Deficiency of parkin causes neurodegeneration and accumulation of pathological α-synuclein in monkey models.

Parkinson's disease (PD) is characterized by age-dependent neurodegeneration and the accumulation of toxic phosphorylated α-synuclein (pS129-α-syn). The mechanisms underlying these crucial pathological changes remain unclear. Mutations in parkin RBR E3 ubiquitin protein ligase (PARK2), the gene encoding parkin that is phosphorylated by PTEN-induced putative kinase 1 (PINK1) to participate in mitophagy, cause early onset PD. However, current parkin-KO mouse and pig models do not exhibit neurodegeneration. In the current study, we utilized CRISPR/Cas9 technology to establish parkin-deficient monkey models at different ages. We found that parkin deficiency leads to substantia nigra neurodegeneration in adult monkey brains and that parkin phosphorylation decreases with aging, primarily due to increased insolubility of parkin. Phosphorylated parkin is important for neuroprotection and the reduction of pS129-α-syn. Consistently, overexpression of WT parkin, but not a mutant form that cannot be phosphorylated by PINK1, reduced the accumulation of pS129-α-syn. These findings identify parkin phosphorylation as a key factor in PD pathogenesis and suggest it as a promising target for therapeutic interventions.

Screening key sorghum germplasms for low-nitrogen tolerance at the seedling stage and identifying from the carbon and nitrogen metabolism.

Introduction: Sorghum (Sorghum bicolor L.) can withstand drought and heat stress and efficiently utilize water and nutrients. However, the underlying mechanism of its tolerance to low-nitrogen (N) stress remains poorly understood. Materials and methods: This study assessed low-N tolerance in 100 sorghum-inbred lines and identified those with exceptional resilience. Principal component analysis, Pearson's correlation, and Y value analysis were used to examine various seedling growth metrics, including plant and root dimensions, biomass, chlorophyll content, root N content, shoot N content, and root/shoot ratio. Results and discussion: The genotypes were categorized into four distinct groups based on their respective Y values, revealing a spectrum from highly tolerant to sensitive. Low-N-tolerant sorghum lines maintained higher photosynthetic rates and exhibited increased enzymatic activities linked to carbon and N metabolism in the leaves and roots. Furthermore, low-N-tolerant genotypes had higher levels of key amino acids, including cystine, glycine, histidine, isoleucine, leucine, phenylalanine, threonine, and tyrosine, indicating a robust internal metabolic response to N deficiency. Conclusion: This study provides a comprehensive and reliable approach for the evaluation of sorghum tolerance to low-N environments, sheds light on its morphological and physiological adaptations, and provides valuable insights for future breeding programs and agricultural practices.

A recyclable hydrogel-based sustained release system for formaldehyde monitoring in foods.

In this work, 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole (AHMT) was pre-doped into agarose hydrogels; consequently, sustained hydrogel systems with modulated release performance were constructed for simple operation and recyclability in point-of-care detection of formaldehyde (FA). With the increase in FA concentrations, the absorbance response of the supernatant solutions showed linear relationships and the color of the reaction mixtures gradually increased. The detection limit was calculated to be 0.013 µg mL-1. To verify its practical application, a simple, rapid and low-cost FA detection platform was built on the basis of the optimized conditions, and the method shows the merits of simplicity, high sensitivity and selectivity. More importantly, the developed hydrogels are recyclable and can be used at least five times without any loss in sensing performance. Significantly, the sensory hydrogels can be employed by non-skilled people for monitoring food safety and applied for the practical detection of FA in foods.

Engineering in situ growth of Au nanoclusters on hydrophilic paper fibres for fluorescence calligraphy-based chemical logic gates and information encryption.

Gold nanoclusters (AuNCs) are a type of rising-star fluorescence nanomaterials, but their properties and applications are hindered by the multi-step synthesis and purification routes, as well as the lack of desired supporting substrates. To enhance optical performance and working efficiency, the synthesis and applications of AuNCs are suggested to be merged with emerging substrates. Herein, glutathione-modified hydrophilic rice papers are incubated in chloroauric acid aqueous solutions, and the oxidation-reduction reaction between glutathione and Au ions enables the in situ formation of fluorescent AuNCs on the solid fibres of rice papers. The in situ growth of fluorescent AuNCs on rice papers resulted in eye-catching fluorescence tracks, similar to traditional Chinese conventional calligraphy; thus, this fluoresence calligraphy is defined in this work. The entire process, including synthesis and signal responses, is extremely simple, rapid, and repeatable. Moreover, the diversity of additive chemical reagents in the studied rice papers resulted in responsive fluorescence calligraphy, and the as-synthesized AuNC materials exhibited high reliability and optical stability. Significantly, with the integration of synchronous formation and application of Au nanoclusters on hydrophilic paper substrates, high-performance logical gates and information encryption systems were constructed, remarkably facilitating the progress of molecular sensing and important information transmission.

Modifying MSCs-derived EVs with esterase-responsive and charge-reversal cationic polymers enhances bone regeneration.

Extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) for the treatment of bone defects have been widely reported as a cell-free therapy because of their appropriate stability and biocompatibility. However, EV isolation is expensive and time-consuming. We developed a method of modifying EVs derived from bone marrow MSCs (BMSCs) via the cationic polymer (ERP) with characteristics of charge reversal and esterase response (ERP-EVs). When simply mixing BMSCs-EVs with ERP at a 1:1 ratio, ERP-EVs significantly enhanced the osteogenesis of BMSCs. More EVs were released by ERP in BMSCs than in fibroblasts, realizing the selective release. Last, ERP-EVs were loaded on an nHA/CS-MS scaffold and showed enhanced bone regeneration on rat calvarial bone defects in vivo. In general, this study provided an effective strategy to improve cellular uptake and selective release of BMSCs-EVs in bone-related cells, which had great potential to accelerate the clinical practice of BMSCs-EVs-based bone defect repair.

Discovery of a Highly Potent and Selective Inhibitor Targeting Protein Lysine Methyltransferase NSD2.

The histone lysine methyltransferase NSD2 has been recognized as an attractive target for cancer treatment, due to the functional implication of its dysregulation in the initiation and progression of many cancers. Although considerable efforts have been made to develop NSD2 small-molecule inhibitors, highly potent and selective ones are still rarely available till now. Here, we report the discovery of a series of novel NSD2 inhibitors via an extensive SAR exploration of the privileged quinazoline scaffold within compound 8. The most promising compound 42 showed excellent NSD2 enzymatic inhibitory activity and good antiproliferative activity in cells. In addition, it demonstrated favorable pharmacokinetic properties and significantly inhibited the tumor growth in a RS411 tumor xenograft model with good safety. Taken together, compound 42 could be a promising NSD2 inhibitor and deserves further investigation.

Bunyavirus SFTSV nucleoprotein exploits TUFM-mediated mitophagy to impair antiviral innate immunity.

Severe fever with thrombocytopenia syndrome is an emerging viral hemorrhagic fever caused by a tick-borne bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), with a high case fatality. We previously found that SFTSV nucleoprotein (NP) induces macroautophagy/autophagy to facilitate virus replication. However, the role of NP in antagonizing host innate immunity remains unclear. Mitophagy, a selected form of autophagy, eliminates damaged mitochondria to maintain mitochondrial homeostasis. Here, we demonstrate that SFTSV NP triggers mitophagy to degrade MAVS (mitochondrial antiviral signaling protein), thereby blocking MAVS-mediated antiviral signaling to escape the host immune response. Mechanistically, SFTSV NP translocates to mitochondria by interacting with TUFM (Tu translation elongation factor, mitochondrial), and mediates mitochondrial sequestration into phagophores through interacting with LC3, thus inducing mitophagy. Notably, the N-terminal LC3-interacting region (LIR) motif of NP is essential for mitophagy induction. Collectively, our results demonstrated that SFTSV NP serves as a novel virulence factor, inducing TUFM-mediated mitophagy to degrade MAVS and evade the host immune response.Abbreviation: 3-MA: 3-methyladenine; ACTB: actin beta; co-IP: co-immunoprecipitation; CQ: chloroquine; DAPI: 4',6-diamidino-2-phenylindole, dihydrochloride; DMSO: dimethyl sulfoxide; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; HTNV: Hantan virus; IAV: influenza A virus; IFN: interferon; LAMP1: lysosomal associated membraneprotein 1; LIR: LC3-interacting region; MAP1LC3B/LC3B: microtubule associatedprotein 1 light chain 3 beta; MAVS: mitochondrial antiviral signaling protein; Mdivi-1: mitochondrial division inhibitor 1; MOI: multiplicity of infection; MT-CO2/COXII: mitochondrially encoded cytochrome C oxidase II; NP: nucleoprotein; NSs: nonstructural proteins; poly(I:C): polyinosinic:polycytidylic acid; RIGI: RNA sensor RIG-I; RLR: RIGI-like receptor; SFTSV: severe fever withthrombocytopenia syndrome virus; TCID50: 50% tissue culture infectiousdose; TIMM23: translocase of inner mitochondrial membrane 23; TOMM20:translocase of outer mitochondrial membrane 20; TUFM: Tu translation elongationfactor, mitochondrial.

Comparative phenotypic and transcriptomic analysis reveals genotypic differences in nitrogen use efficiency in sorghum.

Sorghum (Sorghumbicolor L.), a model for C4 grass and an emerging biofuel crop, is known for its robust tolerance to low input field. However, the focus on enhancing nitrogen use efficiency (NUE) in sorghum under low nitrogen (N) conditions has been limited. This study conducted hydroponic experiments and field trials with two sorghum inbred lines, contrasting in their N efficiency: the N-efficient (398B) and the N-inefficient (CS3541) inbred lines. The aim was to analyze the key factors influencing NUE by integrating phenotypic, physiological, and multi-omics approaches under N deficiency conditions. The field experiments revealed that 398B displayed superior NUE and yield performance compared to CS3541. In hydroponic experiments, the growth of 398B outperformed CS3541 following N deficiency, attributing to its higher photosynthetic and sustaining activity of N metabolism-related enzymes. Genomic and transcriptomic integration highlighted fewer genomic diversities and alterations in global gene expression in 398B, which were likely contributor to its high NUE. Additionally, co-expression network analysis suggested the involvement of key genes which impact N uptake efficiency (NUpE) and N utilization efficiency (NUtE) in both lines, such as an N transporter, Sobic.003G371000.v3.2leaf(NPF5.10) and a transcription factor, Sobic.002G202800.v3.2leaf(WRKY) in bolstering NUE under low-N stress. The findings collectively suggested that 398B achieved higher NUpE and NUtE, effectively coordinating photosynthesis and N metabolism to enhance NUE. The candidate genes regulating N uptake and utilization efficiencies could provide valuable insights for developing sorghum breeds with improved NUE, contributing to sustainable agricultural practices and bioenergy crop development.

Discovery of a Highly Potent Lysine Methyltransferases G9a/NSD2 Dual Inhibitor to Treat Solid Tumors.

Both G9a and NSD2 have been recognized as promising therapeutic targets for cancer treatment. However, G9a inhibitors only showed moderate inhibitory activity against solid tumors and NSD2 inhibitors were limited to the treatment of hematological malignancies. Inspired by the advantages of dual-target inhibitors that show great potential in enhancing efficiency, we developed a series of highly potent G9a/NSD2 dual inhibitors to treat solid tumors. The candidate 16 demonstrated much enhanced antiproliferative activity compared to the selective G9a inhibitor 3 and NSD2 inhibitor 15. In addition, it exhibited superior potency in inhibiting colony formation, inducing cell apoptosis, and blocking cancer cell metastasis. Furthermore, it effectively inhibited the catalytic functions of both G9a and NSD2 in cells and exhibited significant antitumor efficacy in the PANC-1 xenograft model with good safety. Therefore, compound 16 as a highly potent G9a/NSD2 dual inhibitor presents an attractive anticancer drug candidate for the treatment of solid tumors.

Impact of dairy supplementation on bone acquisition in children's limbs: a 12-month cluster-randomized controlled trial and meta-analysis.

The impact of milk on bone health in rural preschoolers is under-researched. This study, through a clinical trial and a meta-analysis, finds that milk supplementation enhances forearm and calcaneus bone acquisition in children, supporting the benefits of daily milk consumption. PURPOSE: This study evaluated the impact of dairy supplementation on bone acquisition in children's limbs through a cluster-randomized controlled trial and a meta-analysis. METHODS: The trial involved 315 children (4-6 year) from Northwest China, randomized to receive either 390 ml of milk daily (n = 215) or 20-30 g of bread (n = 100) over 12 months. We primarily assessed bone mineral density (BMD) and content (BMC) changes at the limbs, alongside bone-related biomarkers, measured at baseline, the 6th and 12th months. The meta-analysis aggregated BMD or BMC changes in the forearm/legs/calcaneus from published randomized trials involving children aged 3-18 years supplemented with dairy foods (vs. control group). RESULTS: Of 278 completed the trial, intention-to-treat analysis revealed significant increases in BMD (4.05% and 7.31%) and BMC (4.69% and 7.34%) in the left forearm at the 6th and 12th months in the milk group compared to controls (P < 0.001). The calcaneus showed notable improvements in BMD (2.01%) and BMC (1.87%) at 6 months but not at 12 months. Additionally, milk supplementation was associated with beneficial changes in bone resorption markers, parathyroid hormone (- 12.70%), insulin-like growth factor 1 (6.69%), and the calcium-to-phosphorus ratio (2.22%) (all P < 0.05). The meta-analysis, encompassing 894 children, indicated that dairy supplementation significantly increased BMD (SMD, 0.629; 95%CI: 0.275, 0.983) and BMC (SMD, 0.616; 95%CI: 0.380, 0.851) (P < 0.05) in the arms, but not in the legs (P > 0.05). CONCLUSION: Milk supplementation significantly improves bone health in children's forearms, underscoring its potential as a strategic dietary intervention for bone development. Trial registration NCT05074836.

Cysteine-Induced Chirality Evolution of Molybdenum Disulfide Nanodots from a Bottom-Up Strategy.

The transfer of chirality from molecules to synthesized nanomaterials has recently attracted significant attention. Although most studies have focused on graphene and plasmonic metal nanostructures, layered transition metal dichalcogenides (TMDs), particularly MoS2, have recently garnered considerable attention due to their semiconducting and electrocatalytic characteristics. Herein, we report a new approach for the synthesis of chiral molybdenum sulfide nanomaterials based on a bottom-up synthesis method in the presence of chiral cysteine enantiomers. In the synthesis process, molybdenum trioxide and sodium hydrosulfide serve as molybdenum and sulfur sources, respectively. In addition, ascorbic acid acts as a reducing agent, resulting in the formation of zero-dimensional MoS2 nanodots. Moreover, the addition of cysteine enantiomers to the growth solutions contributes to the chirality evolution of the MoS2 nanostructures. The chirality is attributed to the cysteine enantiomer-induced preferential folding of the MoS2 planes. The growth mechanism and chiral structure of the nanomaterials are confirmed through a series of characterization techniques. This work combines chirality with the bottom-up synthesis of MoS2 nanodots, thereby expanding the synthetic methods for chiral nanomaterials. This simple synthesis approach provides new insights for the construction of other chiral TMD nanomaterials with emerging structures and properties. More significantly, the as-formed MoS2 nanodots exhibited highly defect-rich structures and chiroptical performance, thereby inspiring a high potential for emerging optical and electronic applications.

Neuroimage Analysis Methods and Artificial Intelligence Techniques for Reliable Biomarkers and Accurate Diagnosis of Schizophrenia: Achievements Made by Chinese Scholars Around the Past Decade.

BACKGROUND AND HYPOTHESIS: Schizophrenia (SZ) is characterized by significant cognitive and behavioral disruptions. Neuroimaging techniques, particularly magnetic resonance imaging (MRI), have been widely utilized to investigate biomarkers of SZ, distinguish SZ from healthy conditions or other mental disorders, and explore biotypes within SZ or across SZ and other mental disorders, which aim to promote the accurate diagnosis of SZ. In China, research on SZ using MRI has grown considerably in recent years. STUDY DESIGN: The article reviews advanced neuroimaging and artificial intelligence (AI) methods using single-modal or multimodal MRI to reveal the mechanism of SZ and promote accurate diagnosis of SZ, with a particular emphasis on the achievements made by Chinese scholars around the past decade. STUDY RESULTS: Our article focuses on the methods for capturing subtle brain functional and structural properties from the high-dimensional MRI data, the multimodal fusion and feature selection methods for obtaining important and sparse neuroimaging features, the supervised statistical analysis and classification for distinguishing disorders, and the unsupervised clustering and semi-supervised learning methods for identifying neuroimage-based biotypes. Crucially, our article highlights the characteristics of each method and underscores the interconnections among various approaches regarding biomarker extraction and neuroimage-based diagnosis, which is beneficial not only for comprehending SZ but also for exploring other mental disorders. CONCLUSIONS: We offer a valuable review of advanced neuroimage analysis and AI methods primarily focused on SZ research by Chinese scholars, aiming to promote the diagnosis, treatment, and prevention of SZ, as well as other mental disorders, both within China and internationally.

Effects of Silybum marianum, Pueraria lobate, combined with Salvia miltiorrhiza tablets on non-alcoholic fatty liver disease in adults: A triple-blind, randomized, placebo-controlled clinical trial.

BACKGROUND & AIMS: Several medicinal plant extracts have demonstrated hepatoprotective effects. However, data are scarce regarding their combined effects on non-alcoholic fatty liver disease (NAFLD). This study aimed to investigate the effects of tablets containing Silybum marianum, Pueraria lobata, and Salvia miltiorrhiza (SPS) on NAFLD progression in Chinese adults. METHODS: In this randomized, triple-blind, placebo-controlled clinical trial, 121 NAFLD patients (60 female and 61 male), diagnosed via magnetic resonance imaging (MRI) and aged 18-65 years, were enrolled. Participants were randomly allocated to receive SPS tablets (n = 60; three tablets per dose, twice daily) or placebo (n = 61) for 24 weeks. Each SPS tablet contained approximately 23.0 mg of silybin, 11.4 mg of puerarin, and 10.9 mg of salvianolic acid. There were no differences in appearance, taste and odour between the SPS tablets and placebo manufactured by BYHEALTH Co., LTD (Guangzhou, China). The primary endpoints were changes in the liver fat content (LFC) and steatosis grade from baseline to 24 weeks. Secondary outcomes included changes in biomarkers/scores of liver fibrosis and steatosis, oxidative stress, inflammatory cytokines, alcohol metabolism, and glucose metabolism. RESULTS: A total of 112 participants completed the research. The intention-to-treat results showed a trend toward reduction in both absolute LFC (-0.52%) and percentage of LFC (-4.57%) in the SPS group compared to the placebo group after 24 weeks, but these changes didn't reach statistical significance (p > 0.05). The SPS intervention (vs. placebo) significantly decreased hypersensitive C-reactive protein level (-6.76%) and increased aldehyde dehydrogenase activity (+18.1%) at 24 weeks post-intervention (all p < 0.05). Per-protocol analysis further supported these effects. This trial is registered at Clinical Trials.gov (NCT05076058). CONCLUSION: SPS supplementation may have potential benefits in improving NAFLD, but further larger-scale trials are necessary to confirm these findings.

Mapping the gut microecological multi-omics signatures to serum metabolome and their impact on cardiometabolic health in elderly adults.

BACKGROUND: Mapping gut microecological features to serum metabolites (SMs) will help identify functional links between gut microbiome and cardiometabolic health. METHODS: This study encompassed 836-1021 adults over 9.7 year in a cohort, assessing metabolic syndrome (MS), carotid atherosclerotic plaque (CAP), and other metadata triennially. We analyzed mid-term microbial metagenomics, targeted fecal and serum metabolomics, host genetics, and serum proteomics. FINDINGS: Gut microbiota and metabolites (GMM) accounted for 15.1% overall variance in 168 SMs, with individual GMM factors explaining 5.65%-10.1%, host genetics 3.23%, and sociodemographic factors 5.95%. Specifically, GMM elucidated 5.5%-49.6% variance in the top 32 GMM-explained SMs. Each 20% increase in the 32 metabolite score (derived from the 32 SMs) correlated with 73% (95% confidence interval [CI]: 53%-95%) and 19% (95% CI: 11%-27%) increases in MS and CAP incidences, respectively. Among the 32 GMM-explained SMs, sebacic acid, indoleacetic acid, and eicosapentaenoic acid were linked to MS or CAP incidence. Serum proteomics revealed certain proteins, particularly the apolipoprotein family, mediated the relationship between GMM-SMs and cardiometabolic risks. INTERPRETATION: This study reveals the significant influence of GMM on SM profiles and illustrates the intricate connections between GMM-explained SMs, serum proteins, and the incidence of MS and CAP, providing insights into the roles of gut dysbiosis in cardiometabolic health via regulating blood metabolites. FUNDING: This study was jointly supported by the National Natural Science Foundation of China, Key Research and Development Program of Guangzhou, 5010 Program for Clinical Research of Sun Yat-sen University, and the 'Pioneer' and 'Leading goose' R&D Program of Zhejiang.

Cardiovascular disease therapeutics via engineered oral microbiota: Applications and perspective.

Engineering bacteria are considered as a potential treatment for cardiovascular diseases and related risk factors. Oral bacteria are closely related to the occurrence and development of cardiovascular diseases, and their engineering has broad prospects and potential in the treatment of cardiovascular diseases. Oral pathogenic bacteria undergo protein and genetic engineering, including the incorporation of exogenous plasmids to yield therapeutic effects; genetically engineered oral probiotics can be harnessed to secrete cytokines and reactive oxygen species, offering novel therapeutic avenues for cardiovascular diseases.

Electrophoretic Microplate Protein Identification Based on Gold Staining of Molybdenum Disulfide Hydrogels.

Numerous high-performance nanotechnologies have been developed, but their practical applications are largely restricted by the nanomaterials' low stabilities and high operation complexity in aqueous substrates. Herein, we develop a simple and high-reliability hydrogel-based nanotechnology based on the in situ formation of Au nanoparticles in molybdenum disulfide (MoS2)-doped agarose (MoS2/AG) hydrogels for electrophoresis-integrated microplate protein recognition. After the incubation of MoS2/AG hydrogels in HAuCl4 solutions, MoS2 nanosheets spontaneously reduce Au ions, and the hydrogels are remarkably stained with the color of as-synthetic plasmonic Au hybrid nanomaterials (Au staining). Proteins can precisely mediate the morphologies and optical properties of Au/MoS2 heterostructures in the hydrogels. Consequently, Au staining-based protein recognition is exhibited, and hydrogels ensure the comparable stabilities and sensitivities of protein analysis. In comparison to the fluorescence imaging and dye staining, enhanced sensitivity and recognition performances of proteins are implemented by Au staining. In Au staining, exfoliated MoS2 semiconductors directly guide the oriented growth of plasmonic Au nanostructures in the presence of formaldehyde, showing environment-friendly features. The Au-stained hydrogels merge the synthesis and recognition applications of plasmonic Au nanomaterials. Significantly, the one-step incubation of the electrophoretic hydrogels leads to high simplicity of operation, largely challenging those multiple-step Ag staining routes which were performed with high complexity and formaldehyde toxicity. Due to its toxic-free, simple, and sensitive merits, the Au staining integrated with electrophoresis-based separation and microplate-based high-throughput measurements exhibits highly promising and improved practicality of those developing nanotechnologies and largely facilitates in-depth understanding of biological information.

White light powered antimicrobial nanoagents for triple photothermal, chemodynamic and photodynamic based sterilization.

Antibacterial nanoagents have been increasingly developed due to their favorable biocompatibility, cost-effective raw materials, and alternative chemical or optical properties. Nevertheless, there is still a pressing need for antibacterial nanoagents that exhibit outstanding bacteria-binding capabilities and high antibacterial efficiency. In this study, we constructed a multifunctional cascade bioreactor (GCDCO) as a novel antibacterial agent. This involved incorporating carbon dots (CDs), cobalt sulfide quantum dots (CoSx QDs), and glucose oxidase (GOx) to enhance bacterial inhibition under sunlight irradiation. The GCDCO demonstrated highly efficient antibacterial capabilities attributed to its favorable photothermal properties, photodynamic activity, as well as the synergistic effects of hyperthermia, glucose-augmented chemodynamic action, and additional photodynamic activity. Within this cascade bioreactor, CDs played the role of a photosensitizer for photodynamic therapy (PDT), capable of generating ˙O2- even under solar light irradiation. The CoSx QDs not only functioned as a catalytic component to decompose hydrogen peroxide (H2O2) and generate hydroxyl radicals (˙OH), but they also served as heat generators to enhance the Fenton-like catalysis process. Furthermore, GOx was incorporated into this cascade bioreactor to internally supply H2O2 by consuming glucose for a Fenton-like reaction. As a result, GCDCO could generate a substantial amount of reactive oxygen species (ROS), leading to a significant synergistic effect that greatly induced bacterial death. Furthermore, the in vitro antibacterial experiment revealed that GCDCO displayed notably enhanced antibacterial activity against E. coli (99+ %) when combined with glucose under simulated sunlight, surpassing the efficacy of the individual components. This underscores its remarkable efficiency in combating bacterial growth. Taken together, our GCDCO demonstrates significant potential for use in the routine treatment of skin infections among diabetic patients.

SFTSV nucleoprotein mediates DNA sensor cGAS degradation to suppress cGAS-dependent antiviral responses.

Cyclic GMP-AMP synthase (cGAS) is an important DNA pattern recognition receptor that senses double-stranded DNA derived from invading pathogens or self DNA in cytoplasm, leading to an antiviral interferon response. A tick-borne Bunyavirus, severe fever with thrombocytopenia syndrome virus (SFTSV), is an RNA virus that causes a severe emerging viral hemorrhagic fever in Asia with a high case fatality rate of up to 30%. However, it is unclear whether cGAS interacts with SFTSV infection. In this study, we found that SFTSV infection upregulated cGAS RNA transcription and protein expression, indicating that cGAS is an important innate immune response against SFTSV infection. The mechanism of cGAS recognizing SFTSV is by cGAS interacting with misplaced mitochondrial DNA in the cytoplasm. Depletion of mitochondrial DNA significantly inhibited cGAS activation under SFTSV infection. Strikingly, we found that SFTSV nucleoprotein (N) induced cGAS degradation in a dose-dependent manner. Mechanically, N interacted with the 161-382 domain of cGAS and linked the cGAS to LC3. The cGAS-N-LC3 trimer was targeted to N-induced autophagy, and the cGAS was degraded in autolysosome. Taken together, our study discovered a novel antagonistic mechanism of RNA viruses, SFTSV is able to suppress the cGAS-dependent antiviral innate immune responses through N-hijacking cGAS into N-induced autophagy. Our results indicated that SFTSV N is an important virulence factor of SFTSV in mediating host antiviral immune responses. IMPORTANCE: Severe fever with thrombocytopenia syndrome virus (SFTSV) is a tick-borne RNA virus that is widespread in East and Southeast Asian countries with a high fatality rate of up to 30%. Up to now, many cytoplasmic pattern recognition receptors, such as RIG-I, MDA5, and SAFA, have been reported to recognize SFTSV genomic RNA and trigger interferon-dependent antiviral responses. However, current knowledge is not clear whether SFTSV can be recognized by DNA sensor cyclic GMP-AMP synthase (cGAS). Our study demonstrated that cGAS could recognize SFTSV infection via ectopic mitochondrial DNA, and the activated cGAS-stimulator of interferon genes signaling pathway could significantly inhibit SFTSV replication. Importantly, we further uncovered a novel mechanism of SFTSV to inhibit innate immune responses by the degradation of cGAS. cGAS was degraded in N-induced autophagy. Collectively, this study illustrated a novel virulence factor of SFTSV to suppress innate immune responses through autophagy-dependent cGAS degradation.

Bunyavirus SFTSV NSs utilizes autophagy to escape the antiviral innate immune response.

Severe fever with thrombocytopenia syndrome virus (SFTSV) nonstructural protein (NSs) is an important viral virulence factor that sequesters multiple antiviral proteins into inclusion bodies to escape the antiviral innate immune response. However, the mechanism of the NSs restricting host innate immunity remains largely elusive. Here, we found that the NSs induced complete macroautophagy/autophagy by interacting with the CCD domain of BECN1, thereby promoting the formation of a BECN1-dependent autophagy initiation complex. Importantly, our data showed that the NSs sequestered antiviral proteins such as TBK1 into autophagic vesicles, and therefore promoted the degradation of TBK1 and other antiviral proteins. In addition, the 8A mutant of NSs reduced the induction of BECN1-dependent autophagy flux and degradation of antiviral immune proteins. In conclusion, our results indicated that SFTSV NSs sequesters antiviral proteins into autophagic vesicles for degradation and to escape antiviral immune responses.