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Periodontitis is characterized by dysbiotic biofilms, gingival inflammation, and bone resorption, highlighting the urgent need for a comprehensive approach to drug combination therapy. In this study, we introduce dynamic covalent nanonetworks (dcNNWs) synthesized through a one-pot, four-component reaction-induced self-assembly method using polyamines, 2-formylphenylboronic acid, epigallocatechin gallate, and alendronate. The formation of iminoboronate bonds drives the creation of dcNNWs, allowing controlled release in the periodontitis microenvironment. The inclusion of catechol and bisphosphonate imparts exceptional bioadhesive properties to the dcNNWs, enhancing their efficacy in preventing pathogenic bacterial biofilm formation and eliminating mature biofilms. Moreover, the dcNNWs efficiently absorb pathogen-associated molecular patterns and scavenge excess reactive oxygen species, regulating the local immune response and demonstrating anti-inflammatory effects. Additionally, the released polyphenol and alendronate from the dcNNWs alleviated inflammation and enhanced osteogenesis significantly. The detailed synergistic effects of dcNNWs in biofilm eradication, anti-inflammation, and bone remodeling, with minimal impact on healthy tissues, are confirmed in a rat model of periodontitis. With a facile synthesis process, excellent synergistic effects in periodontitis treatment, and biocompatibility, our dcNNWs present a promising and translational solution for the effective management of periodontitis.

Although major progress has been made in the use of chimeric antigen receptor (CAR)-T-cell therapy for hematological malignancies, this method is ineffective against solid tumors largely because of the limited infiltration, activation and proliferation of CAR-T cells. To overcome this issue, we engineered CAR-T cells with synthetic Notch (synNotch) receptors, which induce local tumor-specific secretion of extracellular matrix (ECM)-degrading enzymes at the tumor site. SynNotch CAR-T cells achieve precise ECM recognition and robustly kill targeted tumors, with synNotch-induced enzyme production enabling the degradation of components of the tumor ECM. In addition, this regulation strongly increased the infiltration of CAR-T cells and the clearance of solid tumors, resulting in tumor regression without toxicity in vivo. Notably, synNotch CAR-T cells also promoted the persistent activation of CAR-T cells in patient-derived tumor organoids. Thus, we constructed a synthetic T-cell system that increases the infiltration and antitumor function of CAR-T cells, providing a strategy for targeting ECM-rich solid tumors., Competing Interests: Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (© 2024. The Author(s), under exclusive licence to CSI and USTC.)

The rise of antibiotic resistance, coupled with a dwindling antibiotic pipeline, presents a significant threat to public health. Consequently, there is an urgent need for novel therapeutics targeting antibiotic-resistant pathogens. Nisin, a promising peptide antibiotic, exhibits potent bactericidal activity through a mechanism distinct from that of clinically used antibiotics. However, its cationic nature leads to hemolysis and cytotoxicity, which has limited its clinical application. Here, nanodelivery systems have been developed by mimicking the mechanisms bacteriophages use to deliver their genomes to host bacteria. These systems utilize bacteriophage receptor-binding proteins conjugated to loading modules, enabling efficient targeting of bacterial pathogens. Peptide antibiotics are loaded via dynamic covalent bonds, allowing for infection microenvironment-responsive payload release. These nanodelivery systems demonstrate remarkable specificity against target pathogens and effectively localize to bacteria-infected lungs in vivo. Notably, they significantly reduce the acute toxicity of nisin, rendering it suitable for intravenous administration. Additionally, these bacteriophage-mimicking nanomedicines exhibit excellent therapeutic efficacy in a mouse model of MRSA-induced pneumonia. The facile synthesis, potent antimicrobial performance, and favorable biocompatibility of these nanomedicines highlight their potential as alternative therapeutics for combating antibiotic-resistant pathogens. This study underscores the effectiveness of bacteriophage mimicry as a strategy for transforming peptide antibiotics into viable therapeutics., (© 2024 The Author(s). Advanced Science published by Wiley‐VCH GmbH.)

The World Health Organization has warned that without effective action, deaths from drug-resistant bacteria can exceed 10 million annually, making it the leading cause of death. Conventional antibiotics are becoming less effective due to rapid bacterial drug resistance and slowed new antibiotic development, necessitating new strategies. Recently, materials with catalytic/enzymatic properties, known as nanozymes, have been developed, inspired by natural enzymes essential for bacterial eradication. Unlike recent literature reviews that broadly cover nanozyme design and biomedical applications, this review focuses on the latest advancements in nanozymes for combating bacterial drug resistance, emphasizing their design, structural characteristics, applications in combination therapy, and future prospects. This approach aims to promote nanozyme development for combating bacterial drug resistance, especially towards clinical translation., (© 2024 Wiley‐VCH GmbH.)

Food safety is closely related to environmental pollution. It is worth noting that the long-term accumulation of Cd, a toxic heavy metal, in animals may pose a threat to human health through food chain. Previous studies have found that Cd exposure may cause liver metabolic disorders of black goats, but the mechanism of its impact on liver proteome of goats has not been widely studied. Therefore, in this study, ten male goats (Nubian black goat × native black goat) were exposed to Cd via drinking water containing CdCl2 (20 mg Cd·kg - 1·BW) for 30 days (five male goats per group). Blood physiology and liver antioxidant indices in black goats were determined and differentially expressed proteins (DEPs) in the livers of Cd-exposed goats were profiled by using TMT-labelled proteomics. It was found that plasma Hb and RBC levels as well as PCV values were decreased, liver SOD, GSH-Px, T-AOC and CAT levels were decreased, and MDA level was increased in Cd-treated goats, and 630 DEPs (up 326, down 304) in the livers of Cd-treated goats. Proteomics analysis revealed that Cd exposure affected glutathione metabolism and drug metabolism-cytochrome P450. We identified GP×2, GSTM3, and TBXAS1 as potential protein markers of early Cd toxicity in goats. This study provided theoretical basis for early diagnosis of Cd poisoning in goats., (© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Despite the safety profile of subunit vaccines, the inferior immunogenicity hinders their application in the nasal cavity. This study introduces a novel antigen delivery and adjuvant system utilizing mucoadhesive chitosan-catechol (Chic) on silica spiky nanoparticles (Ssp) to enhance immunity through multiple mechanisms. The Chic functionalizes the Ssp surface and incorporates with SARS-CoV-2 spike protein receptor-binding domain (RBD) and toll-like receptor (TLR)9 agonist unmethylated cytosine-guanine (CpG) motif, forming uniform virus-like nanoparticles (Ssp-Chic-RBD-CpG) via electrostatic and covalent interactions. Ssp-Chic-RBD-CpG, mimicking the morphology and function of inactive virions, effectively prolongs the retention time of RBD in the nasal mucosa by 3.92-fold compared to RBD alone, enhances the maturation of dendritic cells (DCs), and facilitates the antigen trafficking to the draining lymph nodes, which subsequently induces a stronger mucosal immunity. Mechanistically, the enhanced chemokine chemokine (C-C motif) ligand 20 (CCL20)-driven DCs recruitment and maturation by Ssp-Chic-RBD-CpG are evidenced by a cell co-culture model. In addition, the overexpression of TLR4/9 and activation of MYD88/NF-κB signaling pathway in activation of DCs are observed. Proof of principle is obtained for RBD, but similar delivery mechanisms can be applied in other protein-based subunit vaccines as well when intranasal administration is needed., (© 2024 Wiley‐VCH GmbH.)

The overuse of antibiotics has led to the rapid development of multi-drug resistant bacteria, making antibiotics increasingly ineffective against bacterial infections. Consequently, there is an urgent need to develop alternative strategies to combat multi-drug-resistant bacterial infections. In this study, gold nanoparticles modified with ellagic acid (EA-AuNPs) were prepared using a simple and mild one-pot hydrothermal process. EA-AuNPs demonstrated high bactericidal efficacy and broad-spectrum antimicrobial activities against clinical isolates of the antibiotic-resistant ESKAPE pathogens. Furthermore, EA-AuNPs effectively disperse biofilms of multi-drug-resistant bacteria. Additionally, EA-AuNPs mitigated inflammatory responses at the bacterial infection sites. The combined bactericidal and anti-inflammatory treatment with EA-AuNPs resulted in faster curing of peritonitis caused by Staphylococcus aureus in mice compared to treatment with free EA or gentamicin. Moreover, transcriptome analysis revealed that EA-AuNPs exhibited a multi-targeting mechanism, making resistance development in pathogens more challenging than traditional antibiotics that recognize specific cellular targets. Overall, EA-AuNPs emerged as a promising antimicrobial agent against multi-drug-resistant bacterial infections.

Polymyxins have been regarded as an efficient therapeutic against many life-threatening, multidrug resistant Gram-negative bacterial infections; however, the cytotoxicity and emergence of drug resistance associated with polymyxins have greatly hindered their clinical potential. Herein, the reaction-induced self-assembly (RISA) of polymyxins and natural aldehydes in aqueous solution is presented. The resulting assemblies effectively mask the positively charged nature of polymyxins, reducing their cytotoxicity. Moreover, the representative PMBA 4 (composed of polymyxin B (PMB) and (E)-2-heptenal (A 4 )) assemblies demonstrate enhanced binding to Gram-negative bacterial outer membranes and exhibit multiple antimicrobial mechanisms, including increased membrane permeability, elevated bacterial metabolism, suppression of quorum sensing, reduced ATP synthesis, and potential reduction of bacterial drug resistance. Remarkably, PMBA 4 assemblies reverse drug resistance in clinically isolated drug-resistant strains of Gram-negative bacteria, demonstrating exceptional efficacy in preventing and eradicating bacterial biofilms. PMBA 4 assemblies efficiently eradicate Gram-negative bacterial biofilm infections in vivo and alleviate inflammatory response. This RISA strategy offers a practical and clinically applicable approach to minimize side effects, reverse drug resistance, and prevent the emergence of resistance associated with free polymyxins., (© 2024 Wiley‐VCH GmbH.)

Background: Robust and practical prognosis prediction models for hepatocellular carcinoma (HCC) patients play crucial roles in personalized precision medicine., Material and Methods: We recruited two independent HCC cohorts (discovery cohort and validation cohort), totally consisting of 222 HCC patients undergone surgical resection. We quantified the expressions of immune-related proteins (CD8, CD68, CD163, PD-1 and PD-L1) in paired HCC tissues and non-tumor liver tissues from these HCC patients using immunohistochemistry (mIHC) assays. We constructed the HCC prognosis prediction model using five different machine learning methods based on the patients in the discovery cohort, such as Cox proportional hazards (CoxPH)., Results: We identified 19 features that were associated with overall survival of HCC patients in the discovery cohort (p < 0.1), such as immune-related features CD68 + and CD8 + cell infiltration. We constructed five HCC prognosis prediction models using five different machine learning methods. Among the five different machine learning models, the CoxPH model achieved the best performance (area under the curve [AUC], 0.839; C-index, 0.779). According to the risk score from CoxPH model, we divided HCC patients into high-risk group/low-risk group. In both discovery cohort and validation cohort, the patients in low-risk group showed longer overall survival compared with those in high-risk group (p = 1.8 × 10 -7 and 3.4 × 10 -5 , respectively). Moreover, our novel scoring system efficiently predicted the 6, 12, and 18 months survival rate of HCC patients with AUC >0.75 in both discovery cohort and validation cohort. In addition, we found that the scoring system could also distinguish the patients with high/low risks of relapse in both discovery cohort and validation cohort (p = 0.00015 and 0.00012)., Conclusion: The novel CoxPH-based risk scoring model on clinical, laboratory-testing and immune-related features showed high prediction efficiencies for overall survival and recurrence of HCCs undergone surgical resection. Our results may be helpful to optimize clinical follow-up or therapeutic interventions., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

MARCH5 is a ring-finger E3 ubiquitin ligase located in the outer membrane of mitochondria. A previous study has reported that MARCH5 was up-regulated and contributed to the migration and invasion of OC cells by serving as a competing endogenous RNA. However, as a mitochondrial localized E3 ubiquitin ligase, the function of MARCH5 in mitochondrial-associated metabolism reprogramming in human cancers remains largely unexplored, including OC. We first assessed the glycolysis effect of MARCH5 in OC both in vitro and in vivo. Then we analyzed the effect of MARCH5 knockdown or overexpression on respiratory activity by evaluating oxygen consumption rate, activities of OXPHOS complexes and production of ATP in OC cells with MARCH5. Co-immunoprecipitation, western-blot, and in vitro and vivo experiments were performed to investigate the molecular mechanisms underlying MARCH5-enhanced aerobic glycolysis s in OC. In this study, we demonstrate that the abnormal upregulation of MARCH5 is accompanied by significantly increased aerobic glycolysis in OC. Mechanistically, MARCH5 promotes aerobic glycolysis via ubiquitinating and degrading mitochondrial pyruvate carrier 1 (MPC1), which mediates the transport of cytosolic pyruvate into mitochondria by localizing on mitochondria outer membrane. In line with this, MPC1 expression is significantly decreased and its downregulation is closely correlated with unfavorable survival. Furthermore, in vitro and in vivo assays revealed that MARCH5 upregulation-enhanced aerobic glycolysis played a critical role in the proliferation and metastasis of OC cells. Taken together, we identify a MARCH5-regulated aerobic glycolysis mechanism by degradation of MPC1, and provide a rationale for therapeutic targeting of aerobic glycolysis via MARCH5-MPC1 axis inhibition., (© 2024. The Author(s).)

This study aimed to explore the regulatory effect of remifentanil-mediated mitochondrial autophagy on osteoclast formation and further investigate its mechanism. Macrophage cell line RAW264.7 was taken and induced to differentiate into mature osteoclasts using nuclear factor kB receptor activating factor ligand (RANKL). The cell model was treated with different concentrations of remifentanil or down-regulated expression of mitochondrial autophagy-related gene PINK1. The survival, death and ROS production of osteoclasts were detected by CCK8 kit and flow cytometry, MMP level was detected by JC-1 method, mitochondrial morphology and autophagy were observed by transmission electron microscopy, and mitochondrial autophagy-related protein expression was detected by Western blot. The number of osteoclasts in the remifentanil-treated group was significantly reduced compared to the control group, accompanied by a reduction in reactive oxygen species (ROS) and mitochondrial membrane potential levels (MMP). Further results showed that remifentanil could significantly up-regulate the activity of PINK1/Parkin pathway, promote the occurrence of mitochondrial autophagy, and damaged mitochondria, and inhibit the formation of osteoclasts. Remifentanil successfully inhibited osteoclast formation by regulating mitochondrial autophagy mediated by PINK1/Parkin pathway. The results of this study revealed that remifentanil plays an important role in the physiology and pathology of osteoclasts, which may provide new ideas and strategies for the clinical treatment of remifentanil in tibial fractures.

In order to investigate the effect of slaughter weight (SW) on carcass characteristics and meat quality, we measured the carcass characteristics, meat quality, and amino acid metabolomics characteristics of longissimus dorsi ( LD ) muscle from Tianfu finishing (TF) pigs. Based on SW, 13 pigs were divided into three groups (100-kg group, 125-kg group, and 150-kg group with 3, 5, 5 pigs in each group, respectively). Raising SW to 125 kg or 150 kg increased average backfat thickness ( P < 0.01) and intramuscular fat content ( P < 0.01), and decreased shear force ( P < 0.01). A total of 231 amino acid metabolome from three amino acid classes identified with metabolomics were analyzed, and 93 differentially expressed metabolites (DEMs) were identified (69 up-regulated DEMs and 24 down-regulated DEMs). The DEMs, including urea, 3-iodo-L-tyrosine, N-glycyl-L-leucine, and N, N-dimethylglycine with amino acid metabolism, were significantly induced ( P < 0.01). KEGG pathway analysis showed that these DEMs were significantly enriched ( P < 0.01) in 135 metabolism pathways, including pathways related to amino acid metabolism, such as arginine and proline metabolism, glycine, serine and threonine metabolism, alanine, aspartate and glutamate metabolism, tryptophan metabolism, and beta-alanine metabolism. Our research findings provided new insights into the impact of SW on amino acid distribution and theoretical support for genetic breeding of meat quality of TF pigs. However, raising SW to 125 kg, or more, decreased the carcass leanness of live TF pigs and had no benefits to pork quality attributes., Competing Interests: JZ and XA were employed by Sichuan Techlex Industrial Co. Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Li, Tao, Zhao, Zhou and Ao.)

Novel therapeutic strategies against difficult-to-treat bacterial infections are desperately needed, and the faster and cheaper way to get them might be by repurposing existing antibiotics. Nanodelivery systems enhance the efficacy of antibiotics by guiding them to their targets, increasing the local concentration at the site of infection. While recently described nanodelivery systems are promising, they are generally not easy to adapt to different targets, and lack biocompatibility or specificity. Here, nanodelivery systems are created that source their targeting proteins from bacteriophages. Bacteriophage receptor-binding proteins and cell-wall binding domains are conjugated to nanoparticles, for the targeted delivery of rifampicin, imipenem, and ampicillin against bacterial pathogens. They show excellent specificity against their targets, and accumulate at the site of infection to deliver their antibiotic payload. Moreover, the nanodelivery systems suppress pathogen infections more effectively than 16 to 32-fold higher doses of free antibiotics. This study demonstrates that bacteriophage sourced targeting proteins are promising candidates to guide nanodelivery systems. Their specificity, availability, and biocompatibility make them great options to guide the antibiotic nanodelivery systems that are desperately needed to combat difficult-to-treat infections., (© 2024. The Author(s).)

To identify novel susceptibility genes for hepatocellular carcinoma (HCC), we performed a rare-variant association study in Chinese populations consisting of 2,750 cases and 4,153 controls. We identified four HCC-associated genes, including NRDE2, RANBP17, RTEL1, and STEAP3. Using NRDE2 (index rs199890497 [p.N377I], p = 1.19 × 10 -9 ) as an exemplary candidate, we demonstrated that it promotes homologous recombination (HR) repair and suppresses HCC. Mechanistically, NRDE2 binds to the subunits of casein kinase 2 (CK2) and facilitates the assembly and activity of the CK2 holoenzyme. This NRDE2-mediated enhancement of CK2 activity increases the phosphorylation of MDC1 and then facilitates the HR repair. These functions are eliminated almost completely by the NRDE2-p.N377I variant, which sensitizes the HCC cells to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with chemotherapy. Collectively, our findings highlight the relevance of the rare variants to genetic susceptibility to HCC, which would be helpful for the precise treatment of this malignancy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

To investigate the mitigative effects of glycyrrhiza extract (GE) and curcumin (CUR) on the antioxidant and immune functions of the Guizhou black goat exposed to cadmium (Cd), 50 healthy Guizhou black goats (11.08 ± 0.22 kg, male, six months old) were used in a 60-day trial and were randomly assigned to five groups with 10 replicates per group, one goat per replicate. All goats were fed a basal diet, with drinking water and additives varying slightly between groups. Control group: tap water (0.56 μg·L -1 Cd); Cd group: drinking water containing Cd (20 mg Cd·kg -1 ·body weight, CdCl 2 ·2.5H 2 O); GE group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg -1 GE; CUR group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg -1 CUR; combined group: drinking water containing Cd, at days 31 to 60, the basic diet had added 500 mg·kg -1 GE and CUR. Compared with the Cd group, GE and CUR significantly increased the levels of hemoglobin and red blood cell count in the blood, and the activities of serum antioxidant enzyme activity and immune function in the Guizhou black goat ( p < 0.05). The treatment effect in the combined group was better than that in the GE and CUR groups. The results showed that GE and CUR improved the antioxidant and immune functions of the serum and livers of the Guizhou black goat and alleviated the toxicity damage of Cd contamination. This research has positive implications for both livestock management and human health.

Due to the fencing of the Przewalski's gazelle ( Procapra przewalskii ), the microcytic anemia incidence rate continues to increase. The primary pathological symptoms include emaciation, anemia, pica, inappetence, and dyskinesia. To investigate the cause of microcytic anemia ailment in the Przewalski's gazelle, the Upper Buha River Area with an excessive incidence was chosen as the experimental pasture, and the Bird Island Area without microcytic anemia disease was chosen as the control field. Then, the mineral contents in the soil, forage, blood, and liver, as well as the blood routine parameters and biochemical indexes were measured. The findings showed that the experimental pasture had much lower Se content in the soil and forage than the control field ( p < 0.01), while the impacted pasture had significantly higher S content in the forage. The damaged gazelles had considerably lower Se and Cu contents and higher S content in the blood and liver than the healthy gazelles ( p < 0.01). The presences of Hb, HCT, MCV, and MCH were significantly decreased compared to those in healthy gazelles ( p < 0.01). The experimental group had a significantly lower level of GSH-Px activity in their serums compared to the control group ( p < 0.01). In the treatment experiment, ten gazelles from the affected pasture were orally administered CuSO 4 , 6 g/animal once every 10 days for two consecutive times, and all gazelles were successfully cured. Therefore, it is possible that low Se content in the soil induced an increase in the absorption of S content by forage, leading to the deficiency of secondary Cu in the Przewalski's gazelles, resulting in microcytic anemia.

Designing an effective treatment strategy to combat oral diseases caused by complex polymicrobial biofilms remains a great challenge. Herein, a series of metal-phenolic network with Pd nanoparticle nodes using polyphenols as stabilizers and reducing agents is constructed. Among them, sulfonated lignin-Pd (SLS-Pd) with ultrafine size palladium nanoparticles and broadband near infrared absorption exhibit excellent oxidase-like activity and stable photothermal effect. In vitro experiments demonstrate that the superoxide radical generated by SLS-Pd oxidase-like activity exhibits selective antibacterial effects, while its photothermal effect induced hyperthermia exhibits potent antifungal properties. This difference is further elucidated by RNA-sequencing analysis and all-atom simulation. Moreover, the SLS-Pd-mediated synergistic antimicrobial system exhibits remarkable efficacy in combating various biofilms and polymicrobial biofilms. By establishing a root canal model and an oropharyngeal candidiasis model, the feasibility of the synergistic antimicrobial system in treating oral biofilm-related infections is further validated. This system provides a promising therapeutic approach for polymicrobial biofilm-associated infections in the oral cavity., (© 2023 Wiley-VCH GmbH.)

Bacterial sepsis is a life-threatening condition caused by bacteria entering the bloodstream and triggering an immune response, underscoring the importance of early recognition and prompt treatment. Nanomedicine holds promise for addressing sepsis through improved diagnostics, nanoparticle biosensors for detection and imaging, enhanced antibiotic delivery, combating resistance, and immune modulation. However, challenges remain in ensuring safety, regulatory compliance, scalability, and cost-effectiveness before clinical implementation. Further research is needed to optimize design, efficacy, safety, and regulatory strategies for effective utilization of nanomedicines in bacterial sepsis diagnosis and treatment. This review highlights the significant potential of nanomedicines, including improved drug delivery, enhanced diagnostics, and immunomodulation for bacterial sepsis. It also emphasizes the need for further research to optimize design, efficacy, safety profiles, and address regulatory challenges to facilitate clinical translation.

The quest for efficient non-Pt/Pd catalysts has proved to be a formidable challenge for auto-exhaust purification. Herein, we present an approach to construct a robust catalyst by embedding single-atom Ru sites onto the surface of CeO 2 through a gas bubbling-assisted membrane deposition method. The formed single-atom Ru sites, which occupy surface lattice sites of CeO 2 , can improve activation efficiency for NO and O 2 . Remarkably, the Ru 1 /CeO 2 catalyst exhibits exceptional catalytic performance and stability during auto-exhaust carbon particle oxidation (soot), rivaling commercial Pt-based catalysts. The turnover frequency (0.218 h -1 ) is a nine-fold increase relative to the Ru nanoparticle catalyst. We further show that the strong interfacial charge transfer within the atomically dispersed Ru active site greatly enhances the rate-determining step of NO oxidation, resulting in a substantial reduction of the apparent activation energy during soot oxidation. The single-atom Ru catalyst represents a step toward reducing dependence on Pt/Pd-based catalysts., (© 2023. The Author(s).)

Radiation triage and biological dosimetry are critical for the medical management of massive potentially exposed individuals following radiological accidents. Here, we performed a genome-wide screening of radiation-responding mRNAs, whose N6-methyladenosine (m 6 A) levels showed significant alteration after acute irradiation. The m 6 A levels of three genes, Ncoa4, Ate1 and Fgf22, in peripheral blood mononuclear cells (PBMCs) of mice showed excellent dose-response relationships and could serve as biomarkers of radiation exposure. Especially, the RNA m 6 A of Ncoa4 maintained a high level as long as 28 days after irradiation. We demonstrated its responsive specificity to radiation, conservation across the mice, monkeys and humans, and the dose-response relationship in PBMCs from cancer patients receiving radiation therapy. Finally, NOCA4 m 6 A-based biodosimetric models were constructed for estimating absorbed radiation doses in mice or humans. Collectively, this study demonstrated the potential feasibility of RNA m 6 A in radiation accidents management and clinical applications., (© 2023. The Author(s).)

Supported cell membrane coatings meet many requirements set to bioactive nanocarriers and materials, provided sidedness and fluidity of the natural membrane are maintained upon coating. However, the properties of a support-surface responsible for maintaining correct sidedness and fluidity are unknown. Here, we briefly review the properties of natural membranes and membrane-isolation methods, with focus on the asymmetric distribution of functional groups in natural membranes (sidedness) and the ability of molecules to float across a membrane to form functional domains (fluidity). This review concludes that hydrophilic sugar-residues of glycoproteins in the outer-leaflet of cell membranes direct the more hydrophobic inner-leaflet towards a support-surface to create a correctly-sided membrane coating, regardless of electrostatic double-layer interactions. On positively-charged support-surfaces however, strong, electrostatic double-layer attraction of negatively-charged membranes can impede homogeneous coating. In correctly-sided membrane coatings, fluidity is maintained regardless of whether the surface carries a positive or negative charge. However, membranes are frozen on positively-charged, highly-curved, small nanoparticles and localized nanoscopic structures on a support-surface. This leaves an unsupported membrane coating in between nanostructures on planar support-surfaces that is in dual-sided contact with its aqueous environment, yielding enhanced fluidity in membrane coatings on nanostructured, planar support-surfaces as compared with smooth ones., Competing Interests: HJB is also director of a consulting company, SASA BV (GN Schutterlaan 4, 9797 PC Thesinge, The Netherlands). The authors declare no potential conflicts of interest with respect to authorship and/or publication of this article., (© 2023 The Authors.)

Ovarian cancer is insensitive to immunotherapy and has a high mortality rate. CDK4/6 inhibitors (CDK4/6i) regulate the tumor microenvironment and play an antitumor role. Our previous research demonstrated that lymphocyte aggregation (tertiary lymphoid structures, TLSs) was observed after CDK4/6i treatment. This may explain the synergistic action of CDK4/6i with the anti-PD1 antibody. However, the key mechanism by which CDK4/6i promotes TLS formation has not been elucidated. We examine the link between TLS and prognosis. Animal models and high-throughput sequencing were used to explore the potential mechanism by which CDK4/6i promotes TLS formation. Our results showed the presence of TLSs was associated with a favorable prognosis for ovarian cancer. CDK4/6i promoted TLS formation and enhanced the immunotherapeutic effect of the anti-PD1 antibody. The potential mechanism of CDK4/6i affecting the formation of TLS may be through modulating SCD1 and its regulatory molecules ATF3 and CCL4. Our findings provide a theoretical basis for the application of CDK4/6i in ovarian cancer., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Food safety and environmental pollution are the hotspots of general concern globally. Notably, long-term accumulation of trace toxic heavy metals, such as cadmium (Cd), in animals may endanger human health via the food chain. The mechanism of Cd toxicity in the goat, a popular farmed animal, has not been extensively investigated to date. Therefore, in this study, ten male goats (Nubian black goat × native black goat) were exposed to Cd via drinking water containing CdCl 2 (20 mg Cd·kg -1 ·BW) for 30 days (five male goats per group). In this study, we used an integrated approach combining proteomics and metabolomics to profile proteins and metabolites in the serum of Cd-exposed goats. It was found that Cd exposure impacted the levels of 30 serum metabolites and 108 proteins. The combined proteomic and metabolomic analysis revealed that Cd exposure affected arginine and proline metabolism, beta-alanine metabolism, and glutathione metabolism. Further, antioxidant capacity in the serum of goats exposed to Cd was reduced. We identified CKM and spermidine as potential protein and metabolic markers, respectively, of early Cd toxicity in the goat. This study details approaches for the early diagnosis and prevention of Cd-poisoned goats.

Due to the emergence of drug resistance in bacteria and biofilm protection, achieving a satisfactory therapeutic effect for bacteria-infected open wounds with conventional measures is problematic. Here, a photothermal cascade nano-reactor (CPNC@GOx-Fe 2+ ) is constructed through a supramolecular strategy through hydrogen bonding and coordination interactions between chitosan-modified palladium nano-cube (CPNC), glucose oxidase (GOx), and ferrous iron (Fe 2+ ). CPNC@GOx-Fe 2+ exhibits excellent photothermal effects and powers the GOx-assisted cascade reaction to generate hydroxyl radicals, enabling photothermal and chemodynamic combination therapy against bacteria and biofilms. Further proteomics, metabolomics, and all-atom simulation results indicate that the damage of the hydroxyl radical to the function and structure of the cell membrane and the thermal effect enhance the fluidity and inhomogeneity of the bacterial cell membrane, resulting in the synergistic antibacterial effect. In the biofilm-associated tooth extraction wound model, the hydroxyl radical generated from the cascade reaction process can initiate the radical polymerization process to form a hydrogel in situ for wound protection. In vivo experiments confirm that synergistic antibacterial and wound protection can accelerate the healing of infected tooth-extraction wounds without affecting the oral commensal microbiota. This study provides a way to propose a multifunctional supramolecular system for the treatment of open wound infection., (© 2023 Wiley-VCH GmbH.)

Drug combination provides an efficient pathway to combat drug resistance in bacteria and bacterial biofilms. However, the facile methodology to construct the drug combinations and their applications in nanocomposites is still lacking. Here the two-tailed antimicrobial amphiphiles (T 2 A 2 ) composed of nitric oxide (NO)-donor (diethylenetriamine NONOate, DN) and various natural aldehydes are reported. T 2 A 2 self-assemble into nanoparticles due to their amphiphilic nature, with remarkably low critical aggregation concentration. The representative cinnamaldehyde (Cin)-derived T 2 A 2 (Cin-T 2 A 2 ) assemblies demonstrate excellent bactericidal efficacy, notably higher than free Cin and free DN. Cin-T 2 A 2 assemblies kill multidrug-resistant staphylococci and eradicate their biofilms via multiple mechanisms, as proved by mechanism studies, molecular dynamics simulations, proteomics, and metabolomics. Furthermore, Cin-T 2 A 2 assemblies rapidly eradicate bacteria and alleviate inflammation in the subsequent murine infection models. Together, the Cin-T 2 A 2 assemblies may provide an efficient, non-antibiotic alternative in combating the ever-increasing threat of drug-resistant bacteria and their biofilms., (© 2023 Wiley-VCH GmbH.)

New antimicrobial strategies are urgently needed to meet the challenges posed by the emergence of drug-resistant bacteria and bacterial biofilms. This work reports the facile synthesis of antimicrobial dynamic covalent nano-networks (aDCNs) composing antibiotics bearing multiple primary amines, polyphenols, and a cross-linker acylphenylboronic acid. Mechanistically, the iminoboronate bond drives the formation of aDCNs, facilitates their stability, and renders them highly responsive to stimuli, such as low pH and high H 2 O 2 levels. Besides, the representative A1B1C1 networks, composed of polymyxin B1( A1 ), 2-formylphenylboronic acid ( B1 ), and quercetin ( C1 ), inhibit biofilm formation of drug-resistant Escherichia coli , eliminate the mature biofilms, alleviate macrophage inflammation, and minimize the side effects of free polymyxins. Excellent bacterial eradication and inflammation amelioration efficiency of A1B1C1 networks are also observed in a peritoneal infection model. The facile synthesis, excellent antimicrobial performance, and biocompatibility of these aDCNs potentiate them as a much-needed alternative in current antimicrobial pipelines., Competing Interests: Y.L., Y.F.Li, and H.C. declare the following competing interests: a patent has been filed covering the materials and methods reported herein. All other authors declare no other competing interests., (© 2023 The Authors.)

To investigate the response of different levels of molybdenum (Mo) fertilizer to Chinese Merino sheep (Junken Type) grazing on natural heavy metal-contaminated meadows, this study was carried out in the Bayanbulak Grassland lying in the northwest of Xinjiang Uygur Autonomous Region, China. A total of 24-hm 2 polluted meadows were fenced and were randomly divided into four groups (3 replication/group and 2 hm 2 /replication) applied 0-kg Mo, 1-kg Mo, 2-kg Mo, and 3-kg Mo (ammonium molybdate tetrahydrate) per hectare for the CON group, group I, group II, and group III, respectively. Seventy-two healthy 1-year-old Chinese Merino sheep (45.56 ± 2.35 kg) were randomly assigned to the tested pastures for 90 days. Compared with the CON group, the Mo content from fertilized groups and the Se content from group II and group III in serums and livers were significantly increased (P < 0.05), and the Cu content from fertilized groups in serums and livers was significantly decreased (P < 0.05). The levels of blood Hb and RBC, and the activities of serum SOD, CAT, GSH-Px, and Cp in group III, were significantly higher (P < 0.05) than those in the CON group, group I, and group II. Serum MDA content in group III was significantly lower (P < 0.05) than that in the other three groups. In summary, Mo fertilization improved the antioxidant capacity of grazing sheep and also reduced the toxic damage to Chinese Merino sheep grazing on natural grasslands contaminated by heavy metals, but Mo poisoning caused by excessive fertilization should be prevented., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In this research, FeCo 2 O 4 nanomaterial was successfully synthesized by a typical sol-gel method and conducted as an effective agent for peroxymonosulfate (PMS) activation to eliminate antibiotics flurbiprofen (FLU), a strong nonsteroidal drug. FeCo 2 O 4 nanomaterial was characterized by XRD, TEM, SEM, and XPS. Various characterization results proved that FeCo 2 O 4 held stable spinel structure. The interfering factors including initial pH, PMS concentration, catalyst dosage, inorganic anions, and humic acid on FLU removal were also discussed. The conclusion was that the removal efficiency of FLU reached 98.2% within 120 min after adding FeCo 2 O 4 (0.4 g L -1 ) and PMS (3 mM). The optimal pH for FLU degradation was the initial pH of 6.5; too acidic or alkaline was not conductive to the degradation. The existence of HA and Cl - restrained the degradation of FLU, and HCO 3 - promoted the removal, while the influence of NO 3 - and SO 4 2- could not be considered. The radical scavenging experiment confirmed that • OH, O 2 •- , and SO 4 •- participated in FLU removal and SO 4 •- functioned a leading role. FeCo 2 O 4 showed high efficiency for PMS activation in pH range of 3.0 to 10.0. After the fourth cycle operation, the FLU removal rate exceeded 76.9%, and the Co leaching rate was low during the catalytic reaction. This study shows that FeCo 2 O 4 nanomaterial is an efficient and environment-friendly catalyst, which can be applied for PMS activation to remove organic pollutants in water., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Antibiotic-loaded PEG/PAE-based micelles are frequently considered for eradicating infectious biofilms. At physiological pH, PEG facilitates transport through blood. Near an acidic infection-site, PAE becomes protonated causing micellar targeting to a biofilm. However, micellar penetration and accumulation is confined to the surface region of a biofilm. Especially matured biofilms also possess hypoxic regions. We here designed dual-responsive PEG/PAE-b-P(Lys-NBCF) micelles, responding to both acidity and low oxygen-saturation level in matured biofilms. Dual, pH- and hypoxia-responsive micelles targeted and accumulated evenly over the depth of 7- to 14-days old biofilms. Delineation demonstrated that pH-responsiveness was responsible for targeting of the infection-site and accumulation of micelles in the surface region of the biofilm. Hypoxia-responsiveness caused deep penetration in the biofilm. Dual, pH- and hypoxia-responsive micelles loaded with ciprofloxacin yielded more effective, synergistic eradication of 10-days old, matured Staphylococcus aureus biofilms underneath an abdominal imaging-window in living mice than achieved by ciprofloxacin in solution or single, pH- or hypoxia responsive micelles loaded with ciprofloxacin. Also, wound-healing after removal of window and its frame proceeded fastest after tail-vein injection of ciprofloxacin-loaded, dual, pH- and hypoxia-responsive micelles. Concluding, pH- and hypoxia-responsiveness are both required for eradicating mature biofilms and advancing responsive antibiotic nanocarriers to clinical application. STATEMENT OF SIGNIFICANCE: pH-responsive antibiotic nanocarriers have emerged as a possible new strategy to prevent antimicrobial-resistant bacterial infections from becoming the leading cause of death. In this paper, we show that commonly studied, pH-responsive micellar nanocarriers merely allow self-targeting to an infectious biofilm, but do not penetrate deeply into the biofilm. The dual-responsive (acidic pH- and hypoxia) antibiotic-loaded micelles designed here not only self-target to an infectious biofilm, but also penetrate deeply. The in vitro and in vivo advantages of dual-responsive nanocarriers are most obvious when studied in infectious biofilms grown for 10 viz a viz the 2 days, usually applied in the literature. Significantly, clinical treatment of bacterial infection usually starts more than 2 days after appearance of the first symptoms., Competing Interests: Declaration of Competing Interest HJB is also director of a consulting company, SASA BV. The authors declare no potential conflicts of interest with respect to authorship and/or publication of this article. Opinions and assertions contained herein are those of the authors and are not construed as necessarily representing views of their respective employers., (Copyright © 2022. Published by Elsevier Ltd.)

To investigate the effects of nano-selenium (nano-Se) and Macleaya cordata extracts (MCE) on immune function and oxidative damage of sows and intrauterine growth retardation (IUGR) piglets exposed to heat stress (HS) in large-scale farms, a 2 × 2 factorial design was adopted in this test, and the two factors were nano-Se (0, 0.50 mg/kg) and MCE (0, 500 mg/kg). A total of 80 sows ([Landrace × Yorkshire] × Duroc, parity 2) were used in a 25-day trial from day 90 of gestation to delivery with 20 replications per group and 1 sow per replication. The dietary treatments of sows were as follows: (1) CON group, basic diet (0.30 mg/kg added Se, sodium selenite); (2) Nano-Se group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se; (3) MCE group, basic diet (0.00 mg/kg added Se) + 500 mg/kg added MCE; and (4) Combined group, basic diet (0.00 mg/kg added Se) + 0.50 mg/kg added nano-Se and 500 mg/kg added MCE. The activities of serum SOD, CAT, and GSH-Px of sows and IUGR piglets were significantly increased in MCE group and combined group, and the MDA content was extremely decreased. There were extreme differences in serum IgG level of sows and IUGR piglets, colostrum, and serum IgM level of IUGR piglets in MCE group and combined group compared with CON group. Maternal combined diets increased greatly the levels of serum IL-10 and IFN-γ of sows and IUGR piglets, and decreased extremely the contents of serum IL-1β and TNF-α. MCE alone or combination with nano-Se in sow diets decreased greatly mRNA level of Hsp70 and increased mRNA level of Hsp27 in sows and IUGR piglets. In conclusion, nano-Se and/or MCE can be added to sow diets for the amelioration of HS-induced oxidative damage through improving immune function., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Intrauterine growth retardation (IUGR) is the main death cause of newborn piglets in large-scale farms. To investigate the effects of maternal nano-selenium (nano-Se) and Macleaya cordata extracts (MCE) on immune functions of IUGR piglets in large scale farms, a 2 × 2 factorial design was adopted in this test, and two factors were nano-Se (0, 0.50 mg/kg) and MCE (0, 500 mg/kg). A total of 32 ternary hybrid sows (Landrace × Yorkshire × Duroc, parity 2) were used in this 25-day trial from day 90 of pregnancy to delivery. The dietary treatments were as follows: (1) CON group, basic diet (0.0 mg/kg Se); (2) Nano-Se group, basic diet + 0.50 mg/kg added Se (nano-Se); (3) MCE group, basic diet + 500 mg/kg added MCE; (4) Combined group, basic diet + 0.50 mg/kg added nano-Se and 500 mg/kg added MCE. Maternal nano-Se or combination of nano-Se and MCE diets extremely increased the superoxide dismutase (SOD), catalase (CAT), superoxide dismutase (GSH-Px) contents in the serum and liver of IUGR offspring (P < 0.05), and MCE supplementation in sow diets remarkably increased the serum superoxide dismutase (SOD), catalase (CAT), and superoxide dismutase (GSH-Px) contents of IUGR piglets (P < 0.05). Adding nano-Se, MCE, or nano-Se and MCE to sow diets decreased the malondialdehyde (MDA) content in the serum and liver of IUGR piglets (P < 0.05). The supplementation of nano-Se and combined diets extremely increased the activities of immunoglobulin G (IgG) and immunoglobulin A (IgA) in the serum and liver of IUGR offspring (P < 0.05). Maternal nano-Se, MCE, and combined diets greatly decreased the levels of tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and interleukin-1β (IL-1β) in the serum and liver of IUGR piglets (P < 0.05). Together, the application of nano-Se and/or MCE to sow diets improved antioxidant capacities and immune functions of IUGR offspring, and alleviated oxidative stress., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. We show the enrichment of central memory T cells (T CM ) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. We find the MMP9 + macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy., (© 2022. The Author(s).)

Mineral development and metal smelting seriously polluted the surrounding groundwater and soil, threatening human health through the food chain. To investigate the effects of different sources of molybdenum (Mo) fertilizers on immune function of Nanjiang brown goats grazing on natural pastures under compound pollutions, fertilizing experiment was carried out in Liangshan Yi Nationality Prefecture of the Western Sichuan Plateau, China. Eighteen square hectometers of polluted meadows were fenced and were randomly divided into three groups (3 replications/group and 2 hm 2 /replication). A total of 54 healthy Nanjiang brown goats with an average BW of 31.6 ± 1.5 kg (1 year old) were used to this 30-day test (18 goats per group). The goats from CON group, AM group, and PM group were orally supplemented with deionized water, 15 mg Mo/BW·d (ammonium molybdate tetrahydrate), and 15 mg Mo/BW·d (potassium molybdate), respectively. Compared to CON group, the serum Fe content of grazing animals from AM group and PM group was 10.05% and 3.45% higher (P < 0.05), and the serum Cu content of grazing animals from AM group and PM group was 69.05% and 67.86% lower, respectively (P < 0.05). Mo fertilization significantly increased the levels of blood Hb, RBC, and PCV, and the activities of serum SOD, GSH-Px, CAT, and Cp of grazing goats (P < 0.05), and also extremely decreased the MDA content of experimental goats fed Mo compared to the control goats (P < 0.05). Compared to CON group, the activities of serum IgG, IgA, IgM, IL-2, and TNF-α of grazing animals from AM group and PM group were significantly increased (P < 0.05), and the levels of serum IL-6 and IL-1β of grazing goats from AM group and PM group were extremely decreased (P < 0.05). In summary, oral Mo fertilizers can alter the contents of serum mineral elements, reduce oxidative stress, improve immune function, and relieve the toxic damage of goats grazing on contaminated natural grasslands., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To investigate the effects of nano-ammonium octamolybdate (nano-Mo) and Macleaya cordata extracts (MCE) on antioxidant capacity of grazing Nanjiang brown goats on natural prairies under Cu and Cd stress, a 2 × 2 factorial design was adopted in this test, and two factors were nano-Mo (0, 10 mg/kg) and MCE (0, 3000 mg/kg). 24 hm 2 polluted grassland was used in this 30-day trial and was equally divided into twelve fenced units. A total of 36 Nanjiang brown goats (1 year old) with an average body weight (BW) of 40.9 ± 2.1 kg were used in this test. The dietary treatments were (1) CON group, basic diet; (2) Nano-Mo group, basic diet + 10 mg/kg added Mo (nano-Mo); (3) MCE group, basic diet + 3000 mg/kg added MCE; and (4) combined group, basic diet + 10 mg/kg added nano-Mo and 3000 mg/kg added MCE. Nano-Mo or combination of nano-Mo and MCE diets significantly decreased the Cu content in serum and the liver of grazing goats (P < 0.05) and increased the Fe and Mo contents in serum and the liver (P < 0.05). The supplementation of nano-Mo, MCE, and combined diets extremely increased the levels of blood Hb, RBC, and PCV (P < 0.05), as well as the activities of serum SOD, GSH-Px, CAT, and Cp (P < 0.05), and greatly decreased the blood WBC content (P < 0.05) and the serum MDA content (P < 0.05). In conclusion, the application of nano-Mo and/or MCE diets on contaminated grasslands changed the contents of mineral elements in serum and the liver of grazing goats, reduced oxidative stress, and improved antioxidant capacity. The combination of nano-Mo and MCE can alleviate the toxic damage of combined heavy metal contaminations., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In recent decades, the groundwater contaminated by mineral development and metal smelting has seriously polluted natural grasslands, resulting in heavy metal residues in soils and forages exceeding the standard, especially copper (Cu) and cadmium (Cd). After animals intake contaminated forages, heavy metals may accumulate in animal tissues and threaten human health through the food chain. Previous studies found that molybdenum (Mo) fertilizer from ammonium molybdate or potassium molybdate could alleviate the decrease of antioxidant capacity caused by heavy metal poisoning, but the application of nano-Mo fertilizer in sheep is still lacking. To investigate the effects of nano-Mo fertilizer on Cu metabolism of grazing Chinese Merino sheep (Junken Type) on natural pastures under Cu and Cd stress, fertilizing experiment was carried out in the Bayanbulak Grassland in the northwest of Xinjiang Uygur Autonomous Region, China. A total of 24 hm 2 fenced grassland contaminated by heavy metals was randomly divided into four groups (3 replications/group and 2 hm 2 /replication). The experimental groups were applied 0 g Mo, 100 g Mo, 200 g Mo, and 300 g Mo per hectare for the control group, group I, group II, and group III, respectively, through foliar spraying fertilization. A total of 72 Chinese Merino sheep (1 year old, 43.8 ± 2.3 kg) grazing on polluted natural grasslands, with 18 sheep per group, were randomly assigned to the experimental pastures for 30 days. The results showed that the Mo content in soil in group II and group III nwas higher than that in the control group (P < 0.05); the Cd content in soil in group II and group III was lower than that in the control group (P < 0.05), and the Cu content in soil in fertilized pastures was lower than that in the control group (P < 0.05). The Mo content in herbage in fertilized pastures was higher than that in the control group (P < 0.05), and the content of Cu in herbage in fertilized pastures was lower than that in the control group (P < 0.05). The contents of iron (Fe) and Mo in blood and liver of grazing animals from fertilized pastures were higher than that in the control group (P < 0.05). The Cd content in blood of grazing animals in group II and group III was lower than that in the control group (P < 0.05). The Cu content in blood and liver of grazing animals in fertilized pastures was lower than that in the control group (P < 0.05). The content of selenium (Se) in blood of grazing animals in group II and group III was higher than that in the control group (P < 0.05). The levels of blood including hemoglobin (Hb), erythrocyte count (RBC), and packed cell volume (PCV) in group II and group III were higher than that in the control group (P < 0.05). The white blood cell (RBC) count in group II and group III was lower than that in the control group (P < 0.05). The activities of serum superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), and ceruloplasmin (Cp) in group II and group III were higher than that in the control group (P < 0.05). The content of malondialdehyde (MDA) in group II and group III was lower than that in the control group (P < 0.05). In conclusion, the application of nano-Mo fertilizer on Cu- and Cd-contaminated grasslands changed the contents of mineral elements in soil, forage, and blood of grazing sheep, improved the antioxidant capacity, affected the Cu metabolism of grazing Chinese Merino sheep caused by Cu and Cd pollutions, and alleviated the toxic damage of heavy metal pollutions., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Copper (Cu) is an essential trace element, but excessive Cu intake can induce poor performance and Cu poisoning and result in various health problems. Cu and molybdenum (Mo) antagonize each other in vivo. Therefore, Mo can reduce the absorption and utilization of Cu. The aims of this study were to investigate the impacts of Mo fertilization on antioxidant capacity of grazing Nanjiang brown goat on Cu-polluted meadow and explore the control methods of Cu pollution in natural pasture. Fertilization and grazing experiments were carried out in Liangshan Yi Nationality Prefecture of the Western Sichuan Plateau, Sichuan Province, Southwest China. Cu-polluted meadows of 12 hm 2 were fenced, and randomly divided into two groups (3 replications/group, 2 hm 2 /replication), control group and treatment group, fed with basic diets supplemented with 0 and 3 kg Mo/hm 2 [ammonium molybdate tetrahydrate, (NH 4 ) 6 Mo 7 O 24 ·4H 2 O], respectively. In the current study, 36 healthy Nanjiang brown goats (1 year old, 32.8 ± 1.1 kg) were randomly divided into two groups (3 replications/group, 6 goats/replication) and assigned to the experimental pastures. The grazing experiment lasted for 60 days. The results showed that the concentration of Mo in soil in treatment group was 96.28 mg/kg, far exceeding the normal levels. At days 30 and 60, the levels of Hb, RBC, and PCV in blood in treatment group and the activities of serum SOD, GSH-Px, T-AOC, CAT, and Cp were higher than those in control group (P < 0.01). The MDA content in treatment group was lower than that in control group (P < 0.01). The contents of Cu in blood and liver in treatment goats were lower than those in control animals (P < 0.01). The contents of Zn and Mo in blood and liver in treatment goats were higher than those in control animals (P < 0.01). The Mn content in liver in treatment group was higher than that in control animals (P < 0.01). These results indicated that fertilization of (NH 4 ) 6 Mo 7 O 24 not only markedly influenced the mineral contents in blood and liver, but also extremely improved antioxidant capacity of grazing Nanjiang brown goat from fertilized pastures and relieved the damage caused by Cu pollution., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

To assess the impacts of sulfur (S) and molybdenum (Mo) fertilization on antioxidant capacity of grazing Nanjiang brown goat in copper (Cu)-polluted meadow, and explore the control methods of Cu pollution in natural pasture, fertilizer treatments and grazing experiments were carried out in Garzê Tibetan Autonomous Prefecture of the Western Sichuan Plateau, Sichuan Province, Southwest China. 24 hm 2 Cu-polluted meadows were fenced and randomly divided into four groups (3 replications/group, 2 hm 2 /replication): (1) control group, no fertilizer; (2) treatment groups, applied 1 kg Mo+40 kg S, 2 kg Mo+80 kg S, and 3 kg Mo+120 kg S per hectare for group I, group II, and group III, respectively. Seventy-two healthy Nanjiang brown goats (1 year old, 30.9 ± 1.1 kg) were randomly divided into 4 groups (3 replications/group, 6 goats/replication) and assigned to the tested pastures. The grazing experiment lasted for 60 days. The results showed that the contents of N, S, Mn, Zn, and Mo in herbage in fertilized pastures were higher than those in control group (P < 0.01). The contents of Cu and Se in herbage in fertilized pastures were lower than those in control group (P < 0.01). There were no differences among the fertilized pastures (P > 0.05). The contents of Mn, Zn, Mo, and S in serum and liver in the treatment goats were higher than those in control animals (P < 0.01). The contents of Cu and Se in serum and liver in the treatment goats were lower than those in control animals (P < 0.01). There was no difference in Fe and Co contents in herbage, serum, and liver among the four groups (P > 0.05). The levels of Hb, RBC, and PCV in blood in the treatment goats and the activities of SOD, GSH-Px, T-AOC, CAT, and Cp in serum were higher than those in control goats (P < 0.01). The contents of MDA in the treatment goats were lower than those in control animals (P < 0.01). The contents of serum Cu and Mo, and liver Cu in group III were lower than those in group I and group II (P < 0.01). Taken together, the combinations of S and Mo fertilization did not influence the mineral contents in herbage, serum, and liver, but reduced the toxicity of Cu in Cu-polluted grassland and improved antioxidant capacity in grazing Nanjiang brown goat from fertilized pastures., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The purification efficiency of auto-exhaust carbon particles in the catalytic aftertreatment system of vehicle exhaust is strongly dependent on the interface nanostructure between the noble metal component and oxide supports. Herein, we have elaborately synthesized the catalysts (Pt/Fe 2 O 3 -R) of Pt nanoparticles decorated on the hexagonal bipyramid α-Fe 2 O 3 nanocrystals with co-exposed twelve {113} and six {104} facets. The area ratios ( R ) of co-exposed {113} to {104} facets in α-Fe 2 O 3 nanocrystals were adjusted by the fluoride ion concentration in the hydrothermal method. The strong Pt-Fe 2 O 3 {113} facet interaction boosts the formation of coordination unsaturated ferric sites for enhancing adsorption/activation of O 2 and NO. Pt/Fe 2 O 3 -R catalysts exhibited the Fe 2 O 3 {113} facet-dependent performance during catalytic purification of soot particles in the presence of H 2 O. Among the catalysts, the Pt/Fe 2 O 3 -19 catalyst exhibits the highest catalytic activities ( T 50 = 365 °C, TOF = 0.13 h -1 ), the lowest apparent activation energy (69 kJ mol -1 ), and excellent catalytic stability during soot purification. Combined with the results of characterizations and density functional theory calculations, the catalytic mechanism is proposed: the active sites located at the Pt-Fe 2 O 3 {113} interface can boost the key step of NO oxidation to NO 2 . The crystal facet engineering is an effective strategy to obtain efficient catalysts for soot purification in practical applications.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causes a broad clinical spectrum of coronavirus disease 2019 (COVID-19). The development of COVID-19 may be the result of a complex interaction between the microbial, environmental, and host genetic components. To reveal genetic determinants of susceptibility to COVID-19 severity in the Chinese population, we performed a genome-wide association study on 885 severe or critical COVID-19 patients (cases) and 546 mild or moderate patients (controls) from two hospitals, Huoshenshan and Union hospitals at Wuhan city in China. We identified two loci on chromosome 11q23.3 and 11q14.2, which are significantly associated with the COVID-19 severity in the meta-analyses of the two cohorts (index rs1712779: odds ratio [OR] = 0.49; 95% confidence interval [CI], 0.38-0.63 for T allele; P = 1.38 × 10 -8 ; and index rs10831496: OR = 1.66; 95% CI, 1.38-1.98 for A allele; P = 4.04 × 10 -8 , respectively). The results for rs1712779 were validated in other two small COVID-19 cohorts in the Asian populations (P = 0.029 and 0.031, respectively). Furthermore, we identified significant eQTL associations for REXO2, C11orf71, NNMT, and CADM1 at 11q23.3, and CTSC at 11q14.2, respectively. In conclusion, our findings highlight two loci at 11q23.3 and 11q14.2 conferring susceptibility to the severity of COVID-19, which might provide novel insights into the pathogenesis and clinical treatment of this disease., (© 2021. The Author(s).)

The catalytic performances for soot purification over the perovskite-type ABO 3 oxides, as one of the most potential non-noble metal catalysts, are closely correlated with the substitution of A-site and B-site ions. Herein, three-dimensional ordered macroporous (3DOM) structural catalysts of double perovskite-type La 2- x K x NiCoO 6 were prepared by a method of colloidal crystal template. The contact efficiency between the catalyst and soot particles is significantly promoted by the 3DOM structure, and the partial substitution of A-site (La) with low-valence potassium (K) ions in La 2- x K x NiCoO 6 catalysts boosts the increasing surface density of coordinatively unsaturated active B-sites (Co and Ni) and active oxygen. 3DOM La 2- x K x NiCoO 6 catalysts exhibited superior performance during the purification of soot particles, and the 3DOM La 1.80 K 0.20 NiCoO 6 catalyst exhibited the highest activity, that is, the values of T 50 , S CO2 , and turnover frequency are 346 °C, 99.3%, and 0.204 h -1 (at 300 °C), respectively. According to the results of multiple experimental characterizations and density functional theory calculations, the mechanism of the samples during soot removal is proposed: the increase in surface oxygen density induced by the doping of K ions significantly promotes the critical step of the oxidation from NO to NO 2 in catalyzing soot purification. It is one new strategy to develop the high-efficient non-noble metal catalysts for soot purification in practical application.

The Wumeng semi-fine wool sheep is vital to the production system in Southwest China. To study the effects of nano-selenium (Nano-Se) poisoning in the Wumeng semi-fine wool sheep, poisoning model was established. A total of 20 animals with an average initial body weight (BW) of 35.57 ± 3.31 kg were used in this study. After 1-week-long acclimatization period, all animals were randomly divided into two groups: (1) control, with no any treatment; (2) Nano-Se group, orally administered 5 mg Nano-Se (BW/kg/day). There were 10 replications/group and one sheep/replication. The experiment lasted for 30 days. Compared with the control, hemoglobin, erythrocyte count, and packed cell volume in Nano-Se group markedly decreased (P < 0.01), and the activities of serum lactate dehydrogenase, glutamic oxaloacetic transaminase, cereal third transaminase, and alkaline phosphatase in Nano-Se group significantly increased (P < 0.01). T 3 and FT 3 in serum in Nano-Se group were greatly lower than those in the control (P < 0.01). Contents of T 4 , FT 4 , and TSH in serum in Nano-Se group were extremely higher than those in the control (P < 0.01). Levels of IgG, IgM, IgA, interleukin 2 (IL-2), and tumor necrosis factor-alpha (TNF-α) in Nano-Se group were much lower than those of the control (P < 0.01), but levels of interleukin 6 (IL-6) and interleukin-1β (IL-1β) were greatly higher than those in the control (P < 0.01). Compared with the control, serum superoxide dismutase, glutathione peroxide, total antioxidant capacity, and catalase from Nano-Se group extremely decreased (P < 0.01), and content of serum malondialdehyde in Nano-Se group markedly increased (P < 0.01). The current results indicated that the blood parameters in the Wumeng semi-fine wool sheep were affected by Nano-Se poisoning, and the immune function and antioxidant capacity were greatly reduced too.

The dynamic responses of microtubules (MTs) to internal and external signals are modulated by a plethora of microtubule-associated proteins (MAPs). In higher plants, many plant-specific MAPs have emerged during evolution as advantageous to their sessile lifestyle. Some members of the IQ67 domain (IQD) protein family have been shown to be plant-specific MAPs. However, the mechanisms of interaction between IQD proteins and MTs remain elusive. Here we demonstrate that the domain of unknown function 4005 (DUF4005) of the Arabidopsis IQD family protein ABS6/AtIQD16 is a novel MT-binding domain. Cosedimentation assays showed that the DUF4005 domain binds directly to MTs in vitro. GFP-labeled DUF4005 also decorates all types of MT arrays tested in vivo. Furthermore, we showed that a conserved stretch of 15 amino acid residues within the DUF4005 domain, which shares sequence similarity with the C-terminal MT-binding domain of human MAP Kif18A, is required for the binding to MTs. Transgenic lines overexpressing the DUF4005 domain displayed a spectrum of developmental defects, including spiral growth and stunted growth at the organismal level. At the cellular level, DUF4005 overexpression caused defects in epidermal pavement cell and trichome morphogenesis, as well as abnormal anisotropic cell elongation in the hypocotyls of dark-grown seedlings. These data establish that the DUF4005 domain of ABS6/AtIQD16 is a new MT-binding domain, overexpression of which perturbs MT homeostasis in plants. Our findings provide new insights into the MT-binding mechanisms of plant IQD proteins., Competing Interests: Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Drug delivery systems (DDS) have extensively progressed over the past decades for eradicating the bacteria embedded in biofilms while minimizing the side effects of antimicrobials on the normal tissues. They possess potential in solving the challenges of intrinsic antimicrobial-resistance and poor penetration of antimicrobials into biofilms. However, the guidelines for developing a controlled DDS for combating bacterial biofilms are limited. In this review, classical mechanisms and mathematical models of DDS were summarized in order to lay the foundation of controlled DDS development. Strategies for building controlled DDS were proposed based on the process of biofilm formation, including surface coatings, fibers, nanoparticles as DDS to prevent biofilm formation and eradicate bacterial biofilm-associated infections. The challenges that still remain in DDS design were discussed and future directions were suggested. We hope this review could give a "road map" to inspire readers and boost the development of the new generation of controlled drug release system for antimicrobial applications., (Copyright © 2020. Published by Elsevier B.V.)

Purpose: Primary open-angle glaucoma (POAG) is the leading cause of irreversible blindness worldwide and mutations in known genes can only explain 5-6% of POAG. This study was conducted to identify novel POAG-causing genes and explore the pathogenesis of this disease., Methods: Exome sequencing was performed in a Han Chinese cohort comprising 398 sporadic cases with POAG and 2010 controls, followed by replication studies by Sanger sequencing. A heterozygous Ramp2 knockout mouse model was generated for in vivo functional study., Results: Using exome sequencing analysis and replication studies, we identified pathogenic variants in receptor activity-modifying protein 2 (RAMP2) within three genetically diverse populations (Han Chinese, German, and Indian). Six heterozygous RAMP2 pathogenic variants (Glu39Asp, Glu54Lys, Phe103Ser, Asn113Lysfs*10, Glu143Lys, and Ser171Arg) were identified among 16 of 4763 POAG patients, whereas no variants were detected in any exon of RAMP2 in 10,953 control individuals. Mutant RAMP2s aggregated in transfected cells and resulted in damage to the AM-RAMP2/CRLR-cAMP signaling pathway. Ablation of one Ramp2 allele led to cAMP reduction and retinal ganglion cell death in mice., Conclusion: This study demonstrated that disruption of RAMP2/CRLR-cAMP axis could cause POAG and identified a potential therapeutic intervention for POAG.

Displaying Candida antarctica lipase B (CALB) on the cell surface of Aspergillus niger is effectively applied for the industries of food, cosmetics, pharmaceutical and so on. Displaying CALB using induced promoter of glucoamylase on the cell surface of A. niger SH-1 has some problems such as inhibiting its expression under high concentration of glucose, mycelium cleavage and decreasing enzyme activity in the later period of fermentation process. Displaying CALB manipulated by constitutive promoter from glyceraldehyde-3-phosphate dehydrogenase instead of glucoamylase on the cell surface of A. niger SH-1, called AN-GpdA, could solve the above problems effectively. Furthermore, it can not only use glucose, but also xylose as a sole carbon source. Enzyme activity of AN-GpdA using xylose for fermentation reached 1 100.28 U/g of dry cell. We also used lignocellulose such as the hydrolysate of bagasse for fermentation with good performance. The result would provide a novel strategy for the utilization of bagasse.

In higher plants, the development of functional chloroplasts is essential for photosynthesis and many other physiological processes. With a long-term goal of elucidating the genetic regulation of chloroplast development, we identified two allelic leaf variegation mutants, variegated5-1 ( var5-1 ) and var5-2 . Both mutants showed a distinct leaf reticulation phenotype of yellow paraveinal regions and green interveinal regions, and the leaf reticulation phenotype correlated with photosynthetic defects. Through the identification of mutation sites in the two mutant alleles and the molecular complementation, we confirmed that VAR5 encodes a CorA family of Mg 2+ transporters also known as AtMRS2-11/AtMGT10. Using protoplast transient expression and biochemical fractionation assays, we demonstrated that AtMRS2-11/AtMGT10/VAR5 likely localizes to the chloroplast envelope. Moreover, we established that AtMRS2-11/AtMGT10/VAR5 forms large molecular weight complexes in the chloroplast and the sizes of these complexes clearly exceed those of their bacterial counterparts, suggesting the compositions of CorA Mg 2+ transporter complex is different between the chloroplast and bacteria. Our findings indicate that AtMRS2-11/AtMGT10/VAR5 plays an important role in the tissue specific regulation of chloroplast development.

Aurora kinase A (AURKA) is a serine threonine kinase which affects chromosomal separation and mitotic spindle stability through interaction with the centrosome during mitosis. Two functional nonsynonymous polymorphisms of the AURKA gene (Ile31Phe and Val57Ile) have been reported recently. We analyzed the association between the two polymorphisms and risk of the occurrence of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in the Guangxi population consisting of 348 patients with HCC and 359 control subjects, and then validated the significant association in the Guangdong population consisting of 440 cases and 456 controls. All of the participants were of Chinese origin and HBV carriers. The two polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism assay or Sequenom MassARRAY iPLEX platform. In the Guangxi population, carriers of the AURKA 31Phe allele (Ile/Phe + Phe/Phe) were significantly associated with decreased susceptibility to HBV-related HCC when compared with noncarriers (Ile/Ile) (odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.46-0.86, P = 3.4 × 10 -3 ). On the contrary, no significant association was found between Val57Ile and HBV-related HCC occurrence. The association of Ile31Phe with HBV-related HCC occurrence was confirmed in the Guangdong population (OR = 0.64, 95% CI = 0.49-0.83, P = 8.0 × 10 -4 ). The pooled analysis gave a joint P value of 5.5 × 10 -6 (joint OR = 0.63, 95% CI = 0.52-0.77). Our findings suggest that AURKA Ile31Phe may play a role in mediating the susceptibility to HBV-related HCC among Chinese., Competing Interests: CONFLICTS OF INTERESTS The authors have declared that no competing interests exist.

Purpose: Recently, three large genome-wide association studies have identified multiple variants associated with primary open angle glaucoma (POAG) near the ABCA1 gene. Considering that POAG and primary angle closure glaucoma (PACG) share many similar clinical manifestations, the present study was conducted to investigate whether these genetic variants were also associated with PACG in a Han Chinese population., Methods: A case-control association study of 1122 cases (PACG/PAC) and 1311 normal, matched controls was undertaken. Seven single-nucleotide polymorphisms (SNPs) near the ABCA1 gene, including rs2422493, rs2487042, rs2472496, rs2472493, rs2487032, rs2472459, and rs2472519, were genotyped. Genotype and allele frequencies were assessed using χ² tests. Linkage disequilibrium (LD) structure was analyzed by computer software., Results: Among the SNPs genotyped, no association was observed between these SNPs and PACG. However, we discovered that two haplotypes, CATTTAC (corrected P = 0.048) and CGCCCGC (corrected P = 0.048), remained significantly associated with PACG/PAC after Bonferroni correction. Subjects with the CATTTAC haplotype have a 1.71-fold increased possibility of having PACG/PAC, whereas subjects with the CGCCCGC haplotype have 0.47-fold decreased possibility of developing PACG., Conclusions: Our findings suggest that the genetic backgrounds of PACG and POAG might be different. However, whether or not ABCA1 plays a role in the development of PACG is still not made certain by this study. Thus, further research is needed to find the role of ABCA1 in the progress of PACG.

To investigate the neurobehavioral effects of dibutyl phthalate (DBP), an important endocrine disruptor known for reproductive toxicity, on rodent offspring following in utero and lactational exposure, pregnant Wistar rats were treated with DBP (0, 0.037, 0.111, 0.333 and 1% in the diet) from gestation day (GD) 6 to postnatal day (PND) 28, and selected developmental and neurobehavioral parameters of the offspring were measured. There were no significant effects of DBP on body weight gain of the dams during GD 6-20 or on the pups' ages of pinna detachment, incisor eruption or eye opening. Exposure to 1% DBP prolonged gestation period, decreased body weight in both male and female pups, depressed surface righting (PND 7) in male pups, shortened forepaw grip time (PND 10), enhanced spatial learning and reference memory (PND 35) in male pups. Exposure to 0.037% DBP also shortened forepaw grip time (PND 10), but inhibited spatial learning and reference memory in male pups. Sex x treatment effects were found in forepaw grip time (PND 10), spatial learning and reference memory, and the male pups appeared to be more susceptible than the females. However, all levels of DBP exposure did not significantly alter surface righting (PND 4), air righting (PND 16), negative geotaxis (PND 4 or 7), cliff avoidance (PND 7) or open field behavior (PND 28) in either sex. Overall, the dose level of DBP in the present study produced a few adverse effects on the neurobehavioral parameters, and it may alter cognitive abilities of the male rodent.