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A safe, efficacious and deployable vaccine is urgently needed to control COVID-19 pandemic. We report here the preclinical development of a COVID-19 vaccine candidate, ZF2001, which contains tandem-repeat dimeric receptor-binding domain (RBD) protein with alum-based adjuvant. We assessed vaccine immunogenicity and efficacy in both mice and non-human primates (NHPs). ZF2001 induced high levels of RBD-binding and SARS-CoV-2 neutralizing antibody in both mice and NHPs, and also elicited balanced TH1/TH2 cellular responses in NHPs. Two doses of ZF2001 protected Ad-hACE2-transduced mice against SARS-CoV-2 infection, as detected by reduced viral RNA and relieved lung injuries. In NHPs, vaccination of either 25 g or 50 g ZF2001 prevented infection with SARS-CoV-2 in lung, trachea and bronchi, with milder lung lesions. No evidence of disease enhancement is observed in both models. ZF2001 is being evaluated in the ongoing international multi-center Phase 3 trials (NCT04646590) and has been approved for emergency use in Uzbekistan.
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A safe and effective vaccine is urgently needed to control the unprecedented COVID-19 pandemic. Four adenovirus vectored vaccines expressing spike (S) protein have advanced into phase 3 trials, with three approved for use. Here, we generated several recombinant chimpanzee adenovirus (AdC7) vaccines expressing S, receptor-binding domain (RBD) or dimeric tandem-repeat RBD (RBD-tr2). We found vaccination via either intramuscular or intranasal route was highly immunogenic in mice to elicit both humoral and cellular (Th1-based) immune responses. AdC7-RBD-tr2 showed higher antibody responses compared with both AdC7-S and AdC7-RBD. Intranasal administration of AdC7-RBD-tr2 additionally induced mucosal immunity with neutralizing activity in bronchoalveolar lavage fluid. Either single-dose or two-dose mucosal administration of AdC7-RBD-tr2 protected mice against SARS-CoV-2 challenge, with undetectable subgenomic RNA in lung and relieved lung injury. These results support AdC7-RBD-tr2 as a promising COVID-19 vaccine candidate.
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Stopping COVID-19 is a priority worldwide. Understanding which cell types are targeted by SARS-CoV-2 virus, whether interspecies differences exist, and how variations in cell state influence viral entry is fundamental for accelerating therapeutic and preventative approaches. In this endeavor, we profiled the transcriptome of nine tissues from a Macaca fascicularis monkey at single-cell resolution. The distribution of SARS-CoV-2 facilitators, ACE2 and TMRPSS2, in different cell subtypes showed substantial heterogeneity across lung, kidney, and liver. Through co-expression analysis, we identified immunomodulatory proteins such as IDO2 and ANPEP as potential SARS-CoV-2 targets responsible for immune cell exhaustion. Furthermore, single-cell chromatin accessibility analysis of the kidney unveiled a plausible link between IL6-mediated innate immune responses aiming to protect tissue and enhanced ACE2 expression that could promote viral entry. Our work constitutes a unique resource for understanding the physiology and pathophysiology of two phylogenetically close species, which might guide in the development of therapeutic approaches in humans. Bullet pointsO_LIWe generated a single-cell transcriptome atlas of 9 monkey tissues to study COVID-19. C_LIO_LIACE2+TMPRSS2+ epithelial cells of lung, kidney and liver are targets for SARS-CoV-2. C_LIO_LIACE2 correlation analysis shows IDO2 and ANPEP as potential therapeutic opportunities. C_LIO_LIWe unveil a link between IL6, STAT transcription factors and boosted SARS-CoV-2 entry. C_LI
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Ischemic stroke is the main cause of death in Chinese population.Among the many risk factors for ischemic stroke,obesity is one of the controllable factors,which can indirectly increase the risk of stroke by causing diseases such as hyperlipidemia,hypertension,and diabetes.However,the current research results on the effects of obesity on the onset,treatment and outcome of stroke are still inconsistent.This article reviews the relationship between obesity and the risks,pathogeneses,outcomes of ischemic stroke,as well as obesity paradox.
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As a noninvasive technique that enables analysis of the arterial wall structure in vivo,high-resolution vascular wall magnetic resonance imaging has been widely used in the diagnosis and assessment of ischemic stroke.This article reviews the application of high-resolution vascular wall magnetic resonance imaging in patients with intraeranial atherosclerotic stroke.
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Objective To compare the contents in polysaccharide of aloe in gel of aloe with preparation in different processing methods on fresh aloe of outer cuticle and investigate their stability. It could provide technology of preparation of polysaccharide of aloe.Methods The aloe gel had been prepared through the fresh juicing method, and alcohol sinking was applied to abstract polysaccharides of aloe in proportion of sixty, seventy, eighty and ninety percent. The colorimetric method of anthracenone - thick sulfuric acid had been taken to determine contents of polysaccharide in different proportions by alcohol sinking. The contents of polysaccharide were compared among different processing methods in fresh aloe of outer cuticle, and then the stability on condition of different temperatures, pH and the reagent of reductant-oxidant with polysaccharides of aloe were investigated. Results The content abstracted from polysaccharide of aloe was the higher when the proportion was eighty percent and its character of powder was better. And content abstracted from polysaccharide of aloe with the outer cuticle was higher than that out of the outer cuticle. The powders from the polysaccharide of aloe with the outer cuticle were gray-green, gray-brown or gray-white. The powders from polysaccharide of aloe without the outer cuticle were partial-white, more well-distributed and delicate. The stability in polysaccharide of aloe was better with the condition of low temperature, reducing agent and the solution with pH from five to seven, while the stability was lower when in high temperature, oxidizing agent and the solution with strong acid and strong alkali. Conclusions The proportion of eighty percent with alcohol sinking, decorticating the outer cuticle of fresh aloe has the higher content and the better character in the polysaccharide of aloe.
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Objective To establish HPLC assaying methods for the determination of albiflorin in the Jinsha-Paishi infusion, and to determine the content of albiflorin of different batches ofJinsha-Paishiinfusion. Methods The chromatographic conditions were with the column of C18 (250 mm × 4.6 mm, 5μm), mobile phase of methyl alcohol-aqua (25:75,V/V), flow rate of 1.0 ml/min, and determined at wave length of 230 nm in room temperature. A total of 3 different batches of albiflorin were determined.Results In the range of 2.5-200μg, the distribution of paeoniflorin was linear (r=0.999 8), and theRSD of precision, stability and repeatability were less than 2%. The average recovery was 98.05%, andRSD was 1.65%. The contents of albiflorin in each batch were 0.080, 0.083, 0.077 mg/g.Conclusion The assaying method of HPLC is convenient, accurate and reliable to determinate the content of albiflrin in theJinsha-Paishi infusion. And the results showed that there was no difference of content of albiflorin among the different batches ofJinsha-Paishi infusion.
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Objective To determine the content of polysaccharide in Aloe barbadensis Miller and Aloe vera L. Var. Chinensis(Haw.)Berger. Methods Carubinose was used as reference substance, measured and compared polysaccharide content with the method of UV spectrophotometry at 610 nm absorbance of growth years for 1, 2, 3, 4 and 5 years of Aloe barbadensis Miller and Aloe vera L. Var. Chinensis(Haw.)Berger. Results The mannose and the absorbance was linear (r=0.998 5) in the range of 0.05 - 0.60 g/L, and the content of Aloe barbadensis Miller polysaccharide in the measured growth period was respectively 1.201, 1.485, 1.665, 2.355 and 5.040 mg/g. The content of polysaccharide in Aloe vera L. Var. Chinensis(Haw.)Berger was 0.780, 0.900, 1.035, 1.650 and 2.355 mg/g. Conclusions The content of polysaccharide in Aloe barbadensis Miller and Aloe vera L. Var. Chinensis(Haw.)Berger differed in growth years, which increased with aging and polysaccharide content in the same age of Aloe barbadensis Miller was significantly higher than that of the Aloe vera L. Var. Chinensis(Haw.)Berger.
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Extracorporeal photochemotherapy can correct immune disease and treat many autoimmune diseases. The aim of this study was to investigate the effects of delta-aminolevulinic acid photodynamic therapy (δ-ALA-PDT) on BXSB mouse. The 24-h urine protein, titers of serum antinuclear antibodies, peripheral blood lymphocyte apoptosis and deposition of immune complex in renal glomeruli were determined in BXSB mice after δ-ALA-PDT treatment. Results showed that δ-ALA-PDT treatment could reduce 24-h urine protein, titers of serum antinuclear antibodies, and deposition of immune complex in renal glomeruli. The δ-ALA-PDT treatment could also lead to significant increase in the rate of peripheral blood lymphocytes.
Subject(s)
Aminolevulinic Acid/therapeutic use , Photopheresis , Photosensitizing Agents/therapeutic use , Animals , Antibodies, Antinuclear/analysis , Disease Progression , Immune Complex Diseases/therapy , Kidney Glomerulus , Male , Mice , Mice, Inbred Strains , Rats , Rats, WistarABSTRACT
Objective To study the effects of transcranial magnetic stimulation (TMS) on learning and memory, and angiogenesis and the dendritic structure of hippocampal CA3 pyramidal neurons after cerebral infarction. Methods Forty-eight male Sprague-Dawley rats were divided into a sham operated group, a model group and a TMS group (n = 16). Rat models of focal cerebral infarction were established with unilateral middle cerebral artery (MCA) suture occlusion in the model and TMS groups. The rats of the TMS group were given 4 weeks of TMS treatment beginning 1 day after the infarction (2 times per day, 30 pulses per time). Their learning and memory abilities were tested with a Y-maze. Angiogenesis and the dendritic structure of their hippocampal CA3 pyramidal neurons were detected after 4 weeks. Results Compared with the model group, learning and memory improved significantly in the TMS group. The average microvessel density of the hippocampus in the TMS group was significantly more than in the model group. The total length of apical dendrites of hippocampal CA3 pyramidal neurons in TMS group was significantly longer than in the model group. Conclusions The improved learning and memory observed following TMS treatment are likely to be related to changes in angiogenesis, the dendritic.structure of the hippocampal CA3 pyramidal neurons, and enhanced synaptic plasticity.
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Objective To study the clinical characteristics of epidemic Japanese encephalitis in 4 adult patients and to improve the level of diagnosis.Methods The clinical characteristics, laboratory results and MRI features of 4 adult patients with epidemic Japanese encephalitis hospitalized in our hospital between 2007 and 2008 was retrospectively reviewed and analyzed.Results All patients were sporadic.Two were female and others were male with the age from 34 to 68 years old and onset in summer and autumn.One patient had diarrhea at onset while others had fever and headache at onset.All patients had high fever and psychiatric symptoms.Two patients had respiratory failure.Obvious elevation of white cells in cerebrospinal fluid was seen in all patients and Japanese viral antibody of IgM was all positive whereas the image of MRI was abnormal only in one patient.Two patients had neurological sequelae.Conclusions The clinical manifestations of epidemic Japanese encephalitis in adults are severe and untypical and the respiratory failure is likely to occur.
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The effect of transcranial magnetic stimulation (TMS) on the neurological functional recovery and expression of c-Fos and brain-derived neurotrophic factor (BDNF) of the cerebral cortex in rats with cerebral infarction was investigated. Cerebral infarction models were established by using left middle cerebral artery occlusion (MCAO) and were randomly divided into a model group (n=40) and a TMS group (n=40). TMS treatment (2 times per day, 30 pulses per time) with a frequency of 0.5 Hz and magnetic field intensity of 1.33 Tesla was carried out in TMS group after MCAO. Modified neurological severity score (NSS) were recorded before and 1, 7, 14, 21, and 28 day(s) after MCAO. The expression of c-Fos and BDNF was immunohistochemically detected 1, 7,14, 21, and 28 day(s) after infarction respectively. Our results showed that a significant recovery of NSS (P<0.05) was found in animals treated by TMS on day 7, 14, 21, and 28 as compared with the animals in the model group. The positive expression of c-Fos and BDNF was detected in the cortex surrounding the infarction areas, while the expression of c-Fos and BDNF increased significantly in TMS treatment group in comparison with those in model group 7, 14, 21, and 28 days (P<0.05) and 7,14, 21 days (P<0.01) after infarction, respectively. It is concluded that TMS has therapeutic effect on cerebral infarction and this may have something to do with TMS's ability to promote the expression of c-Fos and BDNF of the cerebral cortex in rats with cerebral infarction.
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OBJECTIVE:To evaluate the curative efficacy of Yixinshu capsule(YXSC)for patients with chronic heart failure(CHF)and its effects on plasma levels of angiotrnsionⅡ(Ang Ⅱ)and tumor necrosis factor-alpha(TNF-?).MET-HODS:60 patients with CHF were randomly assigned to either treatment group(n=30)or control group(n=30):the control group received conventional symptomatic treatment with western medicines including anti-infection therapy,relieving airway obstruction,continuous low-flow oxygen inhalation,cardiac and diuretic therapy,vasodilator,correcting acid-base imbalance and electrolyte disturbances etc;the treatment group received YXSC in combination with the above conventional symptomatic treatment.Plasma levels of AngⅡ and TNF-? in two groups before and after treatment were detected;and the cardiac function and the indexes of echocardiography(LVEF,A/E)of all cases were recorded in detail before and after treatment.Meanwhile,10 healthy subjects served as normal control.RESULTS:After treatment,plasma levels of AngⅡ and TNF-? in both group decreased remarkably(P
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BACKGROUND: Studies have shown that mild hypertension and hypothermia both offer cerebral protection against focal cerebral ischemia,and their possible synergistic effect may provide even better neuroprotective effects.OBJECTIVE: To investigate the mechanism of cerebral protection by induced hypertension combined with mild hypothermia against focal cerebral ischemia and reperfusion, through observation of the changes in the infarct volume and blood-brain barrier(BBB) in rats.DESIGN: A randomized controlled experimental study based on experimental animals.SETTING: The departments of neurology of two university hospitals and department of dermatology in a municipal hospital.MATERIALS: The study was carried out in the Laboratory of Department of Neurology, Union Hospital Affiliated to Tongji Medical College, Huazhong University of Science and Technology and Laboratory of Department of Neurology, People' s Hospital of Wuhan University from March to July 2001. Sixty-four Wistar rats weighing 180 to 230 g were purchased from the Experimental Animal Center of People' s Hospital of Wuhan University.INTERVENTIONS: Sixty-four rats were randomly divided into control group, hypertension group, mild hypothermia group, and combined therapy group, each group consisting of 16 rats. Reperfusion was initiated after a 3-hour focal cerebral ischemia of the 16 rats, and at 2 hour during the ischemia, the rats in the hypertension and mild hypothermia group were treated with hypertension for 3 hours and mild hypothermia, respectively, and those in the combined therapy group received both treatment. The rats in the control group received no treatments for ischemia and reperfusion. Twenty-four hours later, all rats were killed for examination.MAIN OUTCOME MEASURES: The scores of neurological deficits, infarct volume and degree of BBB damage.RESULTS: The scores for neurological deficits, infarct size and volume of Even' s blue staining were 2. 12 ±0. 54, (17.65 ±4.78)%, and(56.63± 10.70) mm3, respectively, in hypertension group, and 2. 14 ±0.69,(16. 21 ± 3.79)%, and(53.52 ± 8.44) mm3 in mild hypothermia group,and 1.78 ±0. 61, (11, 31 ±3.64)%, and 38.45 ±5.25 mm3 in combined therapy group, which were all decreased significantly as compared with the control group[2.70 ±0. 64, (28.34 ±4. 13)%, and(94.87 ± 15.34) mm3].The combined therapy group had the smallest infarct size and volume of Even's blue staining among the three treatment groups( P < 0.05).CONCLUSION: Hypertension and mild hypothermia may reduce the infarct volume and alleviate BBB damage during focal cerebral ischemia and reperfusion in rats, and the effects of combined treatment are more obvious.
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Objective To evaluate the effects of TMS on the brain plasticity and functional outcome after cerebral infarction in rats. Methods Twenty-four male Sprague-Dawley rats were divided randomly into a model group and a TMS group. The rat models of focal cerebral infarction were established with unilateral middle cerebral artery (MCA) suture occlusion method. The rats of TMS group were given additional 4 weeks of TMS treatment commenced at!1 day after infarction (2 times per day, 30 pulses per time), while those in the control group were reared in their original living state. Synaptic substructure in the sensori-motor cortex area was assessed morphologically and quantitatively. Results When compared with the model group, the rats in the experimental group had a significant improvement in terms of their neural functions (P
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Objective To study the effects of transcranial magnetic stimulation (TMS) on the expression of c-Fos and brain-derived neurotrophic factor (BDNF) of the cerebral cortex in rats with cerebral infarction. Methods Cerebral infarction models were established by using of left middle cerebral artery occlusion (MCAO) and randomly divided into a model group (n=40) and a TMS group (n=40), in additional, TMS treatment (2 times per day, 30 pulses per time) with frequency of 0.5 Hz and magnetic field intensity of 1.33 Tesla was carried out in TMS group after infarction. The expression of c-Fos and BDNF was measured at 1 d, 7 d, 14 d, 21 d and 28 d after infarction, respectively. Results The positive expression c-Fos and BDNF was detected in the cortex around the infarction areas, while the expression of c-Fos and BDNF was increased significantly in TMS group in comparison to those in model group at 7 d, 14 d, 21 d, 28 d (P