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The ongoing COVID-19 pandemic has had great societal and health consequences. Despite the availability of vaccines, infection rates remain high due to immune evasive Omicron sublineages. Broad-spectrum antivirals are needed to safeguard against emerging variants and future pandemics. We used mRNA display under a reprogrammed genetic code to find a spike-targeting macrocyclic peptide that inhibits SARS-CoV-2 Wuhan strain infection and also pseudoviruses containing spike proteins of SARS-CoV-2 variants or related sarbecoviruses. Structural and bioinformatic analyses reveal a conserved binding pocket between the receptor binding domain and other domains, distal to the ACE2 receptor-interaction site. Collectively, our data reveal a hitherto unexplored site of vulnerability in sarbecoviruses that can be targeted by peptides and potentially other drug-like molecules. One-Sentence SummaryWe identify a conserved site on the SARS-CoV-2 spike that can be targeted by a broadly neutralizing macrocyclic peptide.
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The ongoing evolution of SARS-CoV-2 has resulted in the emergence of Omicron, which displays striking immune escape potential. Many of its mutations localize to the spike protein ACE2 receptor-binding domain, annulling the neutralizing activity of most therapeutic monoclonal antibodies. Here we describe a receptor-blocking human monoclonal antibody, 87G7, that retains ultrapotent neutralization against SARS-CoV-2 variants including the Alpha, Beta, Gamma, Delta and Omicron (BA.1/BA.2) Variants-of-Concern (VOCs). Structural analysis reveals that 87G7 targets a patch of hydrophobic residues in the ACE2-binding site that are highly conserved in SARS-CoV-2 variants, explaining its broad neutralization capacity. 87G7 protects mice and/or hamsters against challenge with all current SARS-CoV-2 VOCs. Our findings may aid the development of sustainable antibody-based strategies against COVID-19 that are more resilient to SARS-CoV-2 antigenic diversity. One sentence summaryA human monoclonal antibody confers broad neutralization and protection against Omicron and other SARS-CoV-2 variants
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SARS-CoV-2 has infected millions of people globally and continues to undergo evolution. Emerging variants can be partially resistant to vaccine induced immunity and therapeutic antibodies, emphasizing the urgent need for accessible, broad-spectrum therapeutics. Here, we report a comprehensive study of ensovibep, the first trispecific clinical DARPin candidate, that can simultaneously engage all three units of the spike protein trimer to potently inhibit ACE2 interaction, as revealed by structural analyses. The cooperative binding of the individual modules enables ensovibep to retain inhibitory potency against all frequent SARS-CoV-2 variants, including Omicron BA.1 and BA.2, as of February 2022. Moreover, viral passaging experiments show that ensovibep, when used as a single agent, can prevent development of escape mutations comparably to a cocktail of monoclonal antibodies (mAb). Finally, we demonstrate that the very high in vitro antiviral potency also translates into significant therapeutic protection and reduction of pathogenesis in Roborovski dwarf hamsters infected with either the SARS-CoV-2 wild-type or the Alpha variant. In this model, ensovibep prevents fatality and provides substantial protection equivalent to the standard of care mAb cocktail. These results support further clinical evaluation and indicate that ensovibep could be a valuable alternative to mAb cocktails and other treatments for COVID-19.
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Objective:To summarize and evaluate the domestic and foreign evidence on the intervention and management of neuropathic pain in patients with spinal cord injury, so as to provide evidence-based basis for clinical nursing staff.Methods:According to "6S" evidence model of evidence pyramid, computer evidence retrieval was carried out. Expert consensus and evidence summary quality assessment used the corresponding evaluation criteria of JBI evidence-based Health Care Centers (2016), while evidence-based guidelines quality used AGREE Ⅱinstrument, and high quality evidence was extracted.Results:A total of 6 articles, including 5 guidelines and 1 expert consensus, were included in this study. A total of 22 pieces of evidence were extracted, including the assessment, intervention measures, feedback, education and nursing model of neuropathic pain in patients with spinal cord injury.Conclusion:This study summarizes the evidence for the intervention and management of pathologic pain in spinal cord injury, which can provide scientific basis for clinical nursing staff. As the evidence summarized in this study comes from many countries, sufficient evaluation of clinical environment and other related factors should be conducted before application to promote the quality of nursing.
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Globally accessible therapeutics against SARS-CoV-2 are urgently needed. Here, we report the generation of the first anti-SARS-CoV-2 DARPin molecules with therapeutic potential as well as rapid large-scale production capabilities. Highly potent multivalent DARPin molecules with low picomolar virus neutralization efficacies were generated by molecular linkage of three different monovalent DARPin molecules. These multivalent DARPin molecules target various domains of the SARS-CoV-2 spike protein, thereby limiting possible viral escape. Cryo-EM analysis of individual monovalent DARPin molecules provided structural explanations for the mode of action. Analysis of the protective efficacy of one multivalent DARPin molecule in a hamster SARS-CoV-2 infection model demonstrated a significant reduction of pathogenesis. Taken together, the multivalent DARPin molecules reported here, one of which has entered clinical studies, constitute promising therapeutics against the COVID-19 pandemic.
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Objective To understand the current situation of neurology nurses′self-efficacy and quality of nursing services in Lanzhou area, and explore the relationship between self-efficacy and the quality of nursing services. Methods Using the method of questionnaire, one hundred and the neurology nurses and hospitalized patients in 5 Grade 3 Level hospitals of Lanzhou city were investigated by using self-efficacy scales and Servqual scales. Results Neurology nurses′ self-efficacy in Lanzhou area was lower than the general population ( U=-9.875,P=0.042);the scores of quality of care from high to low were at reliability, tangibles, assurance, responsiveness, cost acceptability and empathy, which were-(0.12 ± 0.05) points,-(0.23 ± 0.03) points,-(0.24 ± 0.06) points,-(0.25 ± 0.02) points,-(0.26 ± 0.05) points,-(0.66 ± 0.03)points.Satisfaction arranged from high to low were assurance (89.98%), reliability (89.69%), responsiveness (89.12%), tangibles (87.66%), cost acceptability (87.08%), empathy (86.67%).There were positive correlations between satisfaction and expectations and perceived service quality, and the correlation between satisfaction and perceived qualities of service was higher. Moreover, there might exist positive correlation between self-efficacy score and quality of nursing services (reliability, assurance, responsiveness, empathy) (P values were 0.002, 0.001,0.012 and 0.005). Conclusions Neurology nurses in Lanzhou area have lower self-efficacy, and the perceived qualities of care from patients never exceed their expectations. As results, hospital managers should take measures to improve general self-efficacy of nurses, and thus enhance the quality of care.
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Objective To evaluate the effect of emulsified isoflurane postconditioning on nuclear factor?E2 related factor 2 ( Nrf2 )?antioxidant response element ( ARE ) signaling pathway during myocardial ischemia?reperfusion ( I∕R ) in rats in vitro. Methods Healthy male Sprague?Dawley rats, aged 4-5 months, weighing 250-300 g, were heparinized and anesthetized with intraperitoneal 1% amobarbital sodium 40 mg∕kg. Their hearts were excised and perfused in a Langendorff apparatus with K?H solution. Thirty?two isolated rat hearts were randomly divided into 4 groups ( n=8 each ) using a random number table: control group (group C), group I∕R, emulsified isoflurane postconditioning group (EIP group) and fat emulsion group ( group F) . After 20 min of equilibration, group C was continuously perfused with K?H solusion for 100 min. Group I∕R underwent 40 min of ischemia at 32 ℃, followed by reperfusion for 60 min. In EIP and F groups, after undergoing 40 min of global ischemia, the isolated hearts were perfused for 2 min with K?H solution containing 1.68 mmol∕L emulsified isoflurane and 712 mg∕L intralipid, respectively, starting from the onset of reperfusion, and then were continuously perfused with K?H solution containing oxygen at 37 ℃ for 58 min. Heart rate (HR), left ventricular developed pressure (LVDP), left ventricular end?diastolic pressure ( LVEDP ) , and positive maximal pressure of left ventricular increase (+dp∕dtmax ) were recorded at the end of equilibration and reperfusion. At the end of reperfusion, myocardial specimens were obtained from the left ventricle for examination of the ultrastructure of myocardial cells and for determination of Nrf2, heme oxygenase?1 ( HO?1) , quinone oxidoreductase 1 ( NQO1) , and superoxide dismutase 1 ( SOD1) and mRNA expression using Western blot and real?time PCR. Results Compared with group C, HR, +dp∕dtmax and LVDP were significantly decreased, and LVEDP was increased at the end of reperfusion in I∕R and F groups, LVDP was significantly decreased, LVEDP was increased, and no significant changes were found in HR and +dp∕dtmax at the end of reperfusion in EIP group, and Nrf2, HO?1, NQO1 and SOD1 and mRNA expression was down?regulated at the end of reperfusion in I∕R, EIP and F groups. Compared with group I∕R, HR, +dp∕dtmax and LVDP were significantly increased, and LVEDP was decreased at the end of reperfusion in EIP and F groups, Nrf2, HO?1, NQO1 and SOD1 and mRNA expression was significantly up?regulated at the end of reperfusion in EIP group, and Nrf2, HO?1, NQO1 and SOD1 mRNA expression was significantly up?regulated, Nrf2 and HO?1 expression was up?regulated, and no significant changes were found in NQO1 and SOD1 expression at the end of reperfusion in group F. Compared with group EIP, HR, +dp∕dtmax and LVDP were significantly decreased, LVEDP was increased, and Nrf2, HO?1, NQO1 and SOD1 and mRNA expression was down?regulated in group F. Conclusion Emulsified isoflurane postconditioning attenuates myocardial I∕R injury probably by activating Nrf2?ARE signaling pathway in isolated rat hearts.
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The microRNAs is a kind of endogenous and non-coding small RNA ,which possesses biological function negatively regulating gene expression.Recent researches also found that artificial controlling some microRNAs ex-pressions can improve heart function via regulating skeletal myoblasts through multiple mechanisms,so may become a new breakthrough point in myocardial infarction treatment area.
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Objective To evaluate the role of nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signaling pathway in mitigation of anoxia/reoxygenation (A/R)-induced damage to rat cardiomyocytes by emulsified isoflurane postconditioning.Methods Primarily cultured cardiomyocytes obtained from Sprague-Dawley rats,aged 16-20 weeks,were seeded into the laminin pre-treated 6-well plates at a density of 104/cm2 and cultured for 20 h.The cells were randomly divided into 3 groups (n =12 each) using a random number table:control group (group C),group A/R,and emulsified isoflurane postconditioning group (group EI).The cells were cultured for 110 min without any treatment in group C.The cells were exposed to 45 min anoxia followed by 60 min reoxygenation in A/R and EI groups.After 45 min of hypoxia,the cells were cultured with emulsified isoflurane 1.68 mmol/L for 5 min before onset of reoxygenation in group EI.At the end of reoxygenation,transmission electron microscope was used to observe the ultrastructure of myocardial cells,and mitochondrial function was scored.The mRNA and protein expression of Nrf2,heme oxygenase-1 (HO-1),superoxide dismutase 1 (SOD1),and quinone oxidoreductase 1 (NQO1) was detected by real-time PCR and Western blot.Laser scanning confocal microscopy was used to detect Nrf2 nuclear translocation at the end of incubation,and Nrf2 activity was recorded in the nucleus of myocardial cells.Results Compared with group C,the mitochondrial function score was significantly increased,the mRNA and protein expression of Nrf2,HO-1,SOD1 and NQO1 was down-regulated,and Nrf2 activity in the nucleus was enhanced in A/R and EI groups.Compared with group A/R,the mitochondrial function score was significantly decreased,the mRNA and protein expression of Nrf2,HO-1,SOD1 and NQO1 was up-regulated,and Nrf2 activity in the nucleus was enhanced in group EI.Conclusion The mechanism by which emulsified isoflurane postconditioning mitigates A/R-induced damage to rat cardiomyocytes is related to induced nuclear translocation of Nrf2 and activated Nrf2-ARE signaling pathway.
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Objective To observe the inhibitory role of valproic acid (VPA) in hypertrophic cardiomycytes induced by angiotensin Ⅱ (Ang Ⅱ)in rats. Methods The cultured rat cardiomyocytes were divided randomly into control group, hypertrophic group and VPA group. They were treated with Ang Ⅱ to induce hypertrophy and then given with VPA. The morphologic changes of cardiomyocytes were observed under the contrast phase microscope and electron microscope. The mRNA levels ofβ-MHC were exmained by reverse transcriptase polymerase chain reaction (RT-PCR) method. The protein expression of C-FOS was exmanined by immunohistochemistry method. Results Stimulated by Ang Ⅱ, the cardiomyocytes were enlarged under the contrast phase microscope and the ultrastructure also changed. After stimulated by Ang Ⅱ, the mRNA level of β-MHC and the protein expression of C-FOS increased in the hypertrophic cardiocytes. Given by VPA, these data decreased accordingly. Conclusion VPA may inhibit the cardiomyocyte hypertrophy induced by angiotensin Ⅱ in some degree.
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Objective To observe the inhibitory role of valproic acid(VPA) in hypertrophic cardiomycytes induced by angiotensin Ⅱ(AngⅡ)in rats.Methods The cultured rat cardiomyocytes were divided randomly into control group,hypertrophic group and VPA group.They were treated with AngⅡ to induce hypertrophy and then given with VPA.The morphologic changes of cardiomyocytes were observed under the contrast phase microscope and electron microscope.The mRNA levels of ?-MHC were exmained by reverse transcriptase polymerase chain reaction(RT-PCR) method.The protein expression of C-FOS was exmanined by immunohistochemistry method.ResultsStimulated by AngⅡ,the cardiomyocytes were enlarged under the contrast phase microscope and the ultrastructure also changed.After stimulated by AngⅡ,the mRNA level of ?-MHC and the protein expression of C-FOS increased in the hypertrophic cardiocytes.Given by VPA,these data decreased accordingly.Conclusion VPA may inhibit the cardiomyocyte hypertrophy induced by angiotensin Ⅱ in some degree.
