Objective To study degenerative neurons in striatum and hippocampus of rats induced by chronic rotenone intoxication.Methods The model of chronic rotenone intoxication was established in rats by the subcutaneous implantation of miniosmotic pumps. The general state of the rats were observed,and the degenerative neurons and normal neurons in the striatum and hippocampus were detected by Fluoro-JadeB combined with fluorescent Nissl staining.Results The noticeable syndromes like Parkinson’s disease appeared in the rotenone-intoxicateed rats,in whom ,there were a number of the positive degenerative neurons in the striaum and hippocampus.The above-mentioned changes were not found in the control group.Conclusions Compared with traditional rotenone subcutaneous injection,osmotic subcutaneous implantation is an ideal way to establish rotenone chronic intoxication model.Rotenone can cause neuronal degeneration in the striatum and hippocampus of rat.
Abstract Protein–protein interactions (PPIs) play an important role in the different functions of cells, but accurate prediction of the three-dimensional structures for PPIs is still a notoriously difficult task. In this study, HawkDock, a free and open accessed web server, was developed to predict and analyze the structures of PPIs. In the HawkDock server, the ATTRACT docking algorithm, the HawkRank scoring function developed in our group and the MM/GBSA free energy decomposition analysis were seamlessly integrated into a multi-functional platform. The structures of PPIs were predicted by combining the ATTRACT docking and the HawkRank re-scoring, and the key residues for PPIs were highlighted by the MM/GBSA free energy decomposition. The molecular visualization was supported by 3Dmol.js. For the structural modeling of PPIs, HawkDock could achieve a better performance than ZDOCK 3.0.2 in the benchmark testing. For the prediction of key residues, the important residues that play an essential role in PPIs could be identified in the top 10 residues for ∼81.4% predicted models and ∼95.4% crystal structures in the benchmark dataset. To sum up, the HawkDock server is a powerful tool to predict the binding structures and identify the key residues of PPIs. The HawkDock server is accessible free of charge at http://cadd.zju.edu.cn/hawkdock/.
ABSTRACT IMPACT: We devised a new method to produce highly potent SARS-CoV2-specific that can be used to treat severely ill patients with Covid-19. OBJECTIVES/GOALS: Neutralizing antibodies against SARS-CoV-2 are thought to offer the most immediate and effective treatment for those severely afflicted by Covid-19. We devised an approach for rapid and efficient generation of human monoclonal antibodies with neutralizing activity against SARS-CoV-2. METHODS/STUDY POPULATION: SARS-CoV-2 S1 spike protein-specific memory B cells were isolated from 12 subjects recovering from infection with that virus. Paired end single index sequencing was performed using up to 10,000 antigen-specific B cells per subject. Antigen-specific B cell clones were identified by unique diversity and joining gene V(D)J rearrangements and the CDR3 regions. VH and VL regions were cloned and the products expressed in 293T/17 cells to generate spike-specific human monoclonal antibodies. RESULTS/ANTICIPATED RESULTS: Forty-three human monoclonal antibodies were produced. Every monoclonal antibody so generated neutralized viruses pseudotyped with Spike protein of the Wuhan-1 strain. Eighteen monoclonal antibodies neutralized pseudotyped viruses with half-maximal inhibitory concentration (IC50s) between 1 pg/mL and 1 ng/mL (6.7 x 10E-15 M to 6.7 x 10E-12 M), exceeding by 10-100-fold the potency of previously reported anti-SARS-CoV-2-neutralizing monoclonal antibodies. Eight monoclonal antibodies neutralized viruses pseudotyped with mutant spike proteins previously identified in clinical isolates, including receptor binding domain mutants and the C-terminal D614G mutant with IC50<6.7 x10E-12M. DISCUSSION/SIGNIFICANCE OF FINDINGS: We show that SARS-CoV-2 evokes high affinity B cell responses. Some B cells produce antibodies that are broadly neutralizing; others produce strain-specific antibodies. However, antigenic variants that would potentially escape control by immunity or vaccination were nonetheless identified.
Background: Despite an increase in the familiarity of the medical community with the epidemiological and clinical characteristics of coronavirus disease 2019 (COVID-19), there is presently a lack of rapid and effective risk stratification indicators to predict the poor clinical outcomes of COVID-19 especially in severe patients. Methods: In this retrospective single-center study, we included 117 cases confirmed with COVID-19. The clinical, laboratory, and imaging features were collected and analyzed during admission. The Multi-lobular infiltration, hypo-Lymphocytosis, Bacterial coinfection, Smoking history, hyper-Tension and Age (MuLBSTA) Score and Confusion, Urea, Respiratory rate, Blood pressure, Age 65 (CURB65) score were used to assess the death and intensive care unit (ICU) risks in all patients. Results: Among of all 117 hospitalized patients, 21 (17.9%) patients were admitted to the ICU care, and 5 (4.3%) patients were died. The median hospital stay was 12 (10-15) days. There were 18 patients with MuLBSTA score ≥ 12 points and were all of severe type. In severe type, ICU care and death patients, the proportion with MuLBSTA ≥ 12 points were greater than that of CURB65 score ≥ 3 points (severe type patients, 50 vs. 27.8%; ICU care, 61.9 vs. 19.0%; death, 100 vs. 40%). For the MuLBSTA score, the ROC curve showed good efficiency of diagnosis death (area under the curve [AUC], 0.956; cutoff value, 12; specificity, 89.5%; sensitivity, 100%) and ICU care (AUC, 0.875; cutoff value, 11; specificity, 91.7%; sensitivity, 71.4%). The K-M survival analysis showed that patients with MuLBSTA score ≥ 12 had higher risk of ICU (log-rank, P = 0.001) and high risk of death (log-rank, P = 0.000). Conclusions: The MuLBSTA score is valuable for risk stratification and could effectively screen high-risk patients at admission. The higher score at admission have higher risk of ICU care and death in patients infected with COVID.
Background: Several studies have found that body adiposity index (BAI) is a better index of body adiposity than body mass index (BMI) in African and Mexican American adults. This study aims to evaluate the ability of BAI to predict body adiposity in Chinese children and adults. Materials and Methods: In total, 2425 children and 5726 adults were recruited from rural China. All participants completed whole‐body dual‐energy X‐ray absorptiometry (DXA) and anthropometric measures. The correlation of BMI, BAI, and waist circumference (WC) to DXA adiposity indexes was performed across sex‐specific adult and age‐ and sex‐specific child cohorts, using Spearman correlation and linear regression models, respectively. Results: Both BMI and WC had a higher correlation with all adiposity indexes (whole body fat, percent body fat [Bfat%], trunk fat, and percent trunk fat [Tfat%]) measured by DXA than did BAI in both adults and children. Meanwhile, most of the linear regression model associations for BMI with Bfat% and Tfat% had a greater adjusted R 2 than those for BAI among both children and adults. Conclusion: This study indicates that BMI and WC are better tools than BAI for estimating whole body fat and central body fat in a Chinese population.
Abstract SARS‐CoV spike (S) protein‐mediated cell fusion is important for the viral entry mechanism and identification of SARS‐CoV entry inhibitors. In order to avoid the high risks involved in handling SARS‐CoV and to facilitate the study of viral fusion mechanism, we established the cell lines: SR‐COS7 cells that stably express both SARS‐CoV S protein and red fluorescence protein, R‐COS7 cells that stably express red fluorescence protein, and AG‐COS7 cells that stably express both ACE2 and green fluorescence protein, respectively. When SR‐COS7 cells or R‐COS7 cells were cocultured with AG‐COS7 cells, syncytia with yellow fluorescence were conveniently observed after 12 h in SR‐COS7 cells plus AG‐COS7 cells, but not in R‐COS7 cells plus AG‐COS7 cells. The cell‐to‐cell fusion efficiency was simply determined for quantitative analysis based on the number of syncytium detected by flow cytometry. Such new cell‐to‐cell fusion model was further assessed by the potent HR2 peptide inhibitor, which led to the obvious decrease of the cell‐to‐cell fusion efficiency. The successful fusion and inhibition of cell‐based binding assay shows that it can be well used for the study of SARS‐CoV entry and inhibition. iubmb Life, 58: 480 ‐ 486, 2006
In coronavirus disease 2019 (COVID-19) patients, interleukin (IL)-6 is one of the leading factors causing death through cytokine release syndrome. Hence, identification of IL-6 downstream from clinical patients' transcriptome is very valid for analyses of its mechanism. However, clinical study is conditional and time consuming to collect optional size of samples, as patients have the clinical heterogeneity. A possible solution is to deeply mine the relative existing data. Several transcriptome-based studies on other diseases or treatments have revealed different genes to be regulated by IL-6. Through our meta-analysis of these transcriptome datasets, 352 genes were suggested to be regulated by IL-6 in different biological conditions, some of which were related to virus infection and cardiovascular disease. Among them, 232 genes were not identified by current transcriptome studies from clinical research. ICAM1 and PFKFB3 were the most significantly upregulated genes in our meta-analysis and could be employed as biomarkers in patients with severe COVID-19. In general, a meta-analysis of transcriptome datasets could be an alternative way to analyze the immune response and complications of patients suffering from severe COVID-19 and other emergency diseases.
Abstract Background Bictegravir (B)/emtricitabine (F)/tenofovir alafenamide (TAF) is guideline-recommended treatment for human immunodeficiency virus type 1 (HIV-1). We evaluated whether people receiving dolutegravir (DTG) plus F/TAF or F/TDF (tenofovir disoproxil fumarate) with viral suppression can switch to B/F/TAF without compromising safety or efficacy, regardless of preexisting nucleoside reverse transcriptase inhibitor (NRTI) resistance. Methods In this multicenter, randomized, double-blinded, active-controlled, noninferiority trial, we enrolled adults who were virologically suppressed for ≥6 months before screening (with documented/suspected NRTI resistance) or ≥3 months before screening (with no documented/suspected NRTI resistance) on DTG plus either F/TDF or F/TAF. We randomly assigned (1:1) participants to switch to B/F/TAF or DTG + F/TAF once daily for 48 weeks, each with matching placebo. The primary endpoint was proportion of participants with plasma HIV-1 RNA ≥50 copies/mL at week 48 (snapshot algorithm); the prespecified noninferiority margin was 4%. Results Five hundred sixty-seven adults were randomized; 565 were treated (284 B/F/TAF, 281 DTG + F/TAF). At week 48, B/F/TAF was noninferior to DTG + F/TAF, as 0.4% (1/284) vs 1.1% (3/281) had HIV-1 RNA ≥50 copies/mL (difference, −0.7% [95.001% confidence interval {CI}, −2.8% to 1.0%]). There were no significant differences in efficacy among participants with suspected or confirmed prior NRTI resistance (n = 138). No participant had treatment-emergent drug resistance. Median weight change from baseline at week 48 was +1.3 kg (B/F/TAF) vs +1.1 kg (DTG + F/TAF) (P = .46). Weight change differed by baseline NRTIs (+2.2 kg [F/TDF] and +0.6 kg [F/TAF], P < .001), with no differences between B/F/TAF and DTG + F/TAF. Conclusions The single-tablet regimen B/F/TAF is a safe, effective option for people virologically suppressed on DTG plus either F/TDF or F/TAF, including in individuals with preexisting resistance to NRTIs. Clinical Trials Registration NCT03110380.
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