COVID-19 has struck our society as a great calamity, and the need for effective anti-viral drugs is more urgent than ever. Papain-like protease (PLpro) of SARS CoV-2 plays important roles in virus ...maturation, dysregulation of host inflammation, and antiviral immune responses, which is being regarded as a promising druggable target for the treatment of COVID-19. Here, we carried out a combined screening approach to identify novel and highly potent PLpro inhibitors for the treatment of COVID-19.
We used a combined screening approach of structure-based pharmacophore modeling and molecular docking to screen an in-house database containing 35,000 compounds. SARS CoV-2 PLpro inhibition assay was used to carry out the biological evaluation of hit compounds. Molecular dynamics (MD) simulations were conducted to check the stability of the PLpro-hit complexes predicted by molecular docking.
We found that four hit compounds showed excellent inhibitory activities against PLpro with IC
values ranging from 0.6 to 2.4 μM. Among them, the most promising compound, hit 2 is the best PLpro inhibitor and its inhibitory activity was about 4 times higher than that of the positive control (GRL0617). The study of MD simulations indicated that four hits could bind stably to the active site of PLpro. Further study of interaction analysis indicated that hit 2 could form hydrogen-bond interactions with the key amino acids such as Gln269 and Asp164 in the PLpro-active site.
Hit 2 is a novel and highly potent PLpro inhibitor, which will open the way for the development of clinical PLpro inhibitors for the treatment of COVID-19.
For energetic materials (EMs), the key point of the present research is to improve the energetic property and reduce sensitivity. In this work, two new energetic complexes, Mn(atzc)2(H2O)2·2H2O (1) ...and Zn(atzc)2(H2O) (2) (Hatzc = 3-amino-1,2,4-triazole-5-carboxylic acid), were synthesized by solvent evaporation and diffusion methods, respectively. The structural analyses illustrate that 1 and 2 exhibit zero-dimensional structural units, which are linked by hydrogen-bonding interactions to give three-dimensional supramolecular architectures. For complexes 1 and 2, the detonation velocities (D) are 10.4 and 10.2 km·s–1 and detonation pressures (P) are 48.7 and 48.6 GPa, respectively. They are higher than most of the reported EMs, which present prominent detonation characteristics. In addition, two complexes can accelerate the thermal decomposition of ammonium perchlorate and exhibit excellent catalytic activity. Therefore, the two complexes can serve as a new class of promising EMs, which have potential application in the design of new high-efficiency solid catalysts.
Space nuclear reactor power system (SNRPS) is a priority technical solution to meet the future space power requirement of high-power, low-mass, and long-life. The thermoelectric conversion subsystem ...is the key component of SNRPS, which greatly affects the performance, quality, and volume of SNRPS. Among all kinds of proposed thermoelectric conversion technologies, the free-piston Stirling power converter (FPSPC) has become a preferred conversion technology for small-scale advanced SNPRS due to its moderate waste heat emission temperature and high conversion efficiency, mainly composed of a linear alternator and free-piston Stirling engine (FPSE). For studying the performance of FPSPC, a quasi-steady flow thermodynamic cycle analysis model considering parasitic heat losses has been developed for FPSE. And then the performance analysis model for FPSPC has been established by coupling the thermodynamic cycle analysis model with the mechanical motion model of the piston and volt-ampere characteristic model of the linear alternator. Furthermore, the analysis model was compared and validated by the GPU-3 Stirling engine’s experimental data. The performance parameters of Component Test Power Converter (CTPT) FPSPC designed by NASA for SNRPS were also analyzed. The results show that the amplitudes position of CTPC displacer and piston are 15.1 mm and 11.2 mm, respectively. The corresponding average electric power output of CTPC is 17.316 kW. The input thermal power to the CTPT heater is 66.1 kW, leading to the converter efficiency of 26.2%. The average current and voltage of the CTPC alternator are 86.38 A and 193.15 V, respectively. Among all kinds of parasitic energy losses, the regenerator heat loss accounts for the largest proportion, with an average of about 12.7 kW. The effects of cooler and heater temperature on the performance of CTPC FPSPC were also studied.
Recent studies have found that rifampicin has neuroprotective properties in neurodegenerative diseases. However, the exact mechanisms of action remain unclear. The nuclear factor erythroid 2-related ...factor 2 (Nrf2) has been considered a potential target for neuroprotection. In this study, we examined whether rifampicin exhibits beneficial effects mediated by the Nrf2 pathway after global cerebral ischemia (GCI).
Rats were randomly assigned to four groups that included a sham group and three treatment groups with global ischemia-reperfusion control, rifampicin, and rifampicin plus brusatol (an inhibitor of Nrf2). Rats were subjected to transient GCI induced by bilateral common carotid artery occlusion for 20 min with systemic hypotension by blood withdrawal. The Morris water maze test was performed for neurobehavioral testing, whereas the pathological changes were investigated using HE and TUNEL staining. The protein expression of Nrf2, hemeoxygenase-1 (HO-1) and cyclooxygenase-2 (COX-2) in the hippocampus were analyzed by Western blotting. The immunofluorescence staining was used to determine the distribution of Nrf2.
Rifampicin treatment significantly improved spatial learning ability compared with the control group, which was consistent with the pathological changes. In addition, rifampicin significantly elevated the nuclear expression of Nrf2, Nrf2 downstream anti-oxidant protein, HO-1 compared with the control group, and it simultaneously downregulated the expression of COX-2 in the hippocampus on day 3 after ischemia-reperfusion. Interestingly, the forenamed effects of rifampicin were abolished by pretreatment with brusatol, a specific inhibitor of Nrf2 activation.
Rifampicin exerts neuroprotective effects against global cerebral ischemia, which may be attributed to activation of the Nrf2 pathway.
Canine coronavirus (CCoV), a member of the genus
Alphacoronavirus
, is an enveloped, single-stranded positive-sense RNA virus that responsible for gastroenteritis in dogs. In this study, two CCoV ...isolates were successfully propagated from 53 CCoV-positive clinical specimens by serial passaging in A-72 cells. These two strains, CCoV JS1706 and CCoV JS1712, caused cytopathic effects in A-72 cells. The sizes of virus plaque formed by them differed in early passages. Electron microscopy revealed a large quantity of typical coronavirus particles with 80–120 nm in diameter in cell culture media and cytoplasm of infected cells, in which they appeared as inclusion bodies. RT-PCR analysis of
S
gene indicated that these two isolates were belonged to CCoV IIa subtype. Homology of RdRp, S, M and N proteins between the two strains were 100, 99.6, 99.2 and 100.0%, respectively, whereas they were 99.4–100%, 83.1–95.2%, 88.5–99.2% and 91.9–99.7% identity compared to CCoV II reference strains. Phylogenetic analysis of RdRp, S, M and N protein showed that they were closely related to CCoV II strains. These two subtype IIa isolates will be useful for evaluating the pathogenesis and evolution of CCoV and for developing diagnostic reagents and vaccines.
Lymphoma is a common cause of cancer worldwide with an increasing incidence in recent years. A large number of studies have shown that HOX transcript antisense intergenic RNA (HOTAIR) exerts as an ...oncogene in various neoplasms. However, the function of HOTAIR in lymphoma still remains unclear. The present study aimed to investigate the function of HOTAIR in lymphoma and its underlying mechanisms. The expressions of HOTAIR, miR‐148b, and BMI1 in lymphoma samples and cells (AHH‐1, Raji, and U937) were quantified by quantitative reverse polymerase chain reaction (qRT‐PCR). Cell viability was measured by trypan blue assay. The efficiency of transfection was verified by qRT‐PCR or Western blot analysis. Apoptotic cells and cell cycle progression were both detected by flow cytometry assay. Furthermore, Western blot analysis was performed to assess the expression of mitogen‐activated protein kinase (MAPK) and extracellular signal‐regulated kinase (ERK) pathway‐related core factors. We found that HOTAIR knockdown reduced cell viability but increased apoptotic cells and inhibited cell cycle progression in Raji and U937 cells. miR‐148b expression was upregulated by HOTAIR inhibition. Meanwhile, miR‐148b inhibitor abolished the modulation of HOTAIR silence on cell growth, as evidenced by increased cell viability, reduced apoptotic cells, and decreased the rate of G1 phase cells. Furthermore, miR‐148b negatively regulated the expression of BMI1 by targeting its 3′‐untranslated region (3′‐UTR), and BMI1 overexpression blocked the effect of miR‐148b mimic on cell growth. In addition, BMI1 promoted the activation of MAPK and ERK in Raji and U937 cells. In conclusion, the present study demonstrated that HOTAIR knockdown inhibited the cell growth and promoted apoptosis of lymphoma cells via upregulation of miR‐148b and miR‐148b further regulated the expression of BMI1 via MAPK and ERK signaling pathways.
The present study demonstrated that HOTAIR (HOX transcript antisense intergenic RNA) knockdown inhibited the cell growth of lymphoma via upregulation of miR‐148b and miR‐148b, and further regulated the expression of BMI1
Phyllosphere microbial communities are highly diverse and have important ecological implications; in that context, bacterial identification based on 16S rRNA genes is an important research issue. In ...studies of phyllosphere microbial communities, microporous filtration and centrifugation are used to collect microorganism samples, but it is unclear which one has a better collection efficiency. In this study, we compared these two microorganism collection methods and investigated the effects of the DNA extraction process on the estimation of microbial community composition and organization. The following four treatments were examined: (A) filtration, resuspension, and direct PCR; (B) filtration, DNA isolation, and PCR; (C) centrifugation, resuspension, and direct PCR; (D) centrifugation, DNA isolation, and PCR. Our results showed that the percentage of chloroplast sequence contaminants was affected by the DNA extraction process. The bacterial compositions clearly differed between treatments A and C, suggesting that the collection method has an influence on the determination of community structure. Compared with treatments B and D, treatments A and C resulted in higher Shannon index values, indicating that the DNA extraction process might reduce the observed phyllosphere microbial alpha diversity. However, with respect to community structure, treatments B and D yielded very similar results, suggesting that the DNA extraction process erases the effect of the collection method. Our findings provide key information to ensure accurate estimates of diversity and community composition in studies of phyllosphere microorganisms.
Background Air pollution may induce or reinforce nasal inflammation regardless of allergy status. There is limited direct clinical evidence informing the treatment of airborne pollution-related ...rhinitis. Objective To assess the effectiveness of intranasal budesonide in adults with self-reported rhinitis symptoms triggered/worsened by airborne pollution. Methods Adults in northern China with self-reported rhinitis symptoms triggered or worsened by airborne pollution were randomized to budesonide 256 microg/day or placebo for 10 days in pollution season (October 2019 to February 2020). The primary endpoint was the mean change from baseline in 24-h reflective total nasal symptom score (rTNSS) averaged over 10 days. The secondary endpoints were subject-assessed Global Impression of Change (SGIC), mean change from baseline in individual nasal symptom severity, and mean change from baseline in individual non-nasal symptoms of cough and postnasal drip severity. One-sided P < 0.0125 was considered statistically significant. Results After an interruption by COVID-19, an interim analysis showed that the study could be ended for efficacy with n = 206 participants (103/group) since the primary efficacy endpoint demonstrated significant results. The final efficacy results showed that the 10-day-averaged rTNSS change in the budesonide group was greater than with placebo (- 2.20 vs - 1.72, P = 0.0107). Budesonide also significantly improved 10-day-averaged itching/sneezing change (- 0.75 vs - 0.51, P = 0.0009). Results for SGIC and all other individual symptoms did not show significant differences between the two groups. Conclusions Intranasal budesonide 256 microg once daily improved the total nasal symptoms and itching/sneezing over 10 days in adults with rhinitis triggered/worsened by airborne pollution. Keywords: Airborne pollution, Air quality index, Budesonide, Intranasal corticosteroid, Intranasal spray, Non-allergic rhinitis, Perennial allergic rhinitis, Pollution, Rhinitis, Seasonal allergic rhinitis
PDF
