Combined with elastic network model (ENM), the perturbation response scanning (PRS) has emerged as a robust technique for pinpointing allosteric interactions within proteins. Here, we proposed the PRS analysis of drug-target networks (DTNs), which could provide a promising avenue in network medicine. We demonstrated the utility of the method by introducing a deep learning and network perturbation-based framework, for drug repurposing of multiple sclerosis (MS). First, the MS comorbidity network was constructed by performing a random walk with restart algorithm based on shared genes between MS and other diseases as seed nodes. Then, based on topological analysis and functional annotation, the neurotransmission module was identified as the "therapeutic module" of MS. Further, perturbation scores of drugs on the module were calculated by constructing the DTN and introducing the PRS analysis, giving a list of repurposable drugs for MS. Mechanism of action analysis both at pathway and structural levels screened dihydroergocristine as a candidate drug of MS by targeting a serotonin receptor of serotonin 2B receptor (HTR2B). Finally, we established a cuprizone-induced chronic mouse model to evaluate the alteration of HTR2B in mouse brain regions and observed that HTR2B was significantly reduced in the cuprizone-induced mouse cortex. These findings proved that the network perturbation modeling is a promising avenue for drug repurposing of MS. As a useful systematic method, our approach can also be used to discover the new molecular mechanism and provide effective candidate drugs for other complex diseases.

Objective To explore the potential role and underlying mechanism of the functionally uncharacterized gene Gm49394 on regulating β-cell apoptosis under diabetic conditions.Methods The expression and translational activity of Gm49394 in pancreatic β-cell lines and non-β-cell lines were validated using RNA fluorescence in situ hybridization(RNA-FISH),quantitative real-time PCR(qPCR),Western blotting,and immunofluorescence(IF)assay.The β-cell lines(NIT-1/Min6)with Gm49394 overexpression or knockdown were constructed.The proliferation,apoptosis,mitochondrial function,as well as oxidative stress and endoplasmic reticulum stress markers in these β-cell lines under physiological homeostasis or pathological stress conditions,such as high glucose(30 mmol/L),inflammation(10 ng/mL IFN-γ alone or combined with 10 ng/mL IL-6),and hydrogen peroxide(100 μmol/L H2O2)were detected by flow cytometry and Western blotting.Results RNA-FISH and qPCR indicated that Gm49394 was specifically expressed in pancreatic β-cell lines and up-regulated under high glucose or inflammatory stimulation.IF assay and Western blotting showed that Gm49394 had protein-coding activity.Flow cytometry and Western blotting identified that Gm49394 overexpression did not affect β-cell proliferation,but promoted β-cell apoptosis and increased reactive oxygen species(ROS)and mitochondrial superoxide(MitoSOX)levels in β cells under physiological homeostasis or pathological stress conditions(P<0.05).Under physiological conditions,Gm49394 knockdown failed to induce significant alterations on β-cell apoptosis,ROS,or MitoSOX levels.Under pathological stress conditions,Gm49394 knockdown significantly suppressed β-cell proliferation,apoptosis,as well as oxidative and endoplasmic reticulum stress(P<0.05).Conclusion Gm49394 may promote β-cell apoptosis via oxidative stress and endoplasmic reticulum stress.

Objective To compare and analyze the differences in CD8+naive,effector,memory,exhausted and regulatory T cells in order to investigate the impact of gender on the differentiation fate of CD8+T cells in the context of type 1 diabetes (T1D)based on female and male non-obese diabetic (NOD)mice and healthy Institute for Cancer Research (ICR)mice.Methods The frequencies and phenotypes of CD8+T cell differentiation subsets including naive T cells (TN),central memory T cells (TCM),effector T cells(TEFF),effector precursor T cells (TEP),exhausted T cells (TEX),precursor exhausted T cells (TPEX)and regulatory T cells (Tregs)in the spleen,pancreatic draining lymph nodes (pLN)and pancreas infiltrating lymphocytes (PIL)of male and female NOD mice were detected by flow cytometry.Results The frequencies of IFN-γ+,CD107a+and CCL5+CD8+TEFF in pLN and PIL of female NOD mice were significantly higher than those of male NOD mice.However,the frequencies of CD8+TN,CD8+TCM,CD8+TEX,CD8+TPEX and CD122+CD8+Tregs subsets in the spleen were significantly decreased.While there were no significant differences in the above CD8+T cell subsets except CD8+Tregs between female and male ICR mice. Conclusion Androgen may inhibit the differentiation of memory T cells into effector T cells and promote the exhaustion of effector T cells,leading to the difference in morbidity between the male and female mice.

AIM:To explore the effect of polyphenolic compound 3,5-dihydroxy-4-methoxybenzyl alcohol(DHMBA)on hypoxia/reoxygenation(H/R)injury of human umbilical vein endothelial cells(EA.hy926 cells)and its po-tential mechanisms.METHODS:To construct an H/R model,the EA.hy926 cells were cultured in an acidic hypoxia buffer while in an anaerobic workstation.The cells were divided into control,H/R,H/R+different doses of DHMBA,H/R+edaravone(antioxidant)and H/R+reactive oxygen species(ROS)inducer oligomycin A+DHMBA groups.Cell viability was measured by CCK-8 assay,and tumor necrosis factor-α(TNF-α)and interleukin-6(IL-6)levels in cells were mea-sured by ELISA.Phosphorylation of endothelial nitric oxide synthase(eNOS)and nuclear factor-κB(NF-κB)p65 were measured by Western blot.Intracellular NO levels were determined by laser confocal microscopy.Glutathione(GSH)/glu-tathione disulfide(GSSG)oxidation balance was determined by the dinitrobenzoic acid chromogenic method.Intracellular ROS levels were measured by flow cytometry.Lactate dehydrogenase(LDH)leakage was determined using nitro blue tet-razolium staining.Scratch assays were performed to assess cell migration.RESULTS:DHMBA exhibited no significant cytotoxicity between 125 and 1 000 μmol/L.In H/R-injured human umbilical vein endothelial cells,DHMBA improved cell survival,inhibited phosphorylation of NF-κB p65,reduced the content of TNF-α and IL-6,and increased phosphory-lation of eNOS and NO levels.DHMBA also suppressed ROS overload and restored the ratio between GSH and oxidized GSH,decreased in LDH leakage and increased cell migration in H/R-injured human umbilical vein endothelial cells.CONCLUSION:DHMBA can alleviate H/R-induced oxidative stress,inflammation,cellular damage,and dysfunction,which are associated with the ability of DHMBA to inhibit ROS production in human umbilical vein endothelial cells.

We reviewed and developed an indicator system framework for assessing teaching effect of laparoscopic simulation training through literature research, expert consultation, analytic hierarchy process and factor analysis. We also made an empirical study on the constructed index system. The system included 3 domains (A1: evaluation of laparoscopic simulator; A2: operation evaluation of experimental animals; A3: evaluation of clinical practice), 10 second-level indicators and 23 third-level indicators for assessing teaching effect of laparoscopic simulation training. The indicator system framework has good internal consistency (Cronbach α= 0.968) and external consistency (>0.72). The empirical study found that: in the results of A1-A3 in the first level indicator, the score of the experienced group was significantly higher than that of the inexperienced group ( P<0.05). In the evaluation results of the 10 secondary indicators in the secondary indicators B1-B10, the score of the experienced group was significantly higher than that of the inexperienced group ( P<0.01). For the first time, we have established and evaluated a comprehensive evaluation indicator system which is reliable and effective and can be used for further evaluation of teaching effect of laparoscopic simulation training. The following empirical studies have verified the effectiveness and practicability of the evaluation system.

Artificial Intelligence ; Forecasting ; Humans ; Rare Diseases ; Urinary Bladder Neoplasms/diagnosis*

Objective To collect and summarize the opinions of experts on the improvement of China's disease prevention and control system published in the public media, so as to provide reference for the relevant construction planning of the government. Methods: Articles were collected from January to May, 2020, which were published on Chinese mainstream media. Based on the analysis of literature and the basic characteristics of experts, Analytic hierarchy process (AHP) was used to summarize the construction points of experts in different construction fields. Results: A total of 19 opinion articles were finally included in the study and 29 experts were involved. The suggestions of experts on the construction of China's disease prevention and control system were summarized into four aspects. Conclusion: The COVID-19 pandemic is a challenge to the existing public health epidemic prevention and control system in China, and also an important opportunity for the development and construction of the related system.

Objective To investigate the function of sorafenib on the growth of hepatocellular carcinoma by establishing subcutaneous transplantation tumor model with nude mice.To explore the effect of sorafenib on circadian clock gene expression in hepatoma cells.Methods Mouse tumor model was established by implanting hepatocarcinoma cell (HepG2) subcutaneously in Balb/C nude mice.Sixteen experimental mice were randomly divided into two groups:sorafenib treatment group (n =8) and solvent control group (n =8).The nude mice were treated with sorafenib (100 mg/kg) and DMSO daily by intragastric administration,respectively.The volume of tumors was recorded every 3 days.The expressions level of circadian clock genes (Per1,Per2,Per3,CLOCK,Cry1,Cry2,BMAL1 and CKIε) were detected by real-time polymerase chain reaction (Real-time PCR).The correlations between the size of the xenografts and the expressions of the circadian clock genes were further analyzed.Results Compared with the control group,the tumor size in the sorafenib treatment group were significantly smaller comparing with the control group.Results of Real-time PCR showed that the expression level of Per1,Cry1 and BMAL1 mRNA was remarkably decreased in the treatment group (Per1,P =0.02;Cry1,P =0.002;BMAL1,P =0.035),the differences were statistically significant.Correlation analysis showed that the size of subcutaneous transplantation tumorsin nude mice was negatively correlated with the expressions of Per1,Per2,Cry1 and Cry2 mRNA in control group.While,the size of subcutaneous transplantation tumors was negatively correlated with the expressions of Per2,Per3 and BMAL1 levels in the sorafenib treatment group.Conclusions There is a negative correlation between the expression levels of some biological clock genes and the size of transplantation tumor in nude mice.Sorafenib treatment significantly inhibited the growth of hepatocellular carcinoma in nude mice and down-regulation the expressions of Per1,Cry1 and BMAL1 mRNA in hepatoma cells.

Objective To investigate the clinical application of different puncture positions in percutaneous nephrolithotomy (PCNL).Methods From February 2015 to March 2017,102 patients with kidney urinary calculi in our hospital were enrolled in the study.According to the selected puncture position,they were divided into prone position (group A,32 cases),lateral decubitus position (group B,37 cases) and half stone oblique supine position (group C,33 cases).The mean arterial pressure (MAP),heart rate (HR) and blood oxygen saturation (SpO2) were observed before placement of 5 min (T0),after placement of 5 min (T1),30 min (T2),and postoperative 5 min (T3),and the time of established passage,the time of operation and the amount of bleeding during operation and so on.Results The MAP in group B and group C at T1 was significantly higher than that in group A (P ＜ 0.05);The HR in Group B and group C at T2 and T3 were significantly lower than those in group A (P ＜ 0.05);The SpO2 in Group B and group C at T1 and T2 were significantly higher than those in group A (P ＜ 0.05);There was no significant difference in the time of establishment passage,the rate of primary clearing stone and the hospital stay in the groups (P ＞0.05);The operation time and intraoperative blood loss in group C were (120.07 ± 20.19) min and (90.01 ±30.11)ml,significantly less than those in group B and group A (P ＜0.05);The operation time and intraoperative blood loss in group B were (140.17 ±20.48) min and (110.04 ±29.82) ml,significantly less than that in group A [(170.02 ± 21.02) min,(164.02 ± 30.12) ml] (P ＜ 0.05);The postural comfort of group C was better than that of group A and group B (P ＜ 0.05);There was no significant difference in the incidence of postoperative complications in the three groups (P ＞ 0.05).Conclusions Half stone oblique supine position in the PCNL application has good effect,which is conducive to improving the patient's tolerance to surgery,shorten the operation time,and it is worth popularizing.

BACKGROUND:There are many ways for surgical treatment of distal radius fractures. Both volar locking plates and Kirschner wires are common methods. Doctors have considerable flexibility in the choice of the ways of fixation, but both at home and abroad there is no comparison between the effects of the two operations for treating distal radius fractures. OBJECTIVE:To systematicaly review the differences in effectiveness and safety of volar locking plates versusKirschner wires for distal radial fracture. METHODS:Databases such as CBM, CNKI, VIP, PubMed and Cochrane Library were electronicaly searched.Chinese Journal of Orthopaedics,Chinese Journal of Orthopaedic Trauma,Chinese Journal of Trauma andJournal of Practical Orthopaedics were searched by hand. In strict accordance with inclusion and exclusion criteria, articles were screened. Methodological quality of included studies was evaluated according to Cochrane Handbook. Data were extracted, and then analyzed with RevMan 5.2 software. RESULTS AND CONCLUSION:Nine randomized controled trials were included. Meta-analysis results demonstrated that upper limb function scores were better in the volar locking plate group than in the Kirschner wire group [MD=-4.55(-7.89,-1.21),P=0.008] at 3 months of folow-up and [MD=-3.13(-6.08,-0.18),P=0.004] at 12 months. The incidence of infection was lower in the volar locking plate group than in the Kirschner wire group [OR= 0.42(0.23, 0.79),P=0.007]. No significant difference in incidence of complex regional pain syndrome [OR=0.28(0.05, 1.38),P=0.12], incidence of carpal tunnel syndrome [OR=0.75(0.20, 2.76),P=0.66] and tendon injury [OR= 1.66(0.51, 5.41),P=0.64] was detected between the volar locking plate group and Kirschner wire group. These results indicated that compared with the Kirschner wire, volar locking plate fixation for the repair of distal radial fracture is safe and effective. In the permission of economic circumstances, it is suggested that elder osteoporosis patients with distal radial fracture should receive plate fixation.