Homologous modeling and binding ability analysis of Spike protein after point mutation of severe acute respiratory syndrome coronavirus 2 to receptor proteins and potential antiviral drugs / 北京大学学报(医学版)

OBJECTIVE@#To explore the natural mutations in Spike protein (S protein) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the changes of affinity between virus and associated receptors or drug molecules before and after the mutation based on whole length sequencing results.@*METHODS@#In the study, the bioinformatics analysis of all the published sequences of SARS-CoV-2 was conducted and thus the high frequency mutation sites were affirmed. Taking advantages of PolyPhen-2, the functional influence of each mutation in S protein was prospected. The 3D homologous modelling was performed by SWISS-MODEL to establish mutated S protein structural model, in which the protein-docking was then implemented with angiotensin-converting enzyme 2 (ACE2), dipeptidyl peptidase-4 (DPP4) and aminopeptidase N (APN) by ZDOCK, and the combining capacity of each mutated S protein evaluated by FiPD. Finally, the binding ability between mutated S proteins and anti-virus drugs were prospected and evaluated through AutoDock-Chimera 1.14.@*RESULTS@#The mutations in specific region of S protein had greater tendency to destroy the S protein function by analysis of mutated S protein structure. Protein-receptor docking analysis between naturally mutated S protein and host receptors showed that, in the case of spontaneous mutation, the binding ability of S protein to ACE2 tended to be weakened, while the binding ability of DPP4 tended to be enhanced, and there was no significant change in the binding ability of APN. According to the computational simulation results of affinity binding between small molecular drugs and S protein, the affinity of aplaviroc with S protein was significantly higher than that of other small molecule drug candidates.@*CONCLUSION@#The region from 400-1 100 amino acid in S protein of SARS-CoV-2 is the mutation sensitive part during natural state, which was more potential to mutate than other part in S protein during natural state. The mutated SARS-CoV-2 might tend to target human cells with DPP4 as a new receptor rather than keep ACE2 as its unique receptor for human infection. At the same time, aplaviroc, which was used for the treatment of human immunodeficiency virus (HIV) infection, may become a new promising treatment for SARS-CoV-2 and could be a potential choice for the development of SARS-CoV-2 drugs.

Analysis of Common Postoperative Complications after Cranioplasty / 中国康复理论与实践

@# Objective To explore the related factors of common postoperative complications after cranioplasty. Methods From November, 2009 to June, 2013, a total of 211 patients after cranioplasty were reviewed. The conventional two-dimensional titanium alloy was used. The incidence of scalp effusion, seizure and spontaneous intracerebral hemorrhage were recorded, and the related factors including gender, age, primary disease, skull defect site, attack time, concomitant hydrocephalus and intraoperative dural damage were analyzed. Results The incidence of these complications was 4.7% (10/211) in total. There were four cases with scalp effusion, five cases with seizures and one case with spontaneous intracerebral hemorrhage. The scalp effusion was related to hydrocephalus (χ2=4.804, P=0.028) and intraoperative dural damage (χ2=7.510, P=0.006). Seizure and spontaneous intracerebral hemorrhage were not related with any factors above (P>0.05). Conclusion The occurrence of postoperative scalp effusion can be reduced by repairing intraoperative dural damage, and dealing with extreme hydrocephalus timely.

Factors Related with Infection and Local Epidural Hematoma after Cranioplasty: A Retrospective Analysis / 中国康复理论与实践

@#Objective To explore the factors associated with the complications of cranioplasty, infection and local epidural hematoma, such as age, sex, primary disease, skull defect and concomitant hydrocephalus. Methods 211 patients after cranioplasty were reviewed. Results 8 cases (3.8%) complicated one of them, in which 6 cases with local epidural hematoma and 2 cases with infection. The infection was more likely related with the areas of skull defect (P=0.003). No factor was found related with the local epidural hematoma. Conclusion It is necessary to focus the size of the frontal sinus when repairing the the frontal bone, to avoid the screw into the frontal sinus caused infection.

Testosterone suppresses rat vascular smooth muscle cell phenotypic transition and proliferation / 中华内分泌代谢杂志

Objective To investigate the inhibitory effect of testosterone on oxidized low-density lipoproteins ( ox-LDL)-stimulated phenotypic transition and proliferation of vascular smooth muscle cells ( VSMCs) in vitro, and to explore its possible mechanisms. Methods Rat VSMCs cultured in vitro were divided into control group, ox-LDL group(50μg/mlox-LDL),fetalbovineserum(FBS)group(10% FBS),andtestosteronegroups(5×10-8 or5×10-7 mol/L testosterone plus 50μg/ml ox-LDL) . The effect of testosterone on ox-LDL-induced proliferation of VSMCs was explored by WST-1 assay. The cell cycle distribution was determined using flow cytometry. Western blotting was used todetecttheexpressionsofmitofusin2(Mfn2),phosphorylatedextracellularsignal-regulatedkinases1/2(p-ERK1/2) , proliferating cell nuclear antigen ( PCNA) ,α-smooth muscle actin (α-SMA) ,and osteopontin ( OPN) . Results Compared with control group, the proliferation of VSMCs was promoted by ox-LDL, the number of VSMCs decreased in G0/G1 phase and increased in S phase significantly, the expression levels of Mfn2 and α-SMA were significantly reduced, and the expression levels of p-ERK1/2, PCNA, and OPN were significantly raised in ox-LDL group. Compared with ox-LDL group, the proliferation of VSMCs was inhibited, the number of VSMCs increased in G0/G1 phase and decreased in S phase in two testosterone groups, along with the increased expressions of Mfn2 andα-SMA, and the descended expressions of p-ERK1/2, PCNA, and OPN. Conclusions Testosterone inhibits phenotypic transition and proliferation of VSMCs induced by ox-LDL in vitro, which may be related to the up-regulated expression of Mfn 2 and the suppression of ERK1/2 pathway.

Factors Related with Infection and Local Epidural Hematoma after Cranioplasty:A Retrospective Analysis / 中国康复理论与实践

Objective To explore the factors associated with the complications of cranioplasty, infection and local epidural hematoma, such as age, sex, primary disease, skull defect and concomitant hydrocephalus. Methods 211 patients after cranioplasty were reviewed. Re-sults 8 cases (3.8%) complicated one of them, in which 6 cases with local epidural hematoma and 2 cases with infection. The infection was more likely related with the areas of skull defect (P=0.003). No factor was found related with the local epidural hematoma. Conclusion It is necessary to focus the size of the frontal sinus when repairing the the frontal bone, to avoid the screw into the frontal sinus caused infection.

The role of TNF-αand sICAM-1 in periodontitis of rat model exposed to chronic intermittent hypoxic / 实用口腔医学杂志

Objective:To investigate the expression of tumor necrosis factor-α(TNF-α)and soluble intercellular adhesion molecule -1(sICAM-1)in blood serum and gingival tissue in rat periodontitis model in normoxia and chronic intermittent hypoxia environment. Methods:32 male SD rats were randomly divided into 4 groups(n =8):normoxia control group(group A),normoxia periodontitis group(group B),hypoxic control group(group C)and hypoxia periodontitis group(group D).The periodontitis models were estab-lished by ligating the bilateral maxillary second molar and raised by periodontitis diet.The rats in hypoxia groups were raised under chronic intermittent hypoxia environment,while those in normoxia groups were raised under normoxia environment.After 8 weeks, plaque index(PLI),bleeding index(BI)and attachment lost(AL)were measured,TNF-αand sICAM-1 concentrations in blood serum and gingival tissue were measured by ELISA.Results:TNF-αand sICAM-1 concentrations in blood serum and gingival tissue in group A were higher than those in group B,C(P ＜0.05);in group D were lower than in group B and C(P ＜0.05).TNF-αand sICAM-1 levels in blood serum and gingival tissue were positively correlated with AL(P ＜0.05).Conclusion:In chronic intermittent hypoxic environment TNF-αand sICAM-1 may aggravate periodontitis,and promote the inflammatory response to peripheral vascular system.

Effect of Integrin-linked Kinase on Derivation of Neural Stem-like Cells from Mesenchymal Stem Cells / 中国康复理论与实践

Objective To investigate the effect of integrin-linked kinase (ILK) on inducing mesenchymal stem cells (MSCs) to neuron stem-like cell in vitro. Methods MSCs isolated from umbilical cord were transfected with plasmid DNA encoding green fluorescent protein (GFP) and GFP-fusion ILK, wild and mutant, respectively;and cultured in serum-free media with basic fibroblast growth factor, epidermal growth factor and B27. It was assessed with the proliferative activity and the efficiency of differentiation into neural stem-like cell. Results MSCs transfected with GFP-fusion wild ILK expressed ILK and kinase-dead mutant ILK stably. The activity of proliferation increased and more of them differentiated into neural stem-like cell, which express CD133 and Nestin validated by PCR and Western blotting, and more of wild than of mutant. Conclusion Integrin-linked kinase may play a positive role in MSC differentiation into neural stem-like cell, which may associate with the activity of kinase.

Expressions of Transforming Growth Factor β2 and Smad3 in Human Gliomas with Different Pathologic Grade Proliferation and Its Clinical Significance / 中国康复理论与实践

@#Objective To investigate the expressions of Transforming Growth Factorβ2 (TGF-β2) and Smad3 in human gliomas associated with pathologic grading. Methods The expressions of TGFβ2 and Smad3 protein were detected with SP immunhistochemistry in 80 human glioma specimens. The Kapan-Meier survival curves of progression-free survival time and overall survival time in different expression levels was compared with log-rank. Results The expression of TGFβ2 and Smad3 correlated with the pathological grading (r=0.545, r=0.570, P<0.01). Both progression-free survival time and overall survival time were significantly different between low expression group and high expression group (P<0.05). Conclusion Both TGF-β2 and Smad3 correlate well with the occurrence and differentiation of human gliomas,which help for the diagnosis, treatment and prognosis judgment．

Clinical study on intervention of liuwei dihuang pill on hormonotherapy in treating nephrotic syndrome / 中国中西医结合杂志

<p><b>OBJECTIVE</b>To observe the intervention of liuwei dihuang pill (LDP) on therapeutic effectiveness and adverse reaction of hormonotherapy in treating nephrotic syndrome.</p><p><b>METHODS</b>Patients allocated in two groups were medicated with initial dose of prednisone 1 mg/kg once a day at 8 am in the morning. After being medicated for 8 to 12 weeks, the dose of prednisone was decreased by 5.0 mg every 2 weeks till 0.5 mg/kg per day. Then the medication was changed to that two days' dosage orally take once a day with the daily dose reduced by 5.0 mg/kg every 2 to 3 weeks, and maintained at 0.4 mg/kg once every two days. At same time, necessary symptomatic treatment was given. To the treated group oral administration of LDP 8 capsules was given additionally, 3 times per day until prednisone decreased to maintenance dose.</p><p><b>RESULTS</b>Therapeutic effect in the treated group was significant better than that in the control group (P < 0.05). Urinary protein, plasma albumin, triglyceride (TG) and total cholesterol (TC) in both groups were obviously improved (P < 0.05 or P < 0.01). However, as compared with the control group, the improvement was better, and the recurrent rate was lower (P < 0.05) in the treated group. Scores of Yin-deficiency caused excessive Fire syndrome and incidence rate of adverse reaction in the treated group were lower than those in the control group (P < 0.05 or P < 0.01).</p><p><b>CONCLUSION</b>LDP can markedly improve the therapeutic effectiveness and counteract the adverse reaction of hormonotherapy in treating nephrotic syndrome, and reduce the recurrence of the disease.</p>