and microscopic identification characteristics of common cyrtomium Chinese medicines,including Dryopteridis Crassirhizomatis Rhizoma,Osmundae Rhizoma which were recorded in 2020 edition of Chinese Pharmacopoeia and their three chaotic breeds(Woodwardia unigemmata(Makino)Nakai,Woodwardia japonica(L.F.)Smith and Matteuccia struthiopteris(L.)Todaro,providing a reference for the identification and reference of cyrtomium Chinese medicine.Methods Morphological and micro-character identification methods were used in the character identification,and the normal bright field and polarized dark field contrast observation methods were used in the microscopic identification of cross-sections,combined with extended depth of field imaging and large image stitching techniques,to obtain holographic color images and local feature high definition image.The Chiral labeling methods were used to identified the images.Results The image data of the characters,micro-characters and the normal light and polarized light holographic color image data of cross-section of common cyrtomium herbs and its chaotic varieties were obtained at the first time.The main identification feature retrieval tables and correlation tables of medicinal materials,traits,micro traits and microscopic characters were made.Conclusion Common cyrtomium herbs and its three chaotic varieties can be identified by using characters,micro-characters and microscopic identification comprehensively,especially the microscopic character under polarized light of the cross-section,which has obvious identification significance.

Objective To explore the effect of intermittent fasting on blood glucose control in patients with type 2 diabetes mellitus(T2DM)complicated by overweight and obesity.Methods 46 T2DM patients with overweight and obesity were divided into control group(Con,n=22)and intermittent fasting group(IF,n=24)according to their wishes.Con group was given routine diet and drug treatment by specialists in endocrinology.IF group completed the intermittent fasting by using a combination of meal replacement and natural diet,and hypoglycemic drugs were reduced on fasting days.Results Compared with Con group,IF group showed a significant decrease in body weight,BMI,hypoglycemic drug efficacy score,WC,fat index,hip circumference and visceral fat(VF)(P＜0.05).After intervention,the proportion of diabetes in remission or near remission in IF group was higher than that in Con group(P＜0.05).Conclusion Intermittent fasting can reduce the application of hypoglycemic drugs in T2DM patients with overweight and obesity,and can also reduce weight and VF.

Objective: To demonstrate the effects of symbiotic bacteria from lettuce on inactivation of norovirus（NV）. Methods: Symbiotic bacteria were isolated from the lettuces sampled from farmlands and supermarkets. NV mixed with symbiotic bacteria was set as the experimental group,without symbiotic bacteria as the control group. After the inactivation by high temperature,ultraviolet light（UV）and chlorine dioxide,the ratio of NV amount in the experimental group and the control group was calculated to evaluate the effects of symbiotic bacteria. The mechanism of symbiotic bacteria was revealed by detecting their effects on the protection of viral capsid protein from UV and on the adsorption of NV. Results: Eleven symbiotic bacteria were identified from lettuces,all of which were bacilli,mainly Pseudomonas. Ten symbiotic bacteria could improve the heat-resistant ability of NV,with Microbacterium oryzae,Cupriavidus taiwanensis（SC061204）,Pseudomonas furukawaii,Enterobacter tabaci and Pseudomonas resinovorans（SC061211）more significant. Eleven symbiotic bacteria could improve anti-UV ability of NV,with Pseudomonas putida,Microbacterium oryzae and Enterobacter tabaci more significant. Only one strain of Pseudomonas putida could improve anti-chlorine dioxide ability of NV（Class I hazard）. Pseudomonas putida,Microbacterium oryzae and Enterobacter tabaci could significantly reduce the damage of NV capsid protein. Nine symbiotic bacteria could promote NV adsorption into lettuces,with the promotion rates ranged from 1.04% to 46.73%;while Pseudomonas putida and Pseudomonas resinovorans（SC061211） could restrain NV absorption,with the promotion rates of -6.50% and -19.85%. Conclusion Symbiotic bacteria from lettuce may enhance the anti-inactivation of NV by protecting capsid protein and promoting adsorption of NV. It is recommended to control the presence of symbiotic bacteria in the process of inactivating NV.

Objective To establish a clinical cytokine test method based on flow multiple microarray technology,and discuss its clinical significance by observing the change of cytokines level in the early stage of influenza.Methods 54 cases of influenza A virus positive and 20 cases of influenza A virus negative influenza like patients were selected as influenza group.Among them,influenza A virus positive patients were divided into mild group and severe group,influenza A virus negative influenza like patients were as neg-ative group.In addition,35 healthy people were selected as the control group,and the cytokine of all the whole blood samples was detected and statistically analyzed.Results Interleukin-6(IL-6),interleukin-21(IL-21),interleukin-12p70(IL-12p70),interleukin-1 β(IL-1 β)and interleukin-10(IL-10),chemokine-10(IP-10),interleukin-2(IL-2),monocyte chemoattractant protein-1(MCP-1)lev-els were significantly higher in the patients with early onset of influenza,and the difference was statistically significant(P<0.05). The difference of interferon-γ(IFN-γ)between the influenza group and the control group was not statistically significant(P> 0. 05).The levels of IL-6 and IP-10 in the severe group were higher than that of the mild group and the negative group,and the differ-ence was statistically significant(P<0.05).Conclusion IL-6,IL-21,IL-12p70,IL-1 beta,IL-10,IP-10,IL-2 and MCP-1 levels can be used as clinical biological evaluation indicators of patients with fever,of which IL-6 and IP-10 can be used as important indicators for disease progression assessment.

Objective To study the effect of clopidogrel on different CYP2C19 genotypes and platelet reactivity in acute cerebral infarction patients with antiplatelet aggregation.Methods Four hundred and seventy-four cases of cerebral infarction patients in Beijing Tiantan Hospital Affiliated to Capital Medical University from April 2015 to April 2016 were collected.CYP2C19 genotype was determined,and the genotype was divided into the wild type group,the heterozygous type group and the mutant homozygous group.Platelet aggregation inhibition rate(ADP%) and platelet reactivity index induced by ADP were detected.Patients were divided into clopidogrel resistance group(group CR) and non resistant group according to whether ADP% was less than 30.SPSS 16.0 statistical software was used for statistical analysis,the comparison between groups using independent samples t test,chi square test and multivariate analysis using Logistic regression analysis,when P<0.05 difference was statistically significant.Results Among the 474 patients,204 cases(43.04%) were divided into wild-type group,and 204(43.04%) and 66(13.92%) were divided into the mutant heterozygous group and mutant homozygous group.In Chi square test analysis,clopidogrel resistance group and non resistance group CYP2C19 genotype distribution was significantly different(χ2=6.658,P=0.036).CR group angle(α) values((68.87±5.47)°) and MA((66.77±6.25) mm) were higher than that of CS group ((66.55±6.05)° and (63.30±5.66) mm,t=2.199,3.387,P=0.029,0.001).The multivariate logistic regression analysis showed that OR of angle level was 1.028,95%CI was 0.929-1.137 (P=0.595);OR of Ma level was 1.561,95%CI was 0.785-0.970 (P=0.012).Conclusion The effect of clopidogrel on platelet aggregation in patients with acute cerebral infarction is decreased by CYP2C19 gene mutation.CYP2C19 mutant allele is a risk factor for clopidogrel resistance.Angle (α) value and MA value are the risk factors for the diagnosis of CR in the patients with acute cerebral infarction,and the risk of clopidogrel resistance increased when the patients′ Angle (α) value and the value of MA increased.MA value as a predictor of CR and the screening tool has a certain value.

Objective To investigate the relationship between changes of ankle brachial index (ABI) and adverse cardiovascular events. Methods Baseline survey was conducted in 4 160 forty-year-old or older citizens living in Yunyan District of Guiyang City from May to August of 2011, which was in the way of cluster sampling to obtain their ABI and to collect information related to physical and blood biochemical examination and disease history. These citizens were conducted a follow-up survey for (39.29±1.47) months from July to December of 2014. Based on the change of ABI (ΔABI) from initial survey to follow-up survey, participants were subsequently divided into three groups: ΔABI>0.15 group,-0.15≤ΔABI≤0.15 group and ΔABI<-0.15 group. The adverse cardiovascular events during follow-up survey were compared between three groups. The risk factors affecting the adverse cardiovascular events were analyzed. Results Follow-up surveys were completed in 3 220 citizens in 3 years. The follow-up rate was 77.4%. Eighty-two new cases (2.5%) of adverse cardiovascular events were found in 3 220 cases in follow-up. The incidence rates of adverse cardiovascular events were higher inΔABI<-0.15 group compared with those of-0.15≤ΔABI≤0.15 group (8.3%vs. 2.4%, P<0.016 7). Logistic regression analysis indicated that age, hypertension history, and ΔABI<-0.15 were risk factors for adverse cardiovascular events. Exercise was the protective factor for adverse cardiovascular events. Conclusion Subjects withΔABI<-0.15 are at high risk for adverse cardiovascular events. The ΔABI can be used as a means of monitoring of adverse cardiovascular event, which provides certain forecast value for determining the possibility of adverse cardiovascular event.