Objective To clarify the expression and distribution of brain⁃derived neurotrophic factor (BDNF) in the cerebrum of plateau yaks and cattle, and to explore the relationship between BDNF function and the adaptability of altitude hypoxia. Methods Five yaks and five cattles were selected.The content and distribution of BDNF in frontal lobe, temporal lobe, parietal lobe, occipital lobe, cerebrum white matter and hippocampus of yak and cattle were analyzed by Real⁃time PCR, Western blotting and Immunohistochemistry. Results Real⁃time PCR result showed that BDNF mRNA expression in the cerebrum of yaks and cattles was highest in temporal cortex, followed by hippocampus, parietal cortex, occipital cortex and frontal cortex, and lowest in white matter. Western blotting results showed that the content of BDNF protein in the cerebrum of yaks was the highest in temporal cortex,followed by hippocampus. The content of BDNF protein in other tissues was parietal cortex, frontal cortex and cerebrum white matter, and the content of BDNF protein was the lowest in occipital cortex. The content of BDNF protein intlecerebrum of cattles was the highest in the temporal cortex, followed by the hippocampus. The content of BDNF protein in other tissues was parietal cortex, occipital cortex and frontal cortex in descending order, and the protein content in cerebrum white matter was the lowest. Immunohistochemical results showed that the positive expression of BDNF protein in the cerebrum of yaks and cattles was basically similar, mainly distributed in the granulosa cells and glial cells in the frontal cortex, temporal cortex, parietal cortex and occipital cortex, glial cells in cerebrum white matter, pyramidal cell layer and polyform cell layer in the hippocampus. There was the small amount of distribution in Martinotti cells and the molecular layer of hippocampus in the cerebral cortex. Conclusion BDNF mRNA and protein are distributed and expressed in different brain regions of yaks and cattles, but the expression level different, which is speculated to be closely related to the specific functions of different cerebrum regions. The expression level of the cerebrum of yak is higher than that of cattle except occipital cortex, suggesting that it is related to the altitude hypoxic environment. BDNF may play an important role in enhancing hypoxic tolerance and protecting internal environmental homeostasis in the process of animal adaptation to hypoxic environment.

Objective To evaluate the relationship between diabetic nephropathy(DN)and diabetic retinopathy(DR)in patients with type 2 diabetes mellitus(T2DM)based on imaging and clinical testing data.Methods Totally 600 T2DM patients who visited the First People's Hospital of Ziyang from March 2021 to December 2022 were included.The fundus photography and fundus fluorescein angiography were performed on all these patients and their age,gender,T2DM duration,cardiovascular diseases,cerebrovascular disease,hypertension,smoking history,drinking history,body mass in-dex,systolic blood pressure,diastolic blood pressure and other clinical data were collected.The levels of fasting blood glu-cose(FPG),triglyceride(TG),total cholesterol(TC),high-density lipoprotein cholesterol(HDL-C),low-density lipo-protein cholesterol(LDL-C),glycosylated hemoglobin(HbA1c),24 h urinary albumin(UAlb),urinary albumin to creati-nine ratio(ACR),serum creatinine(Scr)and blood urea nitrogen(BUN)were measured.Logistic regression was used to analyze the risk factors associated with DR.DR staging was performed according to fundus images,and the convolutional neural network(CNN)algorithm was used as an image analysis method to explore the correlation between DR and DN based on emission computed tomography(ECT)and clinical testing data.Results The average lesion area rates of DR and DN detected by the CNN in the non-DR,mild-non-proliferative DR(NPDR),moderate-NPDR,severe-NPDR and pro-liferative DR(PDR)groups were higher than those obtained by the traditional algorithm(TCM).As DR worsened,the Scr,BUN,24 h UAlb and ACR gradually increased.Besides,the incidence of DN in the non-DR,mild-NPDR,moderate-NPDR,severe-NPDR and PDR groups was 1.67％,8.83％,16.16％,22.16％and 30.83％,respectively.Logistic regression analysis showed that the duration of T2DM,smoking history,HbA1c,TC,TG,HDL-C,LDL-C,24 h UAlb,Scr,BUN,ACR and glomerular filtration rate(GFR)were independent risk factors for DR.Renal dynamic ECT analysis demonstrated that with the aggravation of DR,renal blood flow perfusion gradually decreased,resulting in diminished renal filtration.Conclusion The application of CCN in the early stage DR and DN image analysis of T2DM patients will improve the diag-nosis accuracy of DR and DN lesion area.The DN is worsening as the aggravation of DR.

The World Health Organization has declared that the outbreak of coronavirus disease 2019(COVID-19) is a global pandemic. As mutations occurred in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the global epidemic still needs further concern. Worryingly, the effectiveness and neutralizing activity of existing antibodies and vaccines against SARS-CoV-2 variants is declining. There is an urgent need to find an effective antiviral medication with broad-spectrum inhibitory effects on novel coronavirus mutant strains against the SARS-CoV-2 infection. Neutralizing antibodies play an important role in the prevention and treatment of COVID-19. The interaction of spike-receptor-binding domain (Spike-RBD) of SARS-CoV-2 and human angiotensin-converting enzyme 2 (ACE2) is the first and critical step of SARS-CoV-2 infection. Hence, the SARS-CoV-2 Spike-RBD is a hot target for neutralizing antibodies development. Evusheld, the combination of Tixagevimab and Cilgavimab monoclonal antibodies (mAbs) targeting Spike-RBD exhibits neutralizing activity against BA.2.12.1, BA.4 and BA.5, which could be used as pre-exposure prophylaxis against SARS-CoV-2 infection. The nucleocapsid (N) protein is a conservative and high-abundance structural protein of SARS-CoV-2. The nCoV396 monoclonal antibody, isolated from the blood of convalescent COVID-19 patients against the N protein of SARS-CoV-2. This mAb not only showed neutralizing activity but also inhibits hyperactivation of complement and lung injury induced by N protein. The mAb 3E8 targeting ACE2 showed broadly neutralizing activity against SARS-CoV-2 and D614G, B.1.1.7, B.1.351, B.1.617.1 and P.1 variants in vitro and in vivo, but did not impact the biological activity of ACE2. Compared with neutralizing antibodies, small molecule inhibitors have several advantages, such as broad-spectrum inhibitory effect, low cost, and simple administration methods. Several small-molecule inhibitors disrupt viral binding by targeting the ACE2 and N-terminal domain (NTD) of SARS-CoV-2 spike protein. Known drugs such as chloroquine and hydroxychloroquine could also block the infection of SARS-CoV-2 by interacting with residue Lys353 in the peptidase domain of ACE2. The transmembrane protease serine 2 (TMPRSS2) inhibitors Camostat mesylate and Proxalutamide inhibit infection by blocking TMPRSS2 mediates viral membrane fusion. The main protease inhibitor Paxlovid and RNA-dependent RNA polymerase inhibitor Azvudine have been approved for treatment of COVID-19 patients. This review summarizes the current research status of neutralizing antibodies and small molecule inhibitors and prospects for their application. We expect to provide more valuable information for further studies in this field.

Objective To evaluate tolerability,safety and pharmacokinetics of JS026 and JS026-JS016 single dose intravenous infusion in healthy adults.Methods This phase 1,randomized,double-blind,placebo-controlled,dose-escalation study totally included 48 participants:32 healthy subjects were enrolled in JS026 single intravenous infusion groups and 16 healthy subjects were enrolled in JS026-JS016 groups.JS026 was sequentially administered from low dose to high dose(30-1 000 mg),with intravenous infusion of JS026 or placebo in JS026 single-dose groups,and intravenous infusion of JS026-JS016 or placebo in the combination drug groups.Blood was collected according to the time point designed for trial.Serum concentrations of JS026 and JS016 were determined by enzyme linked immunosorbnent assay(ELISA),and pharmacokinetics parameters were calculated by WinNonlin 8.2.The power model method was used to evaluate the linear analysis of dose and drug exposure.Results 47 subjects completed trial and 1 subject lost to follow-up.After a single intravenous injection of JS026 of 30 mg,100 mg,300 mg,600 mg,and 1 000 mg,mean Cmax were(9.47±1.53),(33.20±4.95),(96.10±13.70),(177.00±22.20)and(353.00±56.70)μg·mL-1,respectively;mean AUC0-∞ were(4 225.00±607.00),(1.78 × 104±3 268.00),(5.83 × 104±1 038.00),(1.07 × 105±152.00),(1.66 × 105±327.00)μg·h·mL-1,respectively;mean t1/2 of JS026 were 563-709 h.The Cmax and AUC0-∞ of JS026 were basically similar alone or in combination with JS016.The results of Power model showed that Cmax and AUC0-∞ increased approximately linearly with the increasing dose of JS026.Treatment emergent adverse event was not increasing when dose increased and most of adverse event associated with drugs were abnormal on laboratory tests and haematuria,thus JS026 and JS016 was well tolerated in all groups.Conclusion The single intravenous infusion of JS026 can almost be thought to be a linear relationship between the doses and drug serum exposure.JS016 had no significant effect on serum concentration of JS026 and JS026 was well tolerated and safe in healthy subjects within 30-1 000 mg.

Objective By population survey,to explore the epidemiological characteristics of gastric precancerous lesions in Lishui District of Nanjing and provide objective basis for the prevention and treatment of early gastric cancer.Methods From July 2021 to December 2022,21 977 patients who received endoscopy and/or 13C-UBT in Lishui District People's Hospital and 6 medical community units in Nanjing City were retrospectively analyzed for demography characteristics,detection rate of gastric precancerous lesions,and H.Pylori infection rate.Results(1)590 cases of gastric precancerous lesions were detected(detection rate 2.68%);(2)The total detection rate of precancerous lesions and three pathological types in males were all higher than those in females(all P<0.001);(3)The minimum age for the total detection rate of precancerous lesions in males and the mini-mum age for each pathological type were lower than in females(P<0.001,0.009,0.005,0.002);(4)The popu-lation total H.pylori infection rate was 23.10%,the H.pylori infection rate in patients with precancerous lesions was higher than that in non-precancerous lesions(P<0.001),both H.pylori infection rate of male and female in precancerous lesions were all higher than those of non-precancerous lesions of the same sex(all P<0.001),in addition,the H.pylori infection rate of male whether in precancerous or non-precancerous lesions was higher than that of female(all P<0.001);(5)The precancerous lesions detection rate in male,female,and the overall age range of 20～29 to 70～79 years is positively correlated with age growth(P<0.001),and rapidly decreases after the age of 79,the of H.pylori infection rate was also positively correlated with age growth(P<0.001),and the trend of age change(P<0.001)was parallel to the precancerous lesions detection rate.Conclusions The detec-tion rate of gastric precancerous lesions in this region is above the average level in China;the total H.pylori infec-tion rate is at a relatively low level in China;the H.pylori infection rate is parallel to the age trend of the detection rate of gastric precancerous lesions,and increases with age.

Human brain banks use a standardized protocol to collect,process and store post-mortem human brains and related tissues,along with relevant clinical information,and to provide the tissue samples and data as a resource to foster neuroscience research according to a standardized operating protocols(SOP).Human brain bank serves as the foundation for neuroscience research and the diagnosis of neurological disorders,highlighting the crucial rule of ensuring the consistency of standardized quality for brain tissue samples.The first version of SOP in 2017 was published by the China Human Brain Bank Consortium.As members increases from different regions in China,a revised SOP was drafted by experts from the China Human Brain Bank Consortium to meet the growing demands for neuroscience research.The revised SOP places a strong emphasis on ethical standards,incorporates neuropathological evaluation of brain regions,and provides clarity on spinal cord sampling and pathological assessment.Notable enhancements in this updated version of the SOP include reinforced ethical guidelines,inclusion of matching controls in recruitment,and expansion of brain regions to be sampled for neuropathological evaluation.

As interstitial collagen,type Ⅲ collagen(Col Ⅲ)does not express in normal glomeruli.However,in Col Ⅲ nephropathy,a large amount of Col Ⅲ deposit in the mesangial and subendothelial area of the glomeruli.IgA nephropathy with Col Ⅲ deposition was extremely rare.In this article,we reported two cases of such disease.After treating with immunosuppressive agents or traditional Chinese medicine decoction,the renal function of the two patients remained stable and the urinary protein levels reduced significantly.

Objective To monitor the susceptibility of clinical isolates to antimicrobial agents in tertiary hospitals in major regions of China in 2022.Methods Clinical isolates from 58 hospitals in China were tested for antimicrobial susceptibility using a unified protocol based on disc diffusion method or automated testing systems.Results were interpreted using the 2022 Clinical &Laboratory Standards Institute(CLSI)breakpoints.Results A total of 318 013 clinical isolates were collected from January 1,2022 to December 31,2022,of which 29.5％were gram-positive and 70.5％were gram-negative.The prevalence of methicillin-resistant strains in Staphylococcus aureus,Staphylococcus epidermidis and other coagulase-negative Staphylococcus species(excluding Staphylococcus pseudintermedius and Staphylococcus schleiferi)was 28.3％,76.7％and 77.9％,respectively.Overall,94.0％of MRSA strains were susceptible to trimethoprim-sulfamethoxazole and 90.8％of MRSE strains were susceptible to rifampicin.No vancomycin-resistant strains were found.Enterococcus faecalis showed significantly lower resistance rates to most antimicrobial agents tested than Enterococcus faecium.A few vancomycin-resistant strains were identified in both E.faecalis and E.faecium.The prevalence of penicillin-susceptible Streptococcus pneumoniae was 94.2％in the isolates from children and 95.7％in the isolates from adults.The resistance rate to carbapenems was lower than 13.1％in most Enterobacterales species except for Klebsiella,21.7％-23.1％of which were resistant to carbapenems.Most Enterobacterales isolates were highly susceptible to tigecycline,colistin and polymyxin B,with resistance rates ranging from 0.1％to 13.3％.The prevalence of meropenem-resistant strains decreased from 23.5％in 2019 to 18.0％in 2022 in Pseudomonas aeruginosa,and decreased from 79.0％in 2019 to 72.5％in 2022 in Acinetobacter baumannii.Conclusions The resistance of clinical isolates to the commonly used antimicrobial agents is still increasing in tertiary hospitals.However,the prevalence of important carbapenem-resistant organisms such as carbapenem-resistant K.pneumoniae,P.aeruginosa,and A.baumannii showed a downward trend in recent years.This finding suggests that the strategy of combining antimicrobial resistance surveillance with multidisciplinary concerted action works well in curbing the spread of resistant bacteria.

Objective To investigate the changing distribution and antibiotic resistance profiles of clinical isolates of Staphylococcus in hospitals across China from 2015 to 2021.Methods Antimicrobial susceptibility testing was conducted for the clinical isolates of Staphylococcus according to the unified protocol of CHINET(China Antimicrobial Surveillance Network)using disk diffusion method and commercial automated systems.The CHINET antimicrobial resistance surveillance data from 2015 to 2021 were interpreted according to the 2021 CLSI breakpoints and analyzed using WHONET 5.6.Results During the period from 2015 to 2021,a total of 204,771 nonduplicate strains of Staphylococcus were isolated,including 136,731(66.8％)strains of Staphylococcus aureus and 68,040(33.2％)strains of coagulase-negative Staphylococcus(CNS).The proportions of S.aureus isolates and CNS isolates did not show significant change.S.aureus strains were mainly isolated from respiratory specimens(38.9±5.1)％,wound,pus and secretions(33.6±4.2)％,and blood(11.9±1.5)％.The CNS strains were predominantly isolated from blood(73.6±4.2)％,cerebrospinal fluid(12.1±2.5)％,and pleural effusion and ascites(8.4±2.1)％.S.aureus strains were mainly isolated from the patients in ICU(17.0±7.3)％,outpatient and emergency(11.6±1.7)％,and department of surgery(11.2±0.9)％,whereas CNS strains were primarily isolated from the patients in ICU(32.2±9.7)％,outpatient and emergency(12.8±4.7)％,and department of internal medicine(11.2±1.9)％.The prevalence of methicillin-resistant strains was 32.9％in S.aureus(MRSA)and 74.1％in CNS(MRCNS).Over the 7-year period,the prevalence of MRSA decreased from 42.1％to 29.2％,and the prevalence of MRCNS decreased from 82.1％to 68.2％.MRSA showed higher resistance rates to all the antimicrobial agents tested except trimethoprim-sulfamethoxazole than methicillin-susceptible S.aureus(MSSA).Over the 7-year period,MRSA strains showed decreasing resistance rates to gentamicin,rifampicin,and levofloxacin,MRCNS showed decreasing resistance rates to gentamicin,erythromycin,rifampicin,and trimethoprim-sulfamethoxazole,but increasing resistance rate to levofloxacin.No vancomycin-resistant strains were detected.The prevalence of linezolid-resistant MRCNS increased from 0.2％to 2.3％over the 7-year period.Conclusions Staphylococcus remains the major pathogen among gram-positive bacteria.MRSA and MRCNS were still the principal antibiotic-resistant gram-positive bacteria.No S.aureus isolates were found resistant to vancomycin or linezolid,but linezolid-resistant strains have been detected in MRCNS isolates,which is an issue of concern.

Objective:RS4;11 cell line was used to establish BCL-2 inhibitor-resistant cell lines of B-cell acute lymphoblastic leukemia(B-ALL)and explore the possible mechanisms of drug resistance.Methods:RS4;11 cell line was continuously induced and cultured by low and ascending concentrations of BCL-2 inhibitors navitoclax and venetoclax to construct navitoclax-resistant cell line RS4;11/Nav and venetoclax-resistant cell line RS4;11/Ven.The cell viability was detected by MTT assay,and the cell apoptosis was detected by flow cytometry.Differentially expressed genes(DEGs)between RS4;11 drug-resistant cell lines and parental cell line were detected by transcriptome sequencing technology(RNA-seq),and mRNA expression levels of DEGs between drug-resistant cell lines and parental cell line were detected by real-time PCR(RT-PCR).Western blot was used to detect the expression levels of BCL-2 family anti-apoptotic proteins in drug-resistant cell lines and parental cell line.Results:The drug-resistant cell lines RS4;11/Nav and RS4;11/Ven were successfully established.The resistance index(RI)of RS4;11/Nav to navitoclax and RS4;11/Ven to venetoclax was 328.655±47.377 and 2 894.027±300.311,respectively.The results of cell apoptosis detection showed that compared with the drug-resistant cell lines,RS4;11 parental cell line were significantly inhibited by BCL-2 inhibitors,while the apoptosis rate of drug-resistant cell lines was not affected by the drugs.Western blot assay showed that the expression of anti-apoptotic proteins of BCL-2 family did not increase significantly in drug-resistant cell lines.RNA-seq,RT-PCR and Western blot assays showed that the expression of EP300 in drug-resistant cell lines was significantly higher than that in parental cell line(P＜0.05).Conclusion:Drug-resistant B-ALL cell lines could be successfully established by exposing RS4;11 cell line to the ascending concentration of BCL-2 inhibitors,and the drug resistance mechanism may be related to the overexpression of EP300.