A vaccine to protect against COVID-19 is urgently needed. We aimed to assess the safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing ...the spike glycoprotein of a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strain.
We did a dose-escalation, single-centre, open-label, non-randomised, phase 1 trial of an Ad5 vectored COVID-19 vaccine in Wuhan, China. Healthy adults aged between 18 and 60 years were sequentially enrolled and allocated to one of three dose groups (5 × 1010, 1 × 1011, and 1·5 × 1011 viral particles) to receive an intramuscular injection of vaccine. The primary outcome was adverse events in the 7 days post-vaccination. Safety was assessed over 28 days post-vaccination. Specific antibodies were measured with ELISA, and the neutralising antibody responses induced by vaccination were detected with SARS-CoV-2 virus neutralisation and pseudovirus neutralisation tests. T-cell responses were assessed by enzyme-linked immunospot and flow-cytometry assays. This study is registered with ClinicalTrials.gov, NCT04313127.
Between March 16 and March 27, 2020, we screened 195 individuals for eligibility. Of them, 108 participants (51% male, 49% female; mean age 36·3 years) were recruited and received the low dose (n=36), middle dose (n=36), or high dose (n=36) of the vaccine. All enrolled participants were included in the analysis. At least one adverse reaction within the first 7 days after the vaccination was reported in 30 (83%) participants in the low dose group, 30 (83%) participants in the middle dose group, and 27 (75%) participants in the high dose group. The most common injection site adverse reaction was pain, which was reported in 58 (54%) vaccine recipients, and the most commonly reported systematic adverse reactions were fever (50 46%), fatigue (47 44%), headache (42 39%), and muscle pain (18 17%. Most adverse reactions that were reported in all dose groups were mild or moderate in severity. No serious adverse event was noted within 28 days post-vaccination. ELISA antibodies and neutralising antibodies increased significantly at day 14, and peaked 28 days post-vaccination. Specific T-cell response peaked at day 14 post-vaccination.
The Ad5 vectored COVID-19 vaccine is tolerable and immunogenic at 28 days post-vaccination. Humoral responses against SARS-CoV-2 peaked at day 28 post-vaccination in healthy adults, and rapid specific T-cell responses were noted from day 14 post-vaccination. Our findings suggest that the Ad5 vectored COVID-19 vaccine warrants further investigation.
National Key R&D Program of China, National Science and Technology Major Project, and CanSino Biologics.
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.
Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD). Accumulated damaged mitochondria, which are associated with impaired mitophagy, contribute to neurodegeneration in AD. We ...show levels of Disrupted‐in‐schizophrenia‐1 (DISC1), which is genetically associated with psychiatric disorders and AD, decrease in the brains of AD patients and transgenic model mice and in Aβ‐treated cultured cells. Disrupted‐in‐schizophrenia‐1 contains a canonical LC3‐interacting region (LIR) motif (210FSFI213), through which DISC1 directly binds to LC3‐I/II. Overexpression of DISC1 enhances mitophagy through its binding to LC3, whereas knocking‐down of DISC1 blocks Aβ‐induced mitophagy. We further observe overexpression of DISC1, but not its mutant (muFSFI) which abolishes the interaction of DISC1 with LC3, rescues Aβ‐induced mitochondrial dysfunction, loss of spines, suppressed long‐term potentiation (LTP). Overexpression of DISC1 via adeno‐associated virus (serotype 8, AAV8) in the hippocampus of 8‐month‐old APP/PS1 transgenic mice for 4 months rescues cognitive deficits, synaptic loss, and Aβ plaque accumulation, in a way dependent on the interaction of DISC1 with LC3. These results indicate that DISC1 is a novel mitophagy receptor, which protects synaptic plasticity from Aβ accumulation‐induced toxicity through promoting mitophagy.
Summary
Quercus dentata Thunb., a dominant forest tree species in northern China, has significant ecological and ornamental value due to its adaptability and beautiful autumn coloration, with color ...changes from green to yellow into red resulting from the autumnal shifts in leaf pigmentation. However, the key genes and molecular regulatory mechanisms for leaf color transition remain to be investigated.
First, we presented a high‐quality chromosome‐scale assembly for Q. dentata. This 893.54 Mb sized genome (contig N50 = 4.21 Mb, scaffold N50 = 75.55 Mb; 2n = 24) harbors 31 584 protein‐coding genes. Second, our metabolome analyses uncovered pelargonidin‐3‐O‐glucoside, cyanidin‐3‐O‐arabinoside, and cyanidin‐3‐O‐glucoside as the main pigments involved in leaf color transition. Third, gene co‐expression further identified the MYB‐bHLH‐WD40 (MBW) transcription activation complex as central to anthocyanin biosynthesis regulation.
Notably, transcription factor (TF) QdNAC (QD08G038820) was highly co‐expressed with this MBW complex and may regulate anthocyanin accumulation and chlorophyll degradation during leaf senescence through direct interaction with another TF, QdMYB (QD01G020890), as revealed by our further protein–protein and DNA–protein interaction assays.
Our high‐quality genome assembly, metabolome, and transcriptome resources further enrich Quercus genomics and will facilitate upcoming exploration of ornamental values and environmental adaptability in this important genus.
•There is difference in soil property between upper and lower layer of sliding surface.•Landslide erosion intensity linearly increased with increasing main root depth.•Vegetation types have a ...significant influence on shallow loess landslides.•Promote role of plant in landslide during rainfall should be given more attention.
Vegetation is widely used for controlling landslides around the world; however, rainfall-induced shallow landslides occur frequently on vegetation-covered slopes on the Chinese Loess Plateau during the rainy season. To probe this phenomenon, we conducted on-site investigations and measurements in the Nanxiaohegou catchment on the Loess Plateau to explore the effects of soil properties and vegetation on shallow loess landslides. Most of the loess landslides on vegetation-covered slopes were small scale with depths ranging from 0.3m to 1.0m, corresponding to the topsoil being saturated due to rainfall. Majority of shallow landslides occurred on herbage-covered area, which made up 69% of total landslides. There are significant differences in soil properties between the upper layer (root-soil composite) and the lower layer (loess) of the sliding surface. Our study demonstrated that root plays a leading role in landslide erosion and that the most adverse effect of vegetation on landslides is mainly the increase in soil moisture content in the shallow soil through the root zone creating preferential infiltration flow paths. There are remarkable differences in landslide erosion depths and landslide erosion intensities among different vegetation types. The landslide erosion depth and landslide erosion intensity increased linearly with increasing main root depth, indicating that the vegetation root depth determines the landslide erosion intensity during rainfall. Therefore, the potential implications of vegetation especially the herbage to promote landslide occurrences during rainfall should be given more attention in the future.
Let (\mathbf {M}^n, g) be an n-dimensional complete Riemannian manifold. We prove that for any p>\frac {n}{2}, when k(p,1) is small enough, two certain elliptic-type gradient estimates hold for any ...positive solutions of the equation \begin{equation*} u_{t}=\Delta u+au\log u \end{equation*} on geodesic balls B(O,r) in \mathbf {M}^n with 0<r\leq 1. Here the assumption that k(p,1) is small allows the situation where the manifold is collapsing. As applying, two forms of elliptic type gradient estimates to the heat equation on M^n under integral curvature conditions are obtained. Besides, each of the two forms of gradient estimate has its own advantages and differences (see Remark 4).
The methyltransferase like 3 （METTL3）-containing methyltransferase complex catalyzes the N6-methyladenosine （m6A） formation, a novel epitranscriptomic marker; however, the nature of this complex ...remains largely unknown. Here we report two new components of the human m6A methyltransferase complex, Wilms＇ tumor 1-associating protein （WTAP） and methyltransferase like 14 （METTL14）. WTAP interacts with METTL3 and METTL14, and is required for their localization into nuclear speckles enriched with pre-mRNA processing factors and for catalytic ac- tivity of the m6A methyltransferase in vivo. The majority of RNAs bound by WTAP and METTL3 in vivo represent mRNAs containing the consensus m6A motif. In the absence of WTAP, the RNA-binding capability of METTL3 is strongly reduced, suggesting that WTAP may function to regulate recruitment of the m6A methyltransferase complex to mRNA targets. Furthermore, transcriptomic analyses in combination with photoactivatable-ribonucleoside-en- hanced crosslinking and immunoprecipitation （PAR-CLIP） illustrate that WTAP and METTL3 regulate expression and alternative splicing of genes involved in transcription and RNA processing. Morpholino-mediated knockdown targeting WTAP and/or METTL3 in zebrafish embryos caused tissue differentiation defects and increased apoptosis. These findings provide strong evidence that WTAP may function as a regulatory subunit in the m6A methyltransferase complex and play a critical role in epitranscriptomic regulation of RNA metabolism.
Different from phased array providing only angle-dependent transmit beampattern, frequency diverse array (FDA) employs a small frequency increment across its array elements to provide ...range–angle-dependent transmit beampattern. This enables the array beam to scan without the need of phase shifters or mechanical steering. Since FDA has received much attention in antenna and radar signal processing societies, it is necessary to make an overview on this interesting topic. This study introduces what FDA is and why it could be exploited for radar and navigation applications from a top-level system description and appeal to the radar signal processing and system engineering communities for more investigations on this promising array technique. The status of FDA studies is overviewed and the most recent advances of FDA radar are discussed. The basic FDA system architectures are introduced, along with performance compared to a conventional phased-array. Next, guidelines for choosing good system parameters and typical implementation schemes are provided. Finally, potential applications in range and angle estimation of targets, cognitive FDA radar and low probability of identification FDA radar are discussed, along with several technical challenges.
An ideal cancer treatment should not only destroy primary tumors but also improve the immunogenicity of the tumor microenvironment to achieve a satisfactory anti‐tumor immune effect. We designed a ...carbonic anhydrase IX (CAIX)‐anchored rhenium(I) photosensitizer, named CA‐Re, that not only performs type‐I and type‐II photodynamic therapy (PDT) with high efficiency under hypoxia (nanomolar‐level phototoxicity), but also evokes gasdermin D (GSDMD) mediated pyroptotic cell death to effectively stimulate tumor immunogenicity. CA‐Re could disrupt and self‐report the loss of membrane integrity simultaneously. This promoted the maturation and antigen‐presenting ability of dendritic cells (DCs), and fully activated T cells dependent adaptive immune response in vivo, eventually eliminating distant tumors at the same time as destroying primary tumors. To the best of our knowledge, CA‐Re is the first metal complex‐based pyroptosis inducer.
A carbonic anhydrase IX (CAIX)‐anchored photosensitizer CA‐Re was developed. It is capable of inducing and self‐reporting membrane rupture upon irradiation, as well as evoking pyroptosis to activate anti‐tumor immunity.
Nanotechnology has become more and more potentially used in diagnosis or treatment of diseases. Advances in nanotechnology have led to new and improved nanomaterials in biomedical applications. ...Common nanomaterials applicable in biomedical applications include liposomes, polymeric micelles, graphene, carbon nanotubes, quantum dots, ferroferric oxide nanoparticles, gold nanoparticles (Au NPs), and so on. Among them, Au NPs have been considered as the most interesting nanomaterial because of its unique optical, electronic, sensing and biochemical properties. Au NPs have been potentially applied for medical imaging, drug delivery, and tumor therapy in the early detection, diagnosis, and treatment of diseases. This review focuses on some recent advances in the use of Au NPs as drug carriers for the intracellular delivery of therapeutics and as molecular nanoprobes for the detection and monitoring of target molecules.
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