Insulin Attenuates Beta-Amyloid-Associated Insulin/Akt/EAAT Signaling Perturbations in Human Astrocytes

The excitatory amino acid transporters 1 and 2 (EAAT1 and EAAT2), mostly located on astrocytes, are the main mediators for glutamate clearance in humans. Malfunctions of these transporters may lead to excessive glutamate accumulation and subsequent excitotoxicity to neurons, which has been implicated in many kinds of neurodegenerative disorders including Alzheimer’s disease (AD). Yet, the specific mechanism of the glutamate system dysregulation remains vague. To explore whether the insulin/protein kinase B (Akt)/EAAT signaling in human astrocytes could be disturbed by beta-amyloid protein (Aβ) and be protected by insulin, we incubated HA-1800 cells with varying concentrations of Aβ1–42 oligomers and insulin. Then the alterations of several key substrates in this signal transduction pathway were determined. Our results showed that expressions of insulin receptor, phospho-insulin receptor, phospho-protein kinase B, phospho-mammalian target of rapamycin, and EAAT1 and EAAT2 were decreased by the Aβ1–42 oligomers in a dose-dependent manner (p 0.05), and the mRNA levels of EAAT1 and EAAT2 were also unchanged (p > 0.05). Taken together, this study indicates that Aβ1–42 oligomers could cause disturbances in insulin/Akt/EAAT signaling in astrocytes, which might be responsible for AD onset and progression. Additionally, insulin can exert protective functions to the brain by modulating protein modifications or expressions

Effective radiative forcing in the aerosol–climate model CAM5.3-MARC-ARG

Abstract We quantify the effective radiative forcing (ERF) of anthropogenic aerosols modelled by the aerosol–climate model CAM5.3-MARC-ARG. CAM5.3-MARC-ARG is a new configuration of the Community Atmosphere Model version 5.3 (CAM5.3) in which the default aerosol module has been replaced by the two-Moment, Multi-Modal, Mixing-state-resolving Aerosol model for Research of Climate (MARC). CAM5.3-MARC-ARG uses the ARG aerosol-activation scheme, consistent with the default configuration of CAM5.3. We compute differences between simulations using year-1850 aerosol emissions and simulations using year-2000 aerosol emissions in order to assess the radiative effects of anthropogenic aerosols. We compare the aerosol lifetimes, aerosol column burdens, cloud properties, and radiative effects produced by CAM5.3-MARC-ARG with those produced by the default configuration of CAM5.3, which uses the modal aerosol module with three log-normal modes (MAM3), and a configuration using the modal aerosol module with seven log-normal modes (MAM7). Compared with MAM3 and MAM7, we find that MARC produces stronger cooling via the direct radiative effect, the shortwave cloud radiative effect, and the surface albedo radiative effect; similarly, MARC produces stronger warming via the longwave cloud radiative effect. Overall, MARC produces a global mean net ERF of −1.79±0.03 W m−2, which is stronger than the global mean net ERF of −1.57±0.04 W m−2 produced by MAM3 and −1.53±0.04 W m−2 produced by MAM7. The regional distribution of ERF also differs between MARC and MAM3, largely due to differences in the regional distribution of the shortwave cloud radiative effect. We conclude that the specific representation of aerosols in global climate models, including aerosol mixing state, has important implications for climate modelling

A deep semantic network-based image segmentation of soybean rust pathogens

IntroductionAsian soybean rust is a highly aggressive leaf-based disease triggered by the obligate biotrophic fungus Phakopsora pachyrhizi which can cause up to 80% yield loss in soybean. The precise image segmentation of fungus can characterize fungal phenotype transitions during growth and help to discover new medicines and agricultural biocides using large-scale phenotypic screens.MethodsThe improved Mask R-CNN method is proposed to accomplish the segmentation of densely distributed, overlapping and intersecting microimages. First, Res2net is utilized to layer the residual connections in a single residual block to replace the backbone of the original Mask R-CNN, which is then combined with FPG to enhance the feature extraction capability of the network model. Secondly, the loss function is optimized and the CIoU loss function is adopted as the loss function for boundary box regression prediction, which accelerates the convergence speed of the model and meets the accurate classification of high-density spore images.ResultsThe experimental results show that the mAP for detection and segmentation, accuracy of the improved algorithm is improved by 6.4%, 12.3% and 2.2% respectively over the original Mask R-CNN algorithm.DiscussionThis method is more suitable for the segmentation of fungi images and provide an effective tool for large-scale phenotypic screens of plant fungal pathogens

A Cocktail Nanovaccine Targeting Key Entry Glycoproteins Elicits High Neutralizing Antibody Levels Against EBV Infection

Epstein-Barr virus (EBV) infects more than 95% of adults worldwide and is closely associated with various malignancies. Considering the complex life cycle of EBV, developing vaccines targeting key entry glycoproteins to elicit robust and durable adaptive immune responses may provide better protection. EBV gHgL-, gB- and gp42-specific antibodies in healthy EBV carriers contributed to sera neutralizing abilities in vitro, indicating that they are potential antigen candidates. To enhance the immunogenicity of these antigens, we formulate three nanovaccines by co-delivering molecular adjuvants (CpG and MPLA) and antigens (gHgL, gB or gp42). These nanovaccines induce robust humoral and cellular responses through efficient activation of dendritic cells and germinal center response. Importantly, these nanovaccines generate high levels of neutralizing antibodies recognizing vulnerable sites of all three antigens. IgGs induced by a cocktail vaccine containing three nanovaccines confer superior protection from lethal EBV challenge in female humanized mice compared to IgG elicited by individual NP-gHgL, NP-gB and NP-gp42. Importantly, serum antibodies elicited by cocktail nanovaccine immunization confer durable protection against EBV-associated lymphoma. Overall, the cocktail nanovaccine shows robust immunogenicity and is a promising candidate for further clinical trials

Studying the Differences of Bacterial Metabolome and Microbiome in the Colon between Landrace and Meihua Piglets

This study was conducted to compare the microbiome and metabolome differences in the colon lumen from two pig breeds with different genetic backgrounds. Fourteen weaned piglets at 30 days of age, including seven Landrace piglets (a lean-type pig breed with a fast growth rate) and seven Meihua piglets (a fatty-type Chinese local pig breed with a slow growth rate), were fed the same diets for 35 days. Untargeted metabolomics analyses showed that a total of 401 metabolites differed between Landrace and Meihua. Seventy of these 401 metabolites were conclusively identified. Landrace accumulated more short-chain fatty acids (SCFAs) and secondary bile acids in the colon lumen. Moreover, expression of the SCFAs transporter (solute carrier family 5 member 8, SLC5A8) and receptor (G protein-coupled receptor 41, GPR41) in the colon mucosa was higher, while the bile acids receptor (farnesoid X receptor, FXR) had lower expression in Landrace compared to Meihua. The relative abundances of 8 genera and 16 species of bacteria differed significantly between Landrace and Meihua, and were closely related to the colonic concentrations of bile acids or SCFAs based on Pearson's correlation analysis. Collectively, our results demonstrate for the first time that there were differences in the colonic microbiome and metabolome between Meihua and Landrace piglets, with the most profound disparity in production of SCFAs and secondary bile acids

Viral neutralization by antibody-imposed physical disruption

中和抗体是机体抵御病毒入侵的一类免疫球蛋白，也是疫苗发挥作用的主要效应分子。目前已知的中和抗体作用机制，主要包括阻断病毒-细胞相互作用和介导免疫调理作用。最近我校夏宁邵教授团队研究结果揭示了一种由抗体诱导病毒原位崩解的中和新机制。该研究首次揭示了抗体的直接物理碰撞中和机制，并提出诱导这类中和抗体的方法，有助于病毒保护性抗体和疫苗设计，适用于多种病原体，而不仅限于戊型肝炎病毒。分子疫苗学和分子诊断学国家重点实验室夏宁邵教授、李少伟教授和顾颖副教授为该论文的共同通讯作者，郑清炳博士、硕士生蒋婕、博士生何茂洲和郑子峥副教授为共同第一作者。In adaptive immunity, organisms produce neutralizing antibodies (nAbs) to eliminate invading pathogens. Here, we explored whether viral neutralization could be attained through the physical disruption of a virus upon nAb binding. We report the neutralization mechanism of a potent nAb 8C11 against the hepatitis E virus (HEV), a nonenveloped positive-sense single-stranded RNA virus associated with abundant acute hepatitis. The 8C11 binding flanks the protrusion spike of the HEV viruslike particles (VLPs) and leads to tremendous physical collision between the antibody and the capsid, dissociating the VLPs into homodimer species within 2 h. Cryo-electron microscopy reconstruction of the dissociation intermediates at an earlier (15-min) stage revealed smeared protrusion spikes and a loss of icosahedral symmetry with the capsid core remaining unchanged. This structural disruption leads to the presence of only a few native HEV virions in the ultracentrifugation pellet and exposes the viral genome. Conceptually, we propose a strategy to raise collision-inducing nAbs against single spike moieties that feature in the context of the entire pathogen at positions where the neighboring space cannot afford to accommodate an antibody. This rationale may facilitate unique vaccine development and antimicrobial antibody design.This research was supported by grants from the Natural Science Foundation of Fujian Province (Grant 2017J07005), the National Science and Technology Major Project of Infectious Diseases (Grant 2018ZX10101001-002), and the National Natural Science Foundation of China (Grants 81871247, 81991490, and 81571996).国家自然科学基金重大项目、海峡联合项目和面上项目、福建省自然科学杰出青年基金、国家传染病科技重大专项等资助了该项研究

Neutralization sites of human papillomavirus-6 relate to virus attachment and entry phase in viral infection.

Human papillomavirus type 6 (HPV6) is the major etiologic agent of genital warts and recurrent respiratory papillomatosis. Although the commercial HPV vaccines cover HPV6, the neutralization sites and mode for HPV6 are poorly understood. Here, we identify the HPV6 neutralization sites and discriminate the inhibition of virus attachment and entry by three potent neutralizing antibodies (nAbs), 5D3, 17D5, and 15F7. Mutagenesis assays showed that these nAbs predominantly target surface loops BC, DE, and FG of HPV6 L1. Cryo-EM structures of the HPV6 pseudovirus (PsV) and its immune complexes revealed three distinct binding modalities - full-occupation-bound to capsid, top-center-bound-, and top-rim-bound to pentamers - and illustrated a structural atlas for three classes of antibody-bound footprints that are located at center-distal ring, center, and center-proximal ring of pentamer surface for 5D3, 17D5, and 15F7, respectively. Two modes of neutralization were identified: mAb 5D3 and 17D5 block HPV PsV from attaching to the extracellular matrix (ECM) and the cell surface, whereas 15F7 allows PsV attachment but prohibits PsV from entering the cell. These findings highlight three neutralization sites of HPV6 L1 and outline two antibody-mediated neutralization mechanisms against HPV6, which will be relevant for HPV virology and antiviral inhibitor design. HighlightsMajor neutralization sites of HPV6 were mapped on the pseudovirus cryo-EM structuremAb 15F7 binds HPV6 capsid with a novel top-rim binding modality and confers a post-attachment neutralizationmAb 17D5 binds capsid in top-centre manner but unexpectedly prevents virus from attachment to cell surface

Viral neutralization by antibody-imposed physical disruption.

In adaptive immunity, organisms produce neutralizing antibodies (nAbs) to eliminate invading pathogens. Here, we explored whether viral neutralization could be attained through the physical disruption of a virus upon nAb binding. We report the neutralization mechanism of a potent nAb 8C11 against the hepatitis E virus (HEV), a nonenveloped positive-sense single-stranded RNA virus associated with abundant acute hepatitis. The 8C11 binding flanks the protrusion spike of the HEV viruslike particles (VLPs) and leads to tremendous physical collision between the antibody and the capsid, dissociating the VLPs into homodimer species within 2 h. Cryo-electron microscopy reconstruction of the dissociation intermediates at an earlier (15-min) stage revealed smeared protrusion spikes and a loss of icosahedral symmetry with the capsid core remaining unchanged. This structural disruption leads to the presence of only a few native HEV virions in the ultracentrifugation pellet and exposes the viral genome. Conceptually, we propose a strategy to raise collision-inducing nAbs against single spike moieties that feature in the context of the entire pathogen at positions where the neighboring space cannot afford to accommodate an antibody. This rationale may facilitate unique vaccine development and antimicrobial antibody design

Poly ADP-ribose polymerase-1 promotes seed-setting rate by facilitating gametophyte development and meiosis in rice (Oryza sativa L.)

Poly(ADP-ribose) polymerases (PARPs), which transfer either monomer or polymer of ADP-ribose from nicotinamide adenine dinucleotide (NAD(+)) onto target proteins, are required for multiple processes in DNA damage repair, cell cycle, development, and abiotic stress in animals and plants. Here, the uncharacterized rice (Oryza sativa) OsPARP1, which has been predicted to have two alternative OsPARP1 mRNA splicing variants, OsPARP1.1 and OsPARP1.2, was investigated. However, bimolecular fluorescence complementation showed that only OsPARP1.1 interacted with OsPARP3 paralog, suggesting that OsPARP1.1 is a functional protein in rice. OsPARP1 was preferentially expressed in the stamen primordial and pollen grain of mature stamen during flower development. The osparp1 mutant and CRISPR plants were delayed in germination, indicating that defective DNA repair machinery impairs early seed germination. The mutant displayed a normal phenotype during vegetative growth but had a lower seed-setting rate than wild-type plants under normal conditions. Chromosome bridges and DNA fragmentations were detected in male meiocytes at anaphase I to prophase II. After meiosis II, malformed tetrads or tetrads with micronuclei were formed. Meanwhile, the abnormality was also found in embryo sac development. Collectively, these results suggest that OsPARP1 plays an important role in mediating response to DNA damage and gametophyte development, crucial for rice yield in the natural environment