This is the first randomised controlled trial for assessment of the immunogenicity and safety of a candidate non-replicating adenovirus type-5 (Ad5)-vectored COVID-19 vaccine, aiming to determine an ...appropriate dose of the candidate vaccine for an efficacy study.
This randomised, double-blind, placebo-controlled, phase 2 trial of the Ad5-vectored COVID-19 vaccine was done in a single centre in Wuhan, China. Healthy adults aged 18 years or older, who were HIV-negative and previous severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection-free, were eligible to participate and were randomly assigned to receive the vaccine at a dose of 1 × 1011 viral particles per mL or 5 × 1010 viral particles per mL, or placebo. Investigators allocated participants at a ratio of 2:1:1 to receive a single injection intramuscularly in the arm. The randomisation list (block size 4) was generated by an independent statistician. Participants, investigators, and staff undertaking laboratory analyses were masked to group allocation. The primary endpoints for immunogenicity were the geometric mean titres (GMTs) of specific ELISA antibody responses to the receptor binding domain (RBD) and neutralising antibody responses at day 28. The primary endpoint for safety evaluation was the incidence of adverse reactions within 14 days. All recruited participants who received at least one dose were included in the primary and safety analyses. This study is registered with ClinicalTrials.gov, NCT04341389.
603 volunteers were recruited and screened for eligibility between April 11 and 16, 2020. 508 eligible participants (50% male; mean age 39·7 years, SD 12·5) consented to participate in the trial and were randomly assigned to receive the vaccine (1 × 1011 viral particles n=253; 5 × 1010 viral particles n=129) or placebo (n=126). In the 1 × 1011 and 5 × 1010 viral particles dose groups, the RBD-specific ELISA antibodies peaked at 656·5 (95% CI 575·2–749·2) and 571·0 (467·6–697·3), with seroconversion rates at 96% (95% CI 93–98) and 97% (92–99), respectively, at day 28. Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with GMTs of 19·5 (95% CI 16·8–22·7) and 18·3 (14·4–23·3) in participants receiving 1 × 1011 and 5 × 1010 viral particles, respectively. Specific interferon γ enzyme-linked immunospot assay responses post vaccination were observed in 227 (90%, 95% CI 85–93) of 253 and 113 (88%, 81–92) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Solicited adverse reactions were reported by 183 (72%) of 253 and 96 (74%) of 129 participants in the 1 × 1011 and 5 × 1010 viral particles dose groups, respectively. Severe adverse reactions were reported by 24 (9%) participants in the 1 × 1011 viral particles dose group and one (1%) participant in the 5 × 1010 viral particles dose group. No serious adverse reactions were documented.
The Ad5-vectored COVID-19 vaccine at 5 × 1010 viral particles is safe, and induced significant immune responses in the majority of recipients after a single immunisation.
National Key R&D Programme of China, National Science and Technology Major Project, and CanSino Biologics.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Medium-sized rings, including those embedded in bridged and fused bicyclic scaffolds, are common core structures of myriad bioactive molecules. Among various synthetic strategies towards their ...synthesis, intermolecular higher-order cycloaddition provides great potential to build complex medium-sized rings from simple building blocks. Unfortunately, such transformations are often plagued with competitive reaction pathways and low levels of site- and stereoselectivity. Herein, we report catalyst-controlled divergent access to three classes of medium-sized bicyclic compounds in high efficiency and stereoselectivity, by palladium-catalysed cycloadditions of tropones with γ-methylidene-δ-valerolactones. Mechanistic studies and density functional theory calculations disclosed that the divergent reactions stem from the different reaction profiles of the diastereomeric intermediates. While one undergoes either O- or C-allylation to provide 5.5.0 or 4.4.1 bicyclic compounds, the unique conformation of the other diastereomer allows an unconventional alkene isomerization to deliver bridgehead alkene-containing bicyclo4.4.1 compounds. The conversion of these products to diverse complex polycyclic scaffolds has also been demonstrated.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Uniform and patterned orientation of a crystallographic direction of ordered materials is of fundamental significance and of great interest for electronic and photonic applications. However, such ...orientation control is generally complicated and challenging with regard to inorganic and organic crystalline materials due to the occurrence of uncontrollable dislocations or defects. Achieving uniform lattice orientation in frustrated liquid‐crystalline phases, like cubic blue phases, is a formidable task. Taming and tailoring the ordering of such soft, cubic lattices along predetermined or desired directions, and even imparting a prescribed pattern on lattice orientation, are more challenging, due to the entropy‐domination attribute of soft matter. Herein, we disclose a facile way to realize designed micropatterning of a crystallographic direction of a soft, cubic liquid‐crystal superstructure, exhibiting an alternate uniform and random orientation of the lattice crystallographic direction enabled by a photoalignment technique. Because of the rewritable trait of the photoalignment film, the pattern can be erased and rewritten on‐demand by light. Such an oriented soft lattice sensitively responds to various external stimuli such as temperature, electric field, and light irradiation. Furthermore, advanced reflective photonic applications are achieved based on the patterned crystallographic orientation of the cubic blue phase, soft lattice.
A facile way to realize designed micropatterning of a crystallographic direction of a soft, cubic liquid‐crystal superstructure is disclosed, exhibiting an alternate uniform and random orientation of the lattice crystallographic direction, enabled by a photoalignment technique, which has not been accomplished before.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Hepatic sinusoidal obstruction syndrome (HSOS) can be caused by the intake of pyrrolizidine alkaloids (PAs). To date, PAs-induced HSOS has not been extensively studied. In view of the difference in ...etiology of HSOS between the West and China, clinical profiles, imaging findings, treatment, and outcomes of HSOS associated with hematopoietic stem cell transplantation or oxaliplatin might be hardly extrapolated to PAs-induced HSOS. Reactive metabolites derived from PAs form pyrrole-protein adducts that result in toxic destruction of hepatic sinusoidal endothelial cells. PAs-induced HSOS typically manifests as painful hepatomegaly, ascites, and jaundice. Laboratory tests revealed abnormal liver function tests were observed in most of the patients with PAs-induced HSOS. In addition, contrast computed tomography and magnetic resonance imaging scan show that patients with PAs-induced HSOS have distinct imaging features, which reveal that radiological imaging provides an effective noninvasive method for the diagnosis of PAs-induced HSOS. Liver biopsy and histological examination showed that PAs-induced HSOS displayed distinct features in acute and chronic stages. Therapeutic strategies for PAs-induced HSOS include rigorous fluid management, anticoagulant therapy, glucocorticoids, transjugular intrahepatic portosystemic shunt, liver transplantation,
. The aim of this review is to describe the pathogenesis, clinical profiles, diagnostic criteria, treatment, and outcomes of PAs-induced HSOS.
Photosynthetic CO2 assimilation (AN) under fluctuating light (FL) plays a critical role in plant growth and crop yield. C4 crops usually reach greater yields than C3 crops when grown in regions with ...low relative humidity, which might be partly due to the CO2 concentration mechanism and higher AN under FL of C4 crops. To test this hypothesis, we measured gas exchange and chlorophyll fluorescence under different changing frequencies of FL at contrasting relative air humidity (60% and 15%) for leaves of maize (Zea mays, C4) and tomato (Solanum lycopersicum, C3). In general, a more rapid changing frequency of FL would cause a larger loss in AN during shade‐sun transitions, with 20–38% in maize and 16–52% in tomato. Low relative humidity induced a larger decrease of stomatal conductance (gs) under FL in tomato than in maize, leading to a much stronger loss in AN in tomato than in maize. After transition from low to high light, AN of maize was mainly limited by gs with negligible non‐stomatal limitation, and the stomatal limitation was slightly affected by relative humidity. By comparison, low relative humidity significantly increased the stomatal limitation of AN in tomato but hardly affected non‐stomatal limitation. These results highlight the differential impact of decreasing relative humidity on dynamic photosynthesis and productivity between C3 and C4 crops.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Wound healing is a complex and error‐prone process. Wound healing in adults often leads to the formation of scars, a type of fibrotic tissue that lacks skin appendages. Hypertrophic scars and keloids ...can also form when the wound‐healing process goes wrong. Leptin (Lep) and leptin receptors (LepRs) have recently been shown to affect multiple stages of wound healing. This effect, however, is paradoxical for scarless wound healing. On the one hand, Lep exerts pro‐inflammatory and profibrotic effects; on the other hand, Lep can regulate hair follicle growth. This paper summarises the role of Lep and LepRs on cells in different stages of wound healing, briefly introduces the process of wound healing and Lep and LepRs, and examines the possibility of promoting scarless wound healing through spatiotemporal, systemic, and local regulation of Lep levels and the binding of Lep and LepRs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Background and Purpose
Protein palmitoylation is involved in learning and memory, and in emotional disorders. Yet, the underlying mechanisms in these processes remain unclear. Herein, we describe ...that A‐kinase anchoring protein 150 (AKAP150) is essential and sufficient for depressive‐like behaviours in mice via a palmitoylation‐dependent mechanism.
Experimental Approach
Depressive‐like behaviours in mice were induced by chronic restraint stress (CRS) and chronic unpredictable mild stress (CUMS). Palmitoylated proteins in the basolateral amygdala (BLA) were assessed by an acyl‐biotin exchange assay. Genetic and pharmacological approaches were used to investigate the role of the DHHC2‐mediated AKAP150 palmitoylation signalling pathway in depressive‐like behaviours. Electrophysiological recording, western blotting and co‐immunoprecipitation were performed to define the mechanistic pathway.
Key Results
Chronic stress successfully induced depressive‐like behaviours in mice and enhanced AKAP150 palmitoylation in the BLA, and a palmitoylation inhibitor was enough to reverse these changes. Blocking the AKAP150‐PKA interaction with the peptide Ht‐31 abolished the CRS‐induced AKAP150 palmitoylation signalling pathway. DHHC2 expression and palmitoylation levels were both increased after chronic stress. DHHC2 knockdown prevented CRS‐induced depressive‐like behaviours, as well as attenuating AKAP150 signalling and synaptic transmission in the BLA in CRS‐treated mice.
Conclusion and Implications
These results delineate that DHHC2 modulates chronic stress‐induced depressive‐like behaviours and synaptic transmission in the BLA via the AKAP150 palmitoylation signalling pathway, and this pathway may be considered as a promising novel therapeutic target for major depressive disorder.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Recent studies have demonstrated that commercially available lipid‐lowering drugs cause various side effects; therefore, searching for anti‐hyperlipidaemic compounds with lower toxicity is a research ...hotspot. This study was designed to investigate whether the marine‐derived compound, 5‐hydroxy‐3‐methoxy‐5‐methyl‐4‐butylfuran‐2(5H)‐one, has an anti‐hyperlipidaemic activity, and the potential underlying mechanism in vitro. Results showed that the furanone had weaker cytotoxicity compared to positive control drugs. In RAW 264.7 cells, the furanone significantly lowered ox‐LDL‐induced lipid accumulation (~50%), and its triglyceride (TG)‐lowering effect was greater than that of liver X receptor (LXR) agonist T0901317. In addition, it significantly elevated the protein levels of peroxisome proliferator‐activated receptors (PPARα) and ATP‐binding cassette (ABC) transporters, which could be partially inhibited by LXR antagonists, GSK2033 and SR9243. In HepG2 cells, it significantly decreased oleic acid‐induced lipid accumulation, enhanced the protein levels of low‐density lipoprotein receptor (LDLR), ABCG5, ABCG8 and PPARα, and reduced the expression of sterol regulatory element‐binding protein 2 (~32%). PPARα antagonists, GW6471 and MK886, could significantly inhibit the furanone‐induced lipid‐lowering effect. Furthermore, the furanone showed a significantly lower activity on the activation of the expression of lipogenic genes compared to T0901317. Taken together, the furanone exhibited a weak cytotoxicity but had powerful TC‐ and TG‐lowering effects most likely through targeting LXRα and PPARα, respectively. These findings indicate that the furanone has a potential application for the treatment of dyslipidaemia.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Precipitation-hardening high-entropy alloys (PH-HEAs) with good strength-ductility balances are a promising candidate for advanced structural applications. However, current HEAs emphasize ...near-equiatomic initial compositions, which limit the increase of intermetallic precipitates that are closely related to the alloy strength. Here we present a strategy to design ultrastrong HEAs with high-content nanoprecipitates by phase separation, which can generate a near-equiatomic matrix in situ while forming strengthening phases, producing a PH-HEA regardless of the initial atomic ratio. Accordingly, we develop a non-equiatomic alloy that utilizes spinodal decomposition to create a low-misfit coherent nanostructure combining a near-equiatomic disordered face-centered-cubic (FCC) matrix with high-content ductile Ni
Al-type ordered nanoprecipitates. We find that this spinodal order-disorder nanostructure contributes to a strength increase of ~1.5 GPa (>560%) relative to the HEA without precipitation, achieving one of the highest tensile strength (1.9 GPa) among all bulk HEAs reported previously while retaining good ductility (>9%).
This study proposes a strategy for screening and validating of antioxidant compounds and components from leaves of yacon (Smallanthus sonchifolius Poepp. and Endl.) by variable selection based on ...weight analysis. The theoretical basis of variable selection lies in that the varied quantity of variables will influence the activity results of samples. The ethyl acetate fraction (sample 0) with high DPPH scavenging activity was further separated using silica gel chromatographic column to obtain 17 subfractions (samples 1-17). The 18 samples contain different compounds exhibited different DPPH radical scavenging activities. Two components A and B with time range of 2.00-12.00 min and 53.00-64.00 min on the chromatogram were selected by variable selection, respectively. Simultaneously, a large number of compounds with different retention times (RTs) were screened out. Five predicted compounds, including chlorogenic acid, methyl caffeate, ethyl caffeate, homoeriodictyol, quercetin 3,7-dimethyl ether were isolated and verified by DPPH radical scavenging ability assay. The radical scavenging rates of those compounds were higher than that of ethyl acetate fraction and the positive control butylated hydroxyltoluene (BHT). Meanwhile, components A and B also show strong antioxidant activity. The radical scavenging activity of component A is higher than that of compounds which contained in component A, indicating the existence of synergistic antioxidant activity of compounds. The results of variable selection show that the proposed method is simple and reliable in screening the most active components and compounds. The method could be used for screening of compounds and components from other herbal plants with other activities.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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