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The SARS-CoV-2 virus has caused an unprecedented global crisis, and curtailing its spread requires an effective vaccine which elicits a diverse and robust immune response. We have previously shown that vaccines made of a polymeric glyco-adjuvant conjugated to an antigen were effective in triggering such a response in other disease models and hypothesized that the technology could be adapted to create an effective vaccine against SARS-CoV-2. The core of the vaccine platform is the copolymer p(Man-TLR7), composed of monomers with pendant mannose or a toll-like receptor 7 (TLR7) agonist. Thus, p(Man-TLR7) is designed to target relevant antigen-presenting cells (APCs) via mannose-binding receptors and then activate TLR7 upon endocytosis. The p(Man-TLR7) construct is amenable to conjugation to protein antigens such as the Spike protein of SARS-CoV-2, yielding Spike-p(Man-TLR7). Here, we demonstrate Spike-p(Man-TLR7) vaccination elicits robust antigen-specific cellular and humoral responses in mice. In adult and elderly wild-type mice, vaccination with Spike-p(Man-TLR7) generates high and long-lasting titers of anti-Spike IgGs, with neutralizing titers exceeding levels in convalescent human serum. Interestingly, adsorbing Spike-p(Man-TLR7) to the depot-forming adjuvant alum, amplified the broadly neutralizing humoral responses to levels matching those in mice vaccinated with formulations based off of clinically-approved adjuvants. Additionally, we observed an increase in germinal center B cells, antigen-specific antibody secreting cells, activated T follicular helper cells, and polyfunctional Th1-cytokine producing CD4+ and CD8+ T cells. We conclude that Spike-p(Man-TLR7) is an attractive, next-generation subunit vaccine candidate, capable of inducing durable and robust antibody and T cell responses.
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A diverse portfolio of SARS-CoV-2 vaccine candidates is needed to combat the evolving COVID-19 pandemic. Here, we developed a subunit nanovaccine by conjugating SARS-CoV-2 Spike protein receptor binding domain (RBD) to the surface of oxidation-sensitive polymersomes. We evaluated the humoral and cellular responses of mice immunized with these surface-decorated polymersomes (RBDsurf) compared to RBD-encapsulated polymersomes (RBDencap) and unformulated RBD (RBDfree), using monophosphoryl lipid A-encapsulated polymersomes (MPLA PS) as an adjuvant. While all three groups produced high titers of RBD-specific IgG, only RBDsurf elicited a neutralizing antibody response to SARS-CoV-2 comparable to that of human convalescent plasma. Moreover, RBDsurf was the only group to significantly increase the proportion of RBD-specific germinal center B cells in the vaccination-site draining lymph nodes. Both RBDsurf and RBDencap drove similarly robust CD4+ and CD8+ T cell responses that produced multiple Th1-type cytokines. We conclude that multivalent surface display of Spike RBD on polymersomes promotes a potent neutralizing antibody response to SARS-CoV-2, while both antigen formulations promote robust T cell immunity.
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@#This study aimed to investigate the effects of total alkaloids from Picrasma quassioides(TAPQ)on collagen-induced arthritis(CIA)in rats. TAPQ were prepared by acid extraction and alkali precipitation. The qualitative analysis of TAPQ by HPLC-Q-TOF-MS/MS was carried out. Fourteen alkaloids were obtained and three of them were quantitatively analyzed by HPLC. The anti-inflammatory activity of TAPQ was investigated on RAW264. 7 induced by LPS. Dexamethasone was used as a positive control. The model of bovine type II collagen-induced rheumatoid arthritis in SD rats was established. Daily tail intravenous injection of 0. 907 or 1. 814 mg/kg of TAPQ was administered for 18 days continuously, using dexamethasone as a positive control. The changes of mean arthritis scores in the paw of the rats and the volume of the paw were measured every day. Compared with the model group, the TAPQ significantly reduced the degree of paw swelling(P< 0. 001). After the rats were sacrificed, the levels of TNF-α and IL-6 in the serum were measured. The TAPQ could significantly reduce the level of TNF-α(P< 0. 01)and IL-6(P< 0. 001). The pathological changes of the joints were observed by HE staining, the anti-inflammatory activity of TAPQ was good, and the degree of joint damage in rats was obviously reduced.
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Objective To investigate the target blood pressure level of restrictive fluid resuscitation in patients with traumatic hemorrhagic shock. Methods Sixty patients with traumatic hemorrhagic shock admitted to the First Affiliated Hospital of Bengbu Medical College from January 2016 to December 2018 were enrolled. All patients were resuscitated with sodium acetate ringer solution after admission. According to the difference of mean arterial pressure (MAP) target, the patients were divided into low MAP (60 mmHg ≤ MAP < 65 mmHg, 1 mmHg = 0.133 kPa), middle MAP (65 mmHg ≤ MAP < 70 mmHg) and high MAP (70 mmHg ≤ MAP < 75 mmHg) groups by random number table using the admission order with 20 patients in each group. Those who failed to reach the target MAP after 30-minute resuscitation were excluded and supplementary cases were deferred. The restrictive fluid resuscitation phase was divided into three phases: before fluid resuscitation, liquid resuscitation for 30 minutes and 60 minutes. The most suitable resuscitation blood pressure level was further speculated by monitoring the inflammatory markers and hemodynamics in different periods in each group of patients. Pearson correlation analysis was used to detect the correlation of variables. Results Before fluid resuscitation, there was no significant difference in hemodynamics or expressions of serum cytokines among the three groups. Three groups of patients were resuscitated for 30 minutes to achieve the target blood pressure level and maintain 30 minutes. With the prolongation of fluid resuscitation time, the central venous pressure (CVP), cardiac output (CO) and cardiac index (CI) were increased slowly in the three groups, and reached a steady state at about 30 minutes after resuscitation, especially in the high MAP group and the middle MAP group. The expressions of serum inflammatory factors in the three groups were gradually increased with the prolongation of fluid resuscitation time. Compared with the low MAP group and the high MAP group, after 30 minutes of resuscitation the middle MAP group was superior to the other two groups in inhibiting the expressions of pro-inflammatory factors tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and promoting anti-inflammatory factors IL-10 [TNF-α mRNA (2-ΔΔCt):0.21±0.13 vs. 0.69±0.34, 0.57±0.35; IL-6 mRNA (2-ΔΔCt): 0.35±0.31 vs. 0.72±0.39, 0.59±0.42; IL-10 mRNA (2-ΔΔCt): 1.25±0.81 vs. 0.61±0.46, 0.82±0.53; all P < 0.05], but there was no significant difference in promoting the expression of IL-4 mRNA among three groups. At 60 minutes of resuscitation, compared with the low MAP group and the high MAP group, the middle MAP group could significantly inhibit the expressions of TNF-α, IL-6 and promote IL-10 [TNF-α mRNA (2-ΔΔCt): 0.72±0.35 vs. 1.05±0.54, 1.03±0.49; IL-6 mRNA (2-ΔΔCt): 0.57±0.50 vs. 1.27±0.72, 1.01±0.64; IL-10 mRNA (2-ΔΔCt): 1.41±0.90 vs. 0.81±0.48, 0.94±0.61; all P < 0.05]. Compared with the high MAP group, the middle MAP group had significant differences in promoting the expression of IL-4 mRNA (2-ΔΔCt: 1.32±0.62 vs. 0.91±0.60, P < 0.05). There was no significant difference in serum cytokine expressions at different time points of resuscitation between the low MAP group and the high MAP group (all P > 0.05). Correlation analysis showed that there was a strong linear correlation between MAP and mRNA expressions of TNF-α, IL-6, IL-10 in the middle MAP group (r value was 0.766, 0.719, 0.692, respectively, all P < 0.01), but had no correlation with IL-4 (r = 0.361, P = 0.059). Fitting linear regression analysis showed an increase in 1 mmHg per MAP, the expression of TNF-α mRNA increased by 0.027 [95% confidence interval (95%CI) = 0.023-0.031, P < 0.001], IL-6 mRNA increased by 0.021 (95%CI = 0.017-0.024, P < 0.001), and IL-10 mRNA increased by 0.049 (95%CI = 0.041-0.058, P < 0.001). Conclusions When patients with traumatic hemorrhagic shock received restrict fluid resuscitation at MAP of 65-70 mmHg, the effect of reducing systemic inflammatory response and improving hemodynamics is better than the target MAP at 60-65 mmHg or 70-75 mmHg. It is suggested that 65-70 mmHg may be an ideal target MAP level for restrictive fluid resuscitation.
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Aesthetic and comfortable transparent retainers and clear plastic appliances are becoming increasingly popular, and their components, especially thermoplastic materials, are gradually attracting widespread interest. Orthodontic thermoplastic materials are versatile polymers, and thus their properties, such as force delivery, force relaxation, and aging properties have been comprehensively studied. Meanwhile, blending modification technology has been applied for the acquisition of novel materials with enhanced characteristics. In this paper, we review the types and properties of thermoplastic materials, the development process they undergo, factors that influence their properties, and some development prospects.
Subject(s)
Esthetics, Dental , Orthodontic Retainers , Plastics , Materials Testing , PolymersABSTRACT
OBJECTIVE:To establish a method for simultaneous determination of gallic acid,protocatechuic acid,catechuic acid,corilagin and brevifolincarboxylic acid in Geranium carolinianum. METHODS:HPLC was performed on the column of Won-daSil C18 WR with mobile phase of acetonitrile-0.1% Phosphoric acid(gradient elution)at a flow rate of 1.0 ml/min,the detection wavelength was 280 nm,the column temperature was 40 ℃,and the volume injection was 20 μl. RESULTS:The linear range was 0.02-20.02 for gallic acid(r=0.999 9),0.01-20.10 for protocatechuic acid(r=0.999 7),0.02-19.78 for catechuic acid(r=0.999 6), 0.02-20.02 for corilagin(r=0.999 9)and 0.02-20.10 for brevifolincarboxylic acid(r=0.999 5);RSDs of precision,stability and re-producibility tests were lower than <3.0%;recoveries were 95.1%-100.6%(RSD=2.20%,n=6),95.8%-100.6%(RSD=1.74%,n=6),95.1%-101.9%(RSD=2.71%,n=6),97.7%-103.1%(RSD=2.04%,n=6)and 95.3%-99.0%(RSD=1.46%,n=6). CONCLUSIONS:The method is simple,accurate and reproducible,and can be used for the contents determination of gallic ac-id,protocatechuic acid,catechuic acid,corilagin and brevifolincarboxylic acid in G. carolinianum.
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Objective To observe the clinical efficacy of diltiazem in patients with coronary disease following percutaneous coronary intervention(PCI).Methods From Jan 2014 to Jan 2016,116 cases of coronary disease were selected as the research subjects,they were randomly divided into the observation group(62cases)and the control group(54 cases).The control group was given conventional therapy,while the observation group was given diltiazem therapy on the basis of control group.The levels of BP,HR,NT -proBNP,CRP and angina frequency in the two groups were compared before and 24h,48h after PCI.The incidence of major adverse cardiovascular events(MACEs) was assessed at the sixth month after PCI.Results After surgery,the CRP levels of the observation group and control group were (40.1 ±7.4)mg/L and (41.7 ±8.8)mg/L,the NT -proBNP levels of the two groups were (501.8 ± 56.5)ng/L and (445.7 ±50.6)ng/L,which were significantly higher than preoperation(t =5.684,P <0.05).The blood pressure,heart rate,CRP,NT -proBNP of the observation group since 24 hours after PCI were (73.1 ± 6.2)mmHg,(121.7 ±15.8)mmHg,(68.1 ±7.9)times/min,(24.8 ±3.7)mg/L,(201.7 ±20.6)ng/L,which were significantly lower than those of control group [(85.6 ±9.3 )mmHg,(134.3 ±17.4)mmHg,(77.5 ± 9.2)times/min,(36.5 ±7.9)mg/L,(481.5 ±48.2)ng/L].The effect was kept over 48 hours(F =7.281,8.097, 6.945,7.682,6.517,all P <0.05).Angina pectoris after treatment in the observation group and control group were (1.5 ±0.9)times/month,(2.9 ±0.7)times/month,which were significantly lower than before treatment(t =7.584,P <0.05).The incidence rate of total MACE in the observation group was 4.84%,which was significantly lower than that in the control group(χ2 =6.942,P <0.05).Conclusion Diltiazem after PCI can decrease the adverse reaction, and help to improve the prognosis of patients.
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Objective To compare plasma concentrations of biomarkers of endothelial dysfunction between patients with primary aldosteronism (PA) and essential hypertension (EH),and to determine whether elevated levels of these biomarkers could predict development of early organ damage .Methods 56 PA patients ( the observation group) and 56 EH patients(the control group) matched for age,sex,blood pressure and duration of hypertension were included in this study .The plasma levels of biomarkers reflecting endothelial dysfunction [ von Willebrand factor (vWF),soluble intercellular adhesion molecule 1(sICAM-1),oxidized low density lipoprotein(ox-LDL)]were detec-ted and compared between PA and EH patients .The left ventricular mass index ( LVMI) determined by echocardio-graphy,24-hour urinary protein quantitative determination and urinary albumin excretion rate ( UAER) were analyzed to evaluate early organ damage .Results ( 1 ) In the observation group , the plasma markers of endothelial damage vWF (133.4 ±54.9)%,sICAM-1 (412.1 ±75.2)μg/L and ox-LDL (13.7 ±9.0) U/L levels were higher than those in the control group(t=4.642,3.955,2.843,all P<0.05),and the observation group had a higher 24 h urina-ry protein(t=2.042,P<0.05) and LVMI(t=7.235,P<0.05).(2)Correlation analysis showed that LVMI was positively correlated with PAC,ox-LDL,vWF (r=0.447,0.385,0.393,P=0.020,0.046,0.029),and was nega-tively correlated with admission blood K +(r=-0.294,P<0.05).UAER was positively correlated with PAC,vWF and sICAM-1 (r=0.622,0.389,0.499,all P<0.05),and was negatively correlated with admission blood K +(r=-0.314,P<0.05).Conclusion Patients with PA have severer endothelial dysfunction reflected by multiple bio-markers and earlier organ damage than patients with EH ,and plasma aldosterone concentration and multiple endotheli-al dysfunction biomarkers could independently predict early organ damage .
