Preclinical evaluation of RQ3013, a broad-spectrum mRNA vaccine against SARS-CoV-2 variants

The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike(S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the Wild-type, B.1.1.7, B.1.351, B.1.617.2, and the omicron B.1.1.529 variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. We also proved the safety of RQ3013 in NHP models. Our results provided key support for the evaluation of RQ3013 in clinical trials.

Alveolar regeneration following viral infection is independent of tuft cells

Severe injuries following viral infection cause lung epithelial destruction with the presence of ectopic basal progenitor cells (EBCs), although the exact function of EBCs remains controversial. We and others previously showed the presence of ectopic tuft cells in the disrupted alveolar region following severe influenza infection. Here, we further revealed that the ectopic tuft cells are derived from EBCs. This process is amplified by Wnt signaling inhibition but suppressed by Notch inhibition. Further analysis revealed that p63-CreER labeled population de novo arising during regeneration includes alveolar epithelial cells when Tamoxifen was administrated after viral infection. The generation of the p63-CreER labeled alveolar cells is independent of tuft cells, demonstrating segregated differentiation paths of EBCs in lung repair. EBCs and ectopic tuft cells can also be found in the lung parenchyma post SARS-CoV-2 infection, suggesting a similar response to severe injuries in humans.

Factors Influencing Alzheimer's Disease Risk: Whether and How They are Related to the APOE Genotype / 神经科学通报·英文版

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease featuring progressive cognitive impairment. Although the etiology of late-onset AD remains unclear, the close association of AD with apolipoprotein E (APOE), a gene that mainly regulates lipid metabolism, has been firmly established and may shed light on the exploration of AD pathogenesis and therapy. However, various confounding factors interfere with the APOE-related AD risk, raising questions about our comprehension of the clinical findings concerning APOE. In this review, we summarize the most debated factors interacting with the APOE genotype and AD pathogenesis, depict the extent to which these factors relate to APOE-dependent AD risk, and discuss the possible underlying mechanisms.

Effect of miR-506-3p on Proliferation and Apoptosis of Airway Smooth Muscle Cells in Asthmatic Mice by Regulating CCL2 Gene Expression and Mediating TLR4/NF-κB Signaling Pathway Activation.

We aimed to investigate the effect of miR-506-3p on the proliferation and apoptosis of airway smooth muscle cells (ASMCS) in asthmatic mice by regulating the activation of TLR4/NF-κB signaling pathway through targeted regulation of C-C Motif Chemokine Ligand 2 (CCL2) expression. Twenty-four BALB/c mice of specific pathogen-free grade were selected to establish asthmatic mouse model, which were randomly divided into normal control group and asthma model group (n = 12 for each group). HE and IHC staining, bioinformatics and dual luciferase reporter assay, RT-PCR MTT, flow cytometry and Western blot were used in this research. HE staining showed airway epithelium thickening, submucosal inflammatory cell infiltration and airway smooth muscle thickening, and the positive expression rate of CCL2 was significantly increased in asthma model group (all P < 0.05). CCL2 was the target gene of miR-506-3p. Moreover, the expression of miR-506-3p in asthma model group was significantly decreased, the mRNA and protein expression levels of CCL2, TLR4, NF-κB (p65) and Bcl-2 were significantly increased, while those of Bax were decreased (all P < 0.05). In miR-506-3p mimic group or siRNA-CCL2 group, the expression of CCL2, TLR4, NF-κB (p65) and Bcl-2 decreased obviously, while that of Bax increased, cell proliferation decreased, G1 phase prolonged, G2 & S phases shortened, and apoptosis rate increased significantly (all P < 0.05), whereas the opposite trends were found in miR-506-3p inhibitor group (all P < 0.05). However, there was no statistical difference in the above-mentioned indexes in miR-506-3p inhibitor + siRNA-CCL2 group (all P > 0.05). Overexpression of miR-506-3p can inhibit ASMCS proliferation and promote apoptosis via inhibiting CCL2 expression and suppressing the activation of TLR4/NF-κB signaling pathway. Inhibited expression of miR-506-3p can reverse the positive role of CCL2 gene silencing. Our study is the first to prove the beneficial role of miR-506-3p-CCL2-TLR4/NF-κB regulatory axis in the development of asthma.

Investigation of medical social work in Chinese hospitals / 中南大学学报(医学版)

To understand the development of medical social work in China, and provide reference and basis for promoting medical social work in the next stage.
 Methods: A random sampling method was used to survey and analyze the data from questionnaires distributed to hospitals at or above the second level in China.
 Results: Medical social work had been carried out in all parts of the country, but the development was not balanced with the establishment of specialized agencies accounting for about 7.9% of the total survey. Only 17.5% of the hospitals carried out medical social work as a routine work. The medical social work service mainly included volunteer operation and management, patient psychological counseling, and so on.
 Conclusion: The development of medical social work in hospitals in China is still in its infancy, and the regional development is not balanced. Lack of professionals, unclear responsibilities of medical social workers and low social identity of medical social work are the main factors restricting development.

Repair effect of brain protein hydrolysate on H2O2-induced oxidative damage in PC12 cells and optimization of formulation of its stomach floating tablets / 吉林大学学报(医学版)

Objective:To detect the repair effect of brain protein hydrolyzate(BPH)on the oxidative damage induced by H2O2in the PC12 cells,and to optimize the prescription of BPH stomach floating tablets using the star design effect surface method.Methods:The PC12 cells in the logarithmic phase were divided into normal control group,model group(300 μmol·L-1H2O2),BPH group,artificial gastric juice-treated BPH(GBPH)group, artificial intestinal juice-treated BPH(IBPH)group,artificial gastric juice-treated BPH tablets(GBPH-T)group and artificial gastric juice-treated BPH floating tablets(GBPH-FT)group(The latter five groups were added with 20,40,60,80 and 100 mg·L-1BPH treated with different conditions);at the same time blank control group was set up.The PC12 cells in normal control group didn't receive any treatment,the blank control group was added with medium only,and the PC12 cells in model group were treated with H2O2(300 μmol·L-1)for 3 h. The cell viability was detected by MTT assay.Using Design-expert 8.0.6 Trial software,the dosages of HPMC-K4M,octadecanol and acrylic resin Ⅱ were used as the investigation factors,and the 8 h cumulative release in vitro was used as the evaluation index to optimize the prescription.Results:Compared with normal control group, the activity of PCl2cells in 60 mg·L-1BPH group was increased(P<0.05).Compared with model group,the vitalities of PC12 cells in BPH group,IBPH group,GBPH group and GBPH-FT group were increased significantly (P<0.05 or P<0.01).Compared with BPH group,the cell viability in IBPH group was decreased significantly (P<0.05),and there was no significant difference in GBPH group(P>0.05).Compared with GBPH-T group, the cell viability in GBPH-FT group was significantly increased(P<0.05).The optimal prescription was BPH 20 mg,lactose 10 mg,magnesium stearate 0.4 mg,microcrystalline cellulose 20 mg,HPMC-K4M 27 mg, octadecanol 63 mg,acrylic resinⅡ13 mg;all floating tablets drift in 5 s and sustained floating > 8 h;the difference of the measured value of 8 h cumulative release and the predicted value was not statistically significant (P>0.05).Conclusion:BPH has a significant repair effect on the H2O2-induced oxidative damage in the PC12 cells.Star design-effect surface method has good predictability and reproducibility;it is reasonable and feasible, and can be used to optimize the prescription of BPH stomach floating tablets.

Protective effect of high activity deproteinized extract of calf blood on alcohol liver injury of mice / 吉林大学学报(医学版)

Objective:To observe the protective effect of deproteinized extract of calf blood (DECB)on the ethanol-induced liver injury of the mice,and to preliminaryly discuss its mechanism. Methods:Sixty healthy ICR mice were divided into control group,model group,positive drug group,low,medium and high doses of DECB groups (n=10).By intragastric administration,the mice in control group were given 20 mL·kg-1 saline solution, the mice in low,medium and high doses of DECB groups were administrated with 0.125,0.250,0.500 g·kg -1 DECB,and the mice in positive drug group were administrated with 0.63 g·kg -1 Hugan Tablets;once a day for 30 d. 1 h after the last administration,except control group,the mice in other groups were administrated with one-time grant of 50% ethanol 14 mL·kg -1 ,and fasted for 16 h to establish the models of acute alcohol liver injury.The endurance alcohol time and drunk time of the mice were determined,the activities of aspartate aminotransferase (ALT)and alanine transaminase (AST)activity in serum of the mice were detected,the levels of triglyceride (TG),glutathione (GSH)and malonic dialdehyde (MDA)in liver tissue were determined,and the pathological changes of liver tissue were detected.Results:Compared with model group,the drunk symptoms of the mice in different doses of DECB groups were obviously reduced,the endurance time of the mice in high dose of DECB group and positive drug group was prolonged (P <0.05),and the drinking time was shortened (P <0.05);the ALT and AST activities in serum in mediun and high doses of DECB groups were significantly lower than those in model group (P <0.05).Compared with model group,the MDA and TG levels in liver tissue of the mice in medium and high doses of DECB groups and positive drug group were obviously reduced,and the GSH levels were increased (P <0.05);compared with model group,the pathological damages of liver tissue of the mice in high dose of DECB group caused by ethanol were significantly reduced.Conclusion:DECB can improve ethanol-induced liver injury which may be related to the inhibition of hepatic oxidative stress response.

Synchrotron radiation-based Fourier-transform infrared spectromicroscopy for characterization of the protein/peptide distribution in single microspheres

The present study establishes a visualization method for the measurement of the distribution and localization of protein/peptide constituents within a single poly-lactide-co-glycolide (PLGA) microsphere using synchrotron radiation-based Fourier-transform infrared spectromicroscopy (SR-FTIR). The representative infrared wavenumbers specific for protein/peptide (Exenatide) and excipient (PLGA) were identified and chemical maps at the single microsphere level were generated by measuring and plotting the intensity of these specific bands. For quantitative analysis of the distribution within microspheres, Matlab software was used to transform the map file into a 3D matrix and the matrix values specific for the drug and excipient were extracted. Comparison of the normalized SR-FTIR maps of PLGA and Exenatide indicated that PLGA was uniformly distributed, while Exenatide was relatively non-uniformly distributed in the microspheres. In conclusion, SR-FTIR is a rapid, nondestructive and sensitive detection technology to provide the distribution of chemical constituents and functional groups in microparticles and microspheres.

The influence of controlling plasma glycemia in women with gestational diabetes mellitus on the prognosis of maternal and fetus / 中国基层医药

Objective To observe the climical significance of controlling plasma glycemia in pregnant women with gestational diabetes mellitus( GDM ) for improving the pregnant result and reducing the complications of maternal and fetus.Methods 120 pregnant women with GDM were dioided into two groups according to the information of plasma glycemia control,including 86 cases with well-controlled plasma glycemia ( A group) and 34 cases with poorcontrolled plasma glycemia( B group).50 cases normal pregnancy were selected as control group.The differences in complications of maternal and fetus were observed.Results Only the morbidity of PIH of A group was higher than that in normal pregnant women( x2 =5.920,P ＜ 0.05 ),while the morbidity of PIH,polyhydramnios,fetal macrosomia,premature labor,and newborn asphyxia in B group were higher than those in A group( all P ＜ 0.05 ).Conclusion Paying more attention on screening GDM in pregnant women,early diagnosis and control of blood glucose was essential for reducing the incidence of maternal and fetal complications.

Production of CCHF Virus-Like Particle by a Baculovirus-Insect Cell Expression System / 中国病毒学·英文版

Crimean-Congo Haemorrhagic Fever Virus(CCHFV)is a tick-born virus of the Nairovirus genus within the Bunyaviridae family,which is widespread and causes,high fatality. The nucleocapsid of CCHFV is comprised of N proteins that are encoded by the S segment. In this research,the N protein of CCHFV was expressed in insect cells using a recombinant baculovirus. Under an electron microscope,Virus-Like Particles (VLPs)with various size and morphology were observed in cytoplasmic vesicles in the infected cells.Sucrose-gradient purification of the cell lysate indicated that the VLPs were mainly located in the upper fraction after ultracentrifugation,which was confirmed by Western blot analysis and immuno-electron microscopy(IEM).