Characterization of Bacillus amyloliquefaciens BA-4 and its biocontrol potential against Fusarium-related apple replant disease.

Apple replant disease (ARD), caused by Fusarium pathogens, is a formidable threat to the renewal of apple varieties in China, necessitating the development of effective and sustainable control strategies. In this study, the bacterial strain BA-4 was isolated from the rhizosphere soil of healthy apple trees in a replanted orchard, demonstrating a broad-spectrum antifungal activity against five crucial apple fungal pathogens. Based on its morphology, physiological and biochemical traits, utilization of carbon sources, and Gram stain, strain BA-4 was tentatively identified as Bacillus amyloliquefaciens. Phylogenetic analysis using 16S rDNA and gyrB genes conclusively identified BA-4 as B. amyloliquefaciens. In-depth investigations into B. amyloliquefaciens BA-4 revealed that the strain possesses the capacity to could secrete cell wall degrading enzymes (protease and cellulase), produce molecules analogous to indole-3-acetic acid (IAA) and siderophores, and solubilize phosphorus and potassium. The diverse attributes observed in B. amyloliquefaciens BA-4 underscore its potential as a versatile microorganism with multifaceted benefits for both plant well-being and soil fertility. The extracellular metabolites produced by BA-4 displayed a robust inhibitory effect on Fusarium hyphal growth and spore germination, inducing irregular swelling, atrophy, and abnormal branching of fungal hyphae. In greenhouse experiments, BA-4 markedly reduced the disease index of Fusarium-related ARD, exhibiting protective and therapeutic efficiencies exceeding 80% and 50%, respectively. Moreover, BA-4 demonstrated plant-promoting abilities on both bean and Malus robusta Rehd. (MR) seedlings, leading to increased plant height and primary root length. Field experiments further validated the biocontrol effectiveness of BA-4, demonstrating its ability to mitigate ARD symptoms in MR seedlings with a notable 33.34% reduction in mortality rate and improved biomass. Additionally, BA-4 demonstrates robust and stable colonization capabilities in apple rhizosphere soil, particularly within the 10-20 cm soil layer, which indicates that it has long-term effectiveness potential in field conditions. Overall, B. amyloliquefaciens BA-4 emerges as a promising biocontrol agent with broad-spectrum antagonistic capabilities, positive effects on plant growth, and strong colonization abilities for the sustainable management of ARD in apple cultivation.

Functional vertical connectivity of microbial communities in the ocean.

Sinking particles are a critical conduit for the transport of surface microbes to the ocean's interior. Vertical connectivity of phylogenetic composition has been shown; however, the functional vertical connectivity of microbial communities has not yet been explored in detail. We investigated protein and taxa profiles of both free-living and particle-attached microbial communities from the surface to 3000 m depth using a combined metaproteomic and 16S rRNA amplicon sequencing approach. A clear compositional and functional vertical connectivity of microbial communities was observed throughout the water column with Oceanospirillales, Alteromonadales, and Rhodobacterales as key taxa. The surface-derived particle-associated microbes increased the expression of proteins involved in basic metabolism, organic matter processing, and environmental stress response in deep waters. This study highlights the functional vertical connectivity between surface and deep-sea microbial communities via sinking particles and reveals that a considerable proportion of the deep-sea microbes might originate from surface waters and have a major impact on the biogeochemical cycles in the deep sea.

Structural insight into the subclass B1 metallo-ß-lactamase AFM-1.

The emergence of drug-resistant bacteria, facilitated by metallo-beta-lactamases (MBLs), presents a significant obstacle to the effective use of antibiotics in the management of clinical drug-resistant bacterial infections. AFM-1 is a MBL derived from Alcaligenes faecalis and shares 86% homology with the NDM-1 family. Both AFM-1 and NDM-1 demonstrate the ability to hydrolyze ampicillin and other ß-lactam antibiotics, however, their substrate affinities vary, and the specific reason for this variation remains unknown. We present the high-resolution structure of AFM-1. The active center of AFM-1 binds two zinc ions, and the conformation of the key amino acid residues in the active center is in accordance with that of NDM-1. However, the substrate-binding pocket of AFM-1 is considerably smaller than that of NDM-1. Additionally, the mutation of amino acid residues in the Loop3 region, as compared to NDM-1, results in the formation of a dense hydrophobic patch comprised of hydrophobic amino acid residues in this area, which facilitates substrate binding. Our findings lay the foundation for understanding the molecular mechanism of AFM-1 with a high affinity for substrates and provide a novel theoretical foundation for addressing the issue of drug resistance caused by B1 MBLs.

KCNQ1 rs2237895 gene polymorphism increases susceptibility to type 2 diabetes mellitus in Asian populations.

BACKGROUND: The association of single nucleotide polymorphism of KCNQ1 gene rs2237895 with type 2 diabetes mellitus (T2DM) is currently controversial. It is unknown whether this association can be gene realized across different populations. AIM: To determine the association of KCNQ1 rs2237895 with T2DM and provide reliable evidence for genetic susceptibility to T2DM. METHODS: We searched PubMed, Embase, Web of Science, Cochrane Library, Medline, Baidu Academic, China National Knowledge Infrastructure, China Biomedical Liter-ature Database, and Wanfang to investigate the association between KCNQ1 gene rs2237895 and the risk of T2DM up to January 12, 2022. Review Manager 5.4 was used to analyze the association of the KCNQ1 gene rs2237895 polymorphism with T2DM and to evaluate the publication bias of the selected literature. RESULTS: Twelve case-control studies (including 11273 cases and 11654 controls) met our inclusion criteria. In the full population, allelic model [odds ratio (OR): 1.19; 95% confidence interval (95%CI): 1.09-1.29; P < 0.0001], recessive model (OR: 1.20; 95%CI: 1.11-1.29; P < 0.0001), dominant model (OR: 1.27. 95%CI: 1.14-1.42; P < 0.0001), and codominant model (OR: 1.36; 95%CI: 1.15-1.60; P = 0.0003) (OR: 1.22; 95%CI: 1.10-1.36; P = 0.0002) indicated that the KCNQ1 gene rs2237895 polymorphism was significantly correlated with susceptibility to T2DM. In stratified analysis, this association was confirmed in Asian populations: allelic model (OR: 1.25; 95%CI: 1.13-1.37; P < 0.0001), recessive model (OR: 1.29; 95%CI: 1.11-1.49; P = 0.0007), dominant model (OR: 1.35; 95%CI: 1.20-1.52; P < 0.0001), codominant model (OR: 1.49; 95%CI: 1.22-1.81; P < 0.0001) (OR: 1.26; 95%CI: 1.16-1.36; P < 0.0001). In non-Asian populations, this association was not significant: Allelic model (OR: 1.06, 95%CI: 0.98-1.14; P = 0.12), recessive model (OR: 1.04; 95%CI: 0.75-1.42; P = 0.83), dominant model (OR: 1.06; 95%CI: 0.98-1.15; P = 0.15), codominant model (OR: 1.08; 95%CI: 0.82-1.42; P = 0.60. OR: 1.15; 95%CI: 0.95-1.39; P = 0.14). CONCLUSION: KCNQ1 gene rs2237895 was significantly associated with susceptibility to T2DM in an Asian population. Carriers of the C allele had a higher risk of T2DM. This association was not significant in non-Asian populations.

A live attenuated influenza B virus vaccine expressing RBD elicits protective immunity against SARS-CoV-2 in mice.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant threat to human health globally. It is crucial to develop a vaccine to reduce the effect of the virus on public health, economy, and society and regulate the transmission of SARS-CoV-2. Influenza B virus (IBV) can be used as a vector that does not rely on the current circulating influenza A strains. In this study, we constructed an IBV-based vector vaccine by inserting a receptor-binding domain (RBD) into a non-structural protein 1 (NS1)-truncated gene (rIBV-NS110-RBD). Subsequently, we assessed its safety, immunogenicity, and protective efficacy against SARS-CoV-2 in mice, and observed that it was safe in a mouse model. Intranasal administration of a recombinant rIBV-NS110-RBD vaccine induced high levels of SARS-CoV-2-specific IgA and IgG antibodies and T cell-mediated immunity in mice. Administering two doses of the intranasal rIBV-NS110-RBD vaccine significantly reduced the viral load and lung damage in mice. This novel IBV-based vaccine offers a novel approach for controlling the SARS-CoV-2 pandemic.

Integrated phytochemistry and network pharmacology analysis to reveal effective substances and mechanisms of Bushen Quhan Zhiwang decoction in the treatment of rheumatoid arthritis.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen Quhan Zhiwang decoction (BQZD), a formula in traditional Chinese medicine (TCM), effectively delays bone destruction in rheumatoid arthritis (RA) patients. However, its chemical constituents, absorbed components, and metabolites remain unrevealed, and its mechanism in treating bone destruction in RA needs further investigation. AIM OF THE STUDY: Our objective is to identify the chemical constituents, absorbed components, and metabolites of BQZD and explore the potential mechanisms of BQZD in treating bone destruction in RA. MATERIALS AND METHODS: This study systematically identified the chemical constituents, absorbed components, and metabolites of BQZD using ultra-performance liquid chromatography with Q-Exactive Orbitrap mass spectrometry combined with parallel reaction monitoring. The absorbed components and metabolites were subjected to network pharmacology analysis to predict the potential mechanisms of BQZD in treating bone destruction in RA. The in vivo anti-osteoclastogenic and underlying mechanism were further verified in collagen-induced arthritis (CIA) rats. RESULTS: A total of 182 compounds were identified in BQZD, 27 of which were absorbed into plasma and organs and 42 metabolites were identified in plasma and organs. The KEGG analysis revealed that MAPK signaling pathway was highly prioritized. BQZD treatment attenuated paw swelling and the arthritis index; suppressed synovial hyperplasia, bone destruction, and osteoclast differentiation; and inhibited the levels of TNF-α, IL-1ß, and IL-6 in CIA rats. Mechanically, BQZD significantly decreased the protein expression levels of TRAF6, NFATc1, p-JNK, and p-p38, which might be related to 9 absorbed components and 1 metabolite. CONCLUSION: This study revealed the key active components and metabolites of BQZD. BQZD exhibits bone-protective effects via TRAF6/p38/JNK MAPK pathway, which may be associated with 9 absorbed components and 1 metabolite.

Exploration of quality variation and stability of hybrid rice under multi-environments.

Improving quality is an essential goal of rice breeding and production. However, rice quality is not solely determined by genotype, but is also influenced by the environment. Phenotype plasticity refers to the ability of a given genotype to produce different phenotypes under different environmental conditions, which can be a representation of the stability of traits. Seven quality traits of 141 hybrid combinations, deriving from the test-crossing of 7 thermosensitive genic male sterile (TGMS) and 25 restorer lines, were evaluated at 5 trial sites with intermittent sowing of three to five in Southern China. In the Yangtze River Basin, it was observed that delaying the sowing time of hybrid rice combinations leads to an improvement in their overall quality. Twelve parents were identified to have lower plasticity general combing ability (GCA) values with increased ability to produce hybrids with a more stable quality. The parents with superior quality tend to exhibit lower GCA values for plasticity. The genome-wide association study (GWAS) identified 13 and 15 quantitative trait loci (QTLs) associated with phenotype plasticity and BLUP measurement, respectively. Notably, seven QTLs simultaneously affected both phenotype plasticity and BLUP measurement. Two cloned rice quality genes, ALK and GL7, may be involved in controlling the plasticity of quality traits in hybrid rice. The direction of the genetic effect of the QTL6 (ALK) on alkali spreading value (ASV) plasticity varies in different cropping environments. This study provides novel insights into the dynamic genetic basis of quality traits in response to different cropping regions, cultivation practices, and changing climates. These findings establish a foundation for precise breeding and production of stable and high-quality rice. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-024-01442-3.

Single-nucleus multi-omic profiling of human placental syncytiotrophoblasts identifies cellular trajectories during pregnancy.

The human placenta has a vital role in ensuring a successful pregnancy. Despite the growing body of knowledge about its cellular compositions and functions, there has been limited research on the heterogeneity of the billions of nuclei within the syncytiotrophoblast (STB), a multinucleated entity primarily responsible for placental function. Here we conducted integrated single-nucleus RNA sequencing and single-nucleus ATAC sequencing analyses of human placentas from early and late pregnancy. Our findings demonstrate the dynamic heterogeneity and developmental trajectories of STB nuclei and their correspondence with human trophoblast stem cell (hTSC)-derived STB. Furthermore, we identified transcription factors associated with diverse STB nuclear lineages through their gene regulatory networks and experimentally confirmed their function in hTSC and trophoblast organoid-derived STBs. Together, our data provide insights into the heterogeneity of human STB and represent a valuable resource for interpreting associated pregnancy complications.

A multiscale fracture model to reveal the toughening mechanism in bioinspired Bouligand structures.

The Bouligand structure has been observed in a variety of biological materials, such as lamellar bone and exoskeleton of lobsters. It is a hierarchical and non-homogeneous architecture that exhibits excellent damage-resistant performance. This paper presents a multiscale fracture model considering the material inhomogeneity, the multiscale property, and the anisotropy to reveal the toughening mechanisms in the Bouligand structure. Firstly, the macro and micro constitutive properties of this composite are derived. Then, a multiscale fracture model is developed to characterize the local stress intensity factors and the energy release rates at the crack front of twisted cracks. Our results demonstrate that the decrease in the local energy release rate can be attributed to two-step mechanisms. The first mechanism is that the multiscale structure and the material inhomogeneity cause a release of stress near the initial crack tip. The second mechanism is that the twisted crack leads to the transformation from single-mode loading to mixed-mode loading, which enhances the fracture toughness. These results can not only reveal the toughening mechanism of the Bouligand structure but also provide guidelines for the design of high-performance composites. STATEMENT OF SIGNIFICANCE: Biological materials in nature often possess excellent mechanical properties that have not been achieved by synthetic materials. Bioinspired Bouligand structures provide prototypes for designing high-performance materials. In this study, we propose a multiscale theoretical fracture model to investigate the fracture properties of Bouligand structures with twisted cracks. We systematically consider the roles of material inhomogeneity, anisotropy, and multiscale properties. Our analysis demonstrates that the remarkable toughness of Bouligand structures results from the combined effects of material inhomogeneity and twisted cracks. This research contributes to unveiling the secret behind the outstanding toughness of Bouligand structures and provides inspiration for the development of novel designs for man-made composites.

Non-rigid-registration-based positioning and labelling of triaxial OPMs on a flexible cap for wearable magnetoencephalography.

BACKGROUND: Recent advances in highly sensitive miniaturized optically pumped magnetometers (OPMs) have enabled the development of wearable magnetoencephalography (MEG) offering great flexibility in experimental setting. The OPM array for wearable MEG is typically attached to a flexible cap and exhibits a variable spatial layout across different subjects, which imposes challenges concerning the efficient positioning and labelling of OPMs. NEW METHOD: A pair of reflective markers are affixed to each triaxial OPM sensor above its cable to determine its location and sensitive axes. A non-rigid registration of optically digitized marker locations with a pre-labelled template of marker locations is performed to map newly digitized markers to OPMs. RESULTS: The positioning and labelling of 66 OPM sensors could be completed within 35 s. Across ten experiments, all OPMs were accurately labelled, and the mean test-retest errors were 0.48 mm for sensor locations and 0.20 degree for sensitive axes. By combining six OPMs' positions with their respective recordings, magnetic dipoles inside a phantom were located with a mean error of 5.5 mm, and the best fitted dipole for MEG with auditory stimuli presented was located on a subject's primary auditory cortex. COMPARISON WITH EXISTING METHODS: The proposed method reduces the reliance on error-prone and laborious manual operations inherent in existing methods, therefore significantly improving the efficiency of OPM positioning and labelling on a flexible cap. CONCLUSION: We developed a method for the precise and rapid positioning and labelling triaxial OPMs on a flexible cap, thereby facilitating the practical implementation of wearable OPM-MEG.

FTO demethylates regulates cell-cycle progression by controlling CCND1 expression in luteinizing goat granulosa cells.

In mammals, N6-methyladenosine (m6A) stands out as one of the most abundant internal mRNA modifications and plays a crucial role in follicular development. Nonetheless, the precise mechanism by which the demethylase FTO regulates the progression of the goat luteinizing granulosa cells (LGCs) cycle remains to be elucidated. In our study, we primarily assessed the protein and mRNA expression levels of genes using Western blotting and quantitative real-time polymerase chain reaction (qRT-PCR), cell proliferation via EdU, cell viability with CCK-8, and apoptosis and cell cycle progression through flow cytometry. Here, the results demonstrated that knockdown of FTO significantly enhanced apoptosis, impeded cell proliferation, and increased autophagy levels in goat LGCs. Furthermore, the silencing of FTO substantially reduced cyclin D1 (CCND1) expression through the recognition and degradation of YTHDF2, consequently prolonging the cell cycle progression. This study sheds light on the mechanism by which FTO demethylation governs cell cycle progression by controlling the expression of CCND1 in goat LGCs, underscoring the dynamic role of m6A modification in the regulation of cell cycle progression.

Ginsenoside F2-Mediated Intestinal Microbiota and Its Metabolite Propionic Acid Positively Impact the Gut-Skin Axis in Atopic Dermatitis Mice.

Atopic dermatitis (AD) is a complex inflammatory skin disease induced by multiple factors. AD can also cause intestinal inflammation and disorders of the gut microbiota. Ginseng is a kind of edible and medicinal plant; its main active components are ginsenosides. Ginsenosides have a variety of anti-inflammatory effects and regulate the gut microbiota; however, their role in AD and the underlying mechanisms are unclear. In this study, we found that intragastric administration of ginsenoside F2 improved AD-like skin symptoms and reduced inflammatory cell infiltration, serum immunoglobulin E levels, and mRNA expression of inflammatory cytokines in AD mice. 16s rRNA sequencing analysis showed that ginsenoside F2 altered the intestinal microbiota structure and enriched the short-chain fatty acid-producing microbiota in AD mice. Metabolomic analysis revealed that ginsenoside F2 significantly increased the propionic acid (Pa) content of feces and serum in AD mice, which was positively correlated with significant enrichment of Parabacteroides goldsteinii and Lactobacillus plantarum in the intestines. Pa inhibits inflammatory responses in the gut and skin of AD mice through the G-protein-coupled receptor43/NF-κB pathway, thereby improving skin AD symptoms. These results revealed, for the first time, the mechanism by which ginsenoside F2 improves AD through the Pa (a metabolite of intestinal microbiota)-gut-skin axis.

Carboxymethylcellulose hydrogels with stable carbon quantum dots: Enabling dynamic fluorescence modulation, automatic erasure, and secure information encryption.

Inspired by "disappear after reading", a time-modulated encryption hydrogel was synthesized by carboxymethyl cellulose with carbon quantum dots. Carboxymethyl cellulose in this system stabilized carbon quantum dots, which ensured the whole hydrogel worked well. The encryption/decryption of information depended on pH adjustment, application of EDTA and Cr (VI). Furthermore, an in-depth analysis of the fluorescence change mechanism uncovered that fluorescence quenching was potentially influenced by internal filtering effects and static quenching, which involved the amino, carboxyl, and hydroxyl groups present within the hydrogel.

Blocking Metal Nanocluster Growth through Ligand Coordination and Subsequent Polymerization: The Case of Ruthenium Nanoclusters as Robust Hydrogen Evolution Electrocatalysts.

Metal nanoclusters providing maximized atomic surface exposure offer outstanding hydrogen evolution activities but their stability is compromised as they are prone to grow and agglomerate. Herein, a possibility of blocking metal ion diffusion at the core of cluster growth and aggregation to produce highly active Ru nanoclusters supported on an N, S co-doped carbon matrix (Ru/NSC) is demonstrated. To stabilize the nanocluster dispersion, Ru species are initially coordinated through multiple Ru─N bonds with N-rich 4'-(4-aminophenyl)-2,2:6',2''-terpyridine (TPY-NH2 ) ligands that are subsequently polymerized using a Schiff base. After the pyrolysis of the hybrid composite, highly dispersed ultrafine Ru nanoclusters with an average size of 1.55 nm are obtained. The optimized Ru/NSC displays minimal overpotentials and high turnover frequencies, as well as robust durability both in alkaline and acidic electrolytes. Besides, outstanding mass activities of 3.85 A mg-1 Ru at 50 mV, i.e., 16 fold higher than 20 wt.% Pt/C are reached. Density functional theory calculations rationalize the outstanding performance by revealing that the low d-band center of Ru/NSC allows the desorption of *H intermediates, thereby enhancing the alkaline HER activity. Overall, this work provides a feasible approach to engineering cost-effective and robust electrocatalysts based on carbon-supported transition metal nanoclusters for future energy technologies.

Drug-disease association prediction using semantic graph and function similarity representation learning over heterogeneous information networks.

Discovering new indications for existing drugs is a promising development strategy at various stages of drug research and development. However, most of them complete their tasks by constructing a variety of heterogeneous networks without considering available higher-order connectivity patterns in heterogeneous biological information networks, which are believed to be useful for improving the accuracy of new drug discovering. To this end, we propose a computational-based model, called SFRLDDA, for drug-disease association prediction by using semantic graph and function similarity representation learning. Specifically, SFRLDDA first integrates a heterogeneous information network (HIN) by drug-disease, drug-protein, protein-disease associations, and their biological knowledge. Second, different representation learning strategies are applied to obtain the feature representations of drugs and diseases from different perspectives over semantic graph and function similarity graphs constructed, respectively. At last, a Random Forest classifier is incorporated by SFRLDDA to discover potential drug-disease associations (DDAs). Experimental results demonstrate that SFRLDDA yields a best performance when compared with other state-of-the-art models on three benchmark datasets. Moreover, case studies also indicate that the simultaneous consideration of semantic graph and function similarity of drugs and diseases in the HIN allows SFRLDDA to precisely predict DDAs in a more comprehensive manner.

Discovery of Potent and Selective WDR5 Proteolysis Targeting Chimeras as Potential Therapeutics for Pancreatic Cancer.

As a core chromatin-regulatory scaffolding protein, WDR5 mediates numerous protein-protein interactions (PPIs) with other partner oncoproteins. However, small-molecule inhibitors that block these PPIs exert limited cell-killing effects. Here, we report structure-activity relationship studies in pancreatic ductal adenocarcinoma (PDAC) cells that led to the discovery of several WDR5 proteolysis-targeting chimer (PROTAC) degraders, including 11 (MS132), a highly potent and selective von Hippel-Lindau (VHL)-recruiting WDR5 degrader, which displayed positive binding cooperativity between WDR5 and VHL, effectively inhibited proliferation in PDAC cells, and was bioavailable in mice and 25, a cereblon (CRBN)-recruiting WDR5 degrader, which selectively degraded WDR5 over the CRBN neo-substrate IKZF1. Furthermore, by conducting site-directed mutagenesis studies, we determined that WDR5 K296, but not K32, was involved in the PROTAC-induced WDR5 degradation. Collectively, these studies resulted in a highly effective WDR5 degrader, which could be a potential therapeutic for pancreatic cancer and several potentially useful tool compounds.

Biocaiv: an integrative webserver for motif-based clustering analysis and interactive visualization of biological networks.

BACKGROUND: As an important task in bioinformatics, clustering analysis plays a critical role in understanding the functional mechanisms of many complex biological systems, which can be modeled as biological networks. The purpose of clustering analysis in biological networks is to identify functional modules of interest, but there is a lack of online clustering tools that visualize biological networks and provide in-depth biological analysis for discovered clusters. RESULTS: Here we present BioCAIV, a novel webserver dedicated to maximize its accessibility and applicability on the clustering analysis of biological networks. This, together with its user-friendly interface, assists biological researchers to perform an accurate clustering analysis for biological networks and identify functionally significant modules for further assessment. CONCLUSIONS: BioCAIV is an efficient clustering analysis webserver designed for a variety of biological networks. BioCAIV is freely available without registration requirements at http://bioinformatics.tianshanzw.cn:8888/BioCAIV/ .

Structure-based discovery of dual pathway inhibitors for SARS-CoV-2 entry.

Since 2019, SARS-CoV-2 has evolved rapidly and gained resistance to multiple therapeutics targeting the virus. Development of host-directed antivirals offers broad-spectrum intervention against different variants of concern. Host proteases, TMPRSS2 and CTSL/CTSB cleave the SARS-CoV-2 spike to play a crucial role in the two alternative pathways of viral entry and are characterized as promising pharmacological targets. Here, we identify compounds that show potent inhibition of these proteases and determine their complex structures with their respective targets. Furthermore, we show that applying inhibitors simultaneously that block both entry pathways has a synergistic antiviral effect. Notably, we devise a bispecific compound, 212-148, exhibiting the dual-inhibition ability of both TMPRSS2 and CTSL/CTSB, and demonstrate antiviral activity against various SARS-CoV-2 variants with different viral entry profiles. Our findings offer an alternative approach for the discovery of SARS-CoV-2 antivirals, as well as application for broad-spectrum treatment of viral pathogenic infections with similar entry pathways.

Clade 2.3.4.4 H5 chimeric cold-adapted attenuated influenza vaccines induced cross-reactive protection in mice and ferrets.

IMPORTANCE: Clade 2.3.4.4 H5Nx avian influenza viruses (AIVs) have circulated globally and caused substantial economic loss. Increasing numbers of humans have been infected with Clade 2.3.4.4 H5N6 AIVs in recent years. Only a few human influenza vaccines have been licensed to date. However, the licensed live attenuated influenza virus vaccine exhibited the potential of being recombinant with the wild-type influenza A virus (IAV). Therefore, we developed a chimeric cold-adapted attenuated influenza vaccine based on the Clade 2.3.4.4 H5 AIVs. These H5 vaccines demonstrate the advantage of being non-recombinant with circulated IAVs in the future influenza vaccine study. The findings of our current study reveal that these H5 vaccines can induce cross-reactive protective efficacy in mice and ferrets. Our H5 vaccines may provide a novel option for developing human-infected Clade 2.3.4.4 H5 AIV vaccines.

BRISC is required for optimal activation of NF-κB in Kupffer cells induced by LPS and contributes to acute liver injury.

BRISC (BRCC3 isopeptidase complex) is a deubiquitinating enzyme that has been linked with inflammatory processes, but its role in liver diseases and the underlying mechanism are unknown. Here, we investigated the pathophysiological role of BRISC in acute liver failure using a mice model induced by D-galactosamine (D-GalN) plus lipopolysaccharide (LPS). We found that the expression of BRISC components was dramatically increased in kupffer cells (KCs) upon LPS treatment in vitro or by the injection of LPS in D-GalN-sensitized mice. D-GalN plus LPS-induced liver damage and mortality in global BRISC-null mice were markedly attenuated, which was accompanied by impaired hepatocyte death and hepatic inflammation response. Constantly, treatment with thiolutin, a potent BRISC inhibitor, remarkably alleviated D-GalN/LPS-induced liver injury in mice. By using bone marrow-reconstituted chimeric mice and cell-specific BRISC-deficient mice, we demonstrated that KCs are the key effector cells responsible for protection against D-GalN/LPS-induced liver injury in BRISC-deficient mice. Mechanistically, we found that hepatic and circulating levels of TNF-α, IL-6, MCP-1, and IL-1ß, as well as TNF-α- and MCP-1-producing KCs, in BRISC-deleted mice were dramatically decreased as early as 1 h after D-GalN/LPS challenge, which occurred prior to the elevation of the liver injury markers. Moreover, LPS-induced proinflammatory cytokines production in KCs was significantly diminished by BRISC deficiency in vitro, which was accompanied by potently attenuated NF-κB activation. Restoration of NF-κB activation by two small molecular activators of NF-κB p65 effectively reversed the suppression of cytokines production in ABRO1-deficient KCs by LPS. In conclusion, BRISC is required for optimal activation of NF-κB-mediated proinflammatory cytokines production in LPS-treated KCs and contributes to acute liver injury. This study opens the possibility to develop new strategies for the inhibition of KCs-driven inflammation in liver diseases.