Immune checkpoint blockade (ICB) has revolutionized head and neck squamous cell carcinoma (HNSCC) treatment. Yet, a major barrier to response is that tumor cells are epigenetically reprogrammed to resist immunogenic cell death, particularly pyroptosis. To elucidate how tumor cells are pre-conFigured for pyroptosis resistance, we investigated the role of post-translational modifications on epigenetic regulators, focusing on the phosphorylation-dependent control of histone demethylase KDM6A. Through integrated phosphoproteomics and functional genomics in HNSCC models, we identified phosphorylation of KDM6A at Ser829 as a master regulatory switch. Mechanistically, phosphorylation at Ser829 subverts KDM6A function, leading to a global accumulation of repressive H3K27me3 marks. This establishes an epigenetic program that locks key pyroptosis effector genes (GSDMD, NLRP3) in a transcriptionally refractory, heterochromatic state. To pharmacologically dismantle this barrier, we developed a novel lipid nanoparticle (LNP) system encapsulating mRNA encoding a phosphorylation-defective KDM6AS829A variant. This strategy functionally reverses the oncogenic epigenetic state, restoring endogenous demethylase activity specifically at pyroptosis loci and reigniting the cell death pathway. In vivo, a single administration of KDM6AS829A mRNA inhibited tumor growth by 39% (p < 0.01). Strikingly, when combined with anti-PD-1, this strategy achieved a synergistic 79% tumor reduction (p < 0.0001), characterized by robust CD8+ T cell infiltration. Our work identifies KDM6A phosphorylation as a druggable epigenetic-immune checkpoint and establishes mRNA-based modulation of enzyme post-translational status as a transformative paradigm to potentiate ICB in HNSCC.

Phospholipase Cγ2 (PLCG2) serves as a central signal transducer within immune and neural lineages, catalyzing the conversion of membrane phosphoinositides into second messengers to regulate intracellular Ca2+ dynamics. By integrating inputs from B-cell receptor (BCR) signaling, TREM2-mediated microglial activation, and the NF-κB and Akt–mTOR pathways, PLCG2 coordinately regulates essential programs of cell survival, proliferation, and inflammatory response. Recent human genetic and functional studies have established PLCG2 as a pleiotropic driver of disease. Dysregulated expression and specific genetic variants—including gain-of-function, loss-of-function, and protective alleles—are now linked to a broad spectrum of pathologies, ranging from neurodegenerative diseases and hematologic malignancies to autoimmune syndromes, immunodeficiencies, and solid tumors. This review synthesizes current mechanistic and clinical evidence linking PLCG2 biology to these diverse conditions and evaluates the protein’s growing potential as both a diagnostic biomarker and a therapeutic target. While PLCG2 represents a promising nexus for intervention, urgent mechanistic gaps and translational priorities remain. We argue that future efforts must prioritize the development of precise, variant-directed targeting strategies and systematic phenotype–genotype mapping to successfully translate PLCG2 research into tangible patient benefits. Not applicable.

Rheumatoid arthritis (RA) is a complex autoimmune disease. Recently, cell senescence has been identified as a key factor in its pathogenesis. This study integrated multi-omics summary data and applied Mendelian randomization (MR) and co-localization analysis to systematically evaluate the causal relationships between cell senescence-related genes and RA. We collected summary data on blood methylation quantitative trait loci (mQTL), expression quantitative trait loci, and protein quantitative trait loci. The FinnGen database was the primary discovery dataset, validated by the UK Biobank and GWAS Catalog. We used the summary-data-based MR method to assess causal associations between the molecular traits of cell senescence-related genes and RA. Co-localization analysis was then performed to confirm shared genetic variants. After integrating multi-omics data on cell senescence-related mQTL and expression quantitative trait loci, we identified 5 key cell senescence-related genes potentially associated with RA: BCL2L1, DNMT3B, ERRFI1, NEK4, and RAF1. These genes demonstrated significant causal associations across multiple analyses. The mQTL signals based on summary-data-based MR analysis show that the genetically regulated methylation variations at the cg12873919 (odds ratio [OR] = 0.91, 95% CI [0.84-0.99]) and cg13989999 (OR = 0.90, 95% CI [0.82-1.00]) sites of the BCL2L1 gene are negatively associated with RA risk and may mediate disease risk by upregulating gene expression (OR = 0.82, 95% CI [0.76-0.88] and OR = 0.78, 95% CI [0.71-0.87]). Conversely, the mQTL effect size at the cg26432171 site of the RAF1 (OR = 1.17, 95% CI [1.02-1.33]) is positively associated with RA risk and is consistent with the upregulation of gene expression (OR = 1.83, 95% CI [1.49-2.25]), thereby enhancing RA susceptibility. Moreover, several sites in the DNMT3B gene (e.g., cg09149842) exhibited negative correlations with RA risk, suggesting that DNMT3B may play a critical role in RA pathogenesis by affecting gene expression. Methylation sites in ERRFI1 (cg13808198, cg22678073) and NEK4 (cg09524078) were also associated with RA risk, supporting their potential regulatory roles in RA. Co-localization analysis further validated the association between methylation sites and RA, particularly for BCL2L1, RAF1, DNMT3B, ERRFI1, and NEK4, where we identified shared causal signals with RA (posterior probability of H4 > 0.5). This study systematically evaluated the causal relationships between cell senescence-related genes and RA risk. These findings provide new insights into RA pathogenesis and reinforce the clinical value of these genes as potential therapeutic targets.

BACKGROUND:Psoralen can modulate bone metabolism pathways. This study investigated its effects on bone degenerative diseases, amyloid precursor protein (APP) phosphorylation, and the related pathways. METHODS:The Aβ40/Aβ42 levels in mouse serum were analyzed through enzyme-linked immunosorbent assay (ELISA) across ages. mRNA levels of APP, APH-1α, PEN-2, and RAGE were determined through polymerase chain reaction (PCR). Thereafter, three degenerative models, including knee osteoarthritis, osteoporosis, and intervertebral disc degeneration, were established. Mice with APP knockout were generated, and the pathology was evaluated at weeks 4-20 through safranin O staining, osteoclast counting (immunohistochemistry, IHC), and hematoxylin and eosin (H&E) staining. Subsequently, TNF-α and HA contents were examined by ELISA, and Col2 expression and apoptosis were also analyzed. Furthermore, the anti-osteoporotic mechanisms of psoralen were explored at the cellular and animal levels. RESULTS:As the mice aged, the expression of p-APP increased significantly, while that of proteins involved in the pathway decreased markedly. By constructing an APP knockout mouse model, it was found that after APP knockout, the mice developed bone degenerative lesions, which intensified with age. Intervention with psoralen was effective for ameliorating the pathologic condition of bone degenerative lesions in mice, and inhibiting the progression of bone tissue pathology. Notably, this effect exhibited a dose-dependent trend. Besides, intervention with psoralen in osteoblasts promoted osteoblast proliferation and regulated the phosphorylation of MAPK, AKT, and STAT3. For osteoblasts treated with pathway inhibitors and psoralen, psoralen exerted its effects through the MAPK, AKT, and STAT3 signaling pathways. CONCLUSION:The phosphorylation of APP promotes the occurrence and progression of bone degenerative diseases. Psoralen regulates bone degenerative diseases by inhibiting APP phosphorylation, and regulating the MAPK and STAT3 signaling pathways.

Phosphonates are refractory pollutants that contribute to eutrophication through their transformation into bioavailable phosphate. Although Cu-based advanced oxidation processes (AOPs) can degrade phosphonates via high-valent Cu(III) species, the released phosphate strongly coordinates with Cu sites, causing catalyst poisoning and rapid performance decay. Herein, a Cu-containing La-based layered carbonate hydroxide (CuLa-LCH) is designed to couple phosphonate oxidation with in situ phosphate sequestration. The CuLa-LCH/peroxymonosulfate (PMS) system achieves complete degradation of aminotris(methylenephosphonic acid) within 30 min, while simultaneously enabling efficient phosphate sequestration via La sites. Mechanistic and theoretical results reveal that Cu sites activate PMS to form Cu(III) intermediates that initiate C-N bond cleavage and subsequent oxidation toward C-P bond cleavage and phosphate release, whereas spatially coupled La-containing sites preferentially sequester the liberated phosphate, preventing Cu deactivation. This dual-site functionality sustains catalytic activity by continuously removing phosphate from Cu centers. The CuLa-LCH/PMS system also shows good reusability, water-matrix tolerance and operational stability, while preliminary techno-economic analysis suggests its potential practical feasibility. This study provides a viable strategy for coupling phosphonate oxidation with phosphate sequestration for sustainable water treatment.

BACKGROUND:Autophagy is associated with the development of rheumatoid arthritis (RA), but its genetic pathological mechanisms remain incompletely understood. In this study, we employed summary-data-based Mendelian randomization (SMR) and co-localization analysis to systematically investigate the relationship between autophagy-related genes and RA. METHODS:We obtained summary data on blood methylation (mQTL), gene expression (eQTL), and protein abundance (pQTL) from respective quantitative trait locus (QTL) studies. Genetic association data for RA were primarily derived from the FinnGen database, with validation performed using the UK Biobank (UKB) and GWAS Catalog databases. SMR analysis was conducted to evaluate the association between molecular characteristics of autophagy-related genes and RA. Subsequently, co-localization analysis was performed to determine whether the identified signals share the same causal genetic variants. RESULTS:After integrating mQTL-eQTL multi-omics data, we identified two key autophagy genes, BCL2L1 and RAF1, which may have a causal relationship with RA. Significant associations were found for BCL2L1 (cg12873919, cg13989999) and RAF1 (cg26432171) in the SMR analysis of autophagy-related mQTL, eQTL, and GWAS data (p SMR < 0.05). In the integrated mQTL-eQTL SMR analysis, cg12873919 (p SMR = 1.40E-07, OR = 0.82, 95% CI [0.76-0.88]), cg13989999 (p SMR = 1.43E-06, OR = 0.78, 95% CI [0.71-0.87]), and cg26432171 (p SMR = 9.18E-09, OR = 1.83, 95% CI [1.49-2.25]) were all significantly validated. Methylation of cg12873919 and cg13989999 in BCL2L1 was associated with increased BCL2L1 expression, consistent with their negative impact on RA risk. Conversely, the cg26432171 site in RAF1 showed a positive correlation between gene methylation and expression. In the eQTL-GWAS SMR analysis, MAPK3 expression (p SMR = 7.24E-05, OR = 0.91, 95% CI [0.87-0.95]) was negatively correlated with RA risk, a finding supported by co-localization analysis (PPH4 > 0.5), suggesting that this gene may inhibit RA pathogenesis by regulating the autophagy process. Furthermore, protein level analysis also supported the protective role of MAPK3 (p SMR = 7.53E-05, OR = 0.89, 95% CI [0.84-0.94]). CONCLUSION:We identified that autophagy-related genes BCL2L1 and RAF1 may be associated with RA risk, providing strong evidence from multi-omics data. This study identifies autophagy genes related to RA, potentially offering new insights into the pathogenesis of RA.

BACKGROUND:Studies indicate an association between biological aging and orthopedic diseases, but the causality remains unclear. AIMS:This study aims to investigate the bidirectional causal relationship between molecular markers of biological aging age and orthopedic conditions. METHODS:A two-sample Mendelian randomization (MR) analysis based on a genome-wide association study (GWAS) was conducted to explore these causal relationships. Analysis methods included inverse variance weighted (IVW), MR-Egger, weighted median, and weighted mode. Sensitivity analyses involved Cochran's Q, MR-Egger, leave-one-out, and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. RESULTS:The forward MR analysis identified several causal relationships: granulocyte proportions influenced intervertebral disc degeneration (IVDD) (OR 0.2316, P = 0.0101) and low back pain (LBP) (OR 0.2624, P = 0.007); telomere length (TL) affected cervical spondylosis (C/S) (OR 0.8759, P = 0.0167) and IVDD (OR 0.9184, P = 0.023); fibroblast growth factor-23 (FGF-23) impacted frozen shoulder (FS) (OR 1.2424, P = 0.0316); and HannumAge influenced C/S (OR 0.9518, P = 0.0233). The reverse MR analysis found that FS influenced TL (OR 0.9582, P = 0.0002) and α-Klotho (OR 0.7592, P = 0.0256), while sciatica affected TL (OR 0.9344, P = 0.0055) and C/S impacted PhenoAge (OR 1.6583, P = 0.0131) after outlier exclusion. Cochran's Q indicated heterogeneity in certain analyses, and MR-Egger showed no horizontal pleiotropy in significant causal associations. CONCLUSIONS:This study suggests a potential causal associations between molecular markers of biological aging and orthopedic diseases, suggesting avenues for future research into the underlying mechanisms.

Neutrophils respond rapidly to inflammation and infection via defense mechanisms, including degranulation, reactive oxygen species production, and neutrophil extracellular trap formation (known as "NETosis"). As the most abundant neutrophil components, granule proteins constitute the major mediators of neutrophil effector functions and likely orchestrate their functional diversity. However, a systematic profile of these proteins, particularly their temporal release dynamics during inflammatory responses, remains uncharacterized. Here, we performed a "multistate" proteomic study to explore circulating neutrophils' dynamic responses to diverse infectious and inflammatory signals over time. Circulating neutrophils exhibited both conserved and stimulus-specific protein expression programs. Through integrated characterization of the cellular and secretory proteome landscapes, we delineated the release patterns of canonical granule proteins and identified inflammatory mediators, including soluble membrane receptors. Notably, granule membrane receptors were translocated to the cell surface and shed via proteolytic cleavage, highlighting their dynamic regulation and diversity. These findings revealed the complexity of the neutrophil degranulation program, demonstrating its stimulus-dependent and temporally layered nature. Our study provides a functional atlas of neutrophil degranulation upon inflammation, which would strengthen our understanding of neutrophil activation in inflammation and facilitate the exploration of inflammation management therapies.

BACKGROUND:Cell-free DNA (cfDNA) is non-randomly fragmented in human body fluids. Analyzing such fragmentation patterns of cfDNA holds great promise for liquid biopsy. Whole-genome bisulfite sequencing (WGBS) is widely used for cfDNA methylation profiling. However, its applicability for studying fragmentomic characteristics remains largely unexplored. METHODS:We performed paired WGBS and whole-genome sequencing (WGS) on 66 peripheral plasma samples from 58 pregnant women. Then, we systematically compared the fragmentation patterns of cell-free nuclear DNA and mitochondrial DNA (mtDNA) sequenced from these two approaches. Additionally, we evaluated the extent of the size shortening in fetal-derived cfDNA and estimated the fetal DNA fraction in maternal plasma using both sequencing methods. RESULTS:Compared to WGS samples, WGBS samples demonstrated a significantly lower genome coverage and higher GC content in cfDNA. They also showed a significant decrease in the size of cell-free nuclear DNA, along with alterations in the end motif pattern that were specifically associated with CpG and "CC" sites. While there was a slight shift in the inferred nucleosome footprint from cfDNA coverages in WGBS samples, the cfDNA coverage patterns in CTCF and TSS regions remained highly consistent between these two sequencing methods. Both methods accurately reflected gene expression levels through their TSS coverages. Additionally, WGBS samples exhibited an increased abundance and longer length of mtDNA in plasma. Furthermore, we observed the size shortening of fetal cfDNA in plasma consistently, with a highly correlated fetal DNA fraction inferred by cfDNA coverage between WGBS and WGS samples (r = 0.996). However, the estimated fetal cfDNA fraction in WGBS samples was approximately 7 % lower than in WGS samples. CONCLUSIONS:We confirmed that WGBS can introduce artificial breakages to cfDNA, leading to altered fragmentomic patterns in both nuclear and mitochondrial DNA. However, WGBS cfDNA remains suitable for analyzing certain cfDNA fragmentomic characteristics, such as coverage in genome regulation regions and the essential characteristics of fetal DNA in maternal plasma.

BACKGROUND:Acute gout arthritis (AGA) is a common metabolic joint disease and urgently needs a safer alternative therapy due to the significant side effects from long-term use of primary medications. Folium Hibisci Mutabilis, a traditional medicinal herb, has demonstrated promising therapeutic efficacy in the clinical management of AGA, but its pharmacological mechanisms remain to be elucidated. METHODS:Folium Hibisci Mutabili was isolated and refined into the Folium Hibisci Mutabilis Extract (FHME). Then, monosodium urate-induced AGA animal models were applied to identify the anti-inflammatory and analgesic effects of FHME in vivo through various techniques, including ultrasonography, Paw withdrawal thresholds, histological staining, etc. We used RNA-seq, qRT-PCR, ELISA, and flow cytometry to evaluate the efficacy of FHME on M1 polarization. Utilizing transmission electron microscope and oxygen consumption rate examinations in conjunction with Mito-Tracker staining, we observed the effects of FHME on mitochondrial morphology and function. Finally, we employed proteomics analysis, siRNA, qRT-PCR, western blot and other techniques to investigate the underlying mechanism of FHME's actions between the two phenotypes and the key targets. RESULTS:We observed a notable reduction in inflammation and pain, as well as the decreased infiltration of inflammatory cells and expression of IL-1β in synovial tissue of AGA mice upon treatment with FHME. FHME suppressed TNF-α, IL-1β, iNOS, and IL-18 expression in BMDM-derived macrophages and inhibited the formation of F4/80+CD86+ cells. Mechanically, FHME protected mitochondrial morphology and stimulated the expression of key oxidative phosphorylation proteins, such as Ubiquinol Cytochrome c Reductase Core Protein I (UQCRC1), UQCRC2, CYCS, and NDUFA4. Additionally, it enhanced the activity of respiratory complex III, recovered cellular aerobic respiration under LPS and MSU induction. FHME lost its effect to downregulate M1 macrophage polarization with the presence of rotenone or si-UQCRC1. Finally, 10 compounds were identified from FHME having potential binding affinity with the UQCRC1 protein. CONCLUSIONS:The therapeutic potential of FHME for AGA is associated with the maintenance of mitochondrial function to inhibit M1 macrophage polarization, which is intimately linked to the UQCRC1. Our findings highlight the potential of Folium Hibisci Mutabilis as a safe and effective approach for AGA.

Objective: This study aims to investigate the role of the WNT5A signaling pathway in rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS) and uncover the impact of WNT5A on cellular function and signal transduction through proteomic and phosphoproteomic analyses. Methods: MH7A cells were treated with recombinant WNT5A (rhWNT5A), and differential expression proteins (DEPs) and phosphoproteins (DEPPs) were identified through proteomic and phosphoproteomic analyses. Data were further analyzed via volcano plots, heatmaps, enrichment analysis, and protein-protein interaction (PPI) networks to identify key biological processes and signaling pathways regulated by WNT5A. Results: Significant changes in the expression of numerous DEPs and DEPPs were observed following rhWNT5A treatment, including proteins closely related to lipid metabolism, cell migration, inflammation, and cell proliferation. PPI network analysis revealed that key regulatory proteins, such as HNRNPA1, RANBP2, BCLAF1, NPM1, and SMARCA4, occupy central positions in the network. Enrichment analysis indicated that WNT5A influences essential signaling pathways, such as AMPK, mTOR, VEGFA-VEGFR2, Notch, and endoplasmic reticulum stress, regulating cellular energy metabolism, inflammatory response, and cytoskeletal remodeling. Kinase activity analysis identified significant changes in kinases such as CDK1, CSNK2A1, EEF2K, AURKA, and AURKB, which were further integrated into the kinase-substrate regulatory network. Conclusion: This study demonstrates that WNT5A significantly influences the biological functions and inflammatory responses of RA-FLS by regulating key biological processes and signaling pathways. The integrated proteomic and phosphoproteomic analyses provide insights into the potential mechanisms and regulatory networks of WNT5A in RA, suggesting its application as a potential therapeutic target.

Peroxydisulfate (PDS)-based Fenton-like reactions are promising advanced oxidation processes (AOPs) to degrade recalcitrant organic water pollutants. Current research predominantly focuses on augmenting the generation of reactive species (e.g., surface-activated PDS complexes (PDS*) to improve treatment efficiency, but overlooks the potential benefits of enhancing the reactivity of these species. Here, we enhanced PDS* generation and reactivity by incorporating Zn into CuO catalyst lattice, which resulted in 99% degradation of 4-chlorophenol within only 10 min. Zn increased PDS* generation by nearly doubling PDS adsorption while maintaining similar PDS to PDS* conversion efficiency, and induced higher PDS* reactivity than the common catalyst CuO, as indicated by a 4.1-fold larger slope between adsorbed PDS and open circuit potential of a catalytic electrode. Cu-O-Zn formation upshifts the d-band center of Cu sites and lowers the energy barrier for PDS adsorption and sulfate desorption, resulting in enhanced PDS* generation and reactivity. Overall, this study informs strategies to enhance PDS* reactivity and design highly active catalysts for efficient AOPs.

Mitochondria are cellular powerhouses that generate energy through the electron transport chain (ETC). The mitochondrial genome (mtDNA) encodes essential ETC proteins in a compartmentalized manner, however, the mechanism underlying metabolic regulation of mtDNA function remains unknown. Here, we report that expression of tricarboxylic acid cycle enzyme succinate-CoA ligase SUCLG1 strongly correlates with ETC genes across various TCGA cancer transcriptomes. Mechanistically, SUCLG1 restricts succinyl-CoA levels to suppress the succinylation of mitochondrial RNA polymerase (POLRMT). Lysine 622 succinylation disrupts the interaction of POLRMT with mtDNA and mitochondrial transcription factors. SUCLG1-mediated POLRMT hyposuccinylation maintains mtDNA transcription, mitochondrial biogenesis, and leukemia cell proliferation. Specifically, leukemia-promoting FMS-like tyrosine kinase 3 (FLT3) mutations modulate nuclear transcription and upregulate SUCLG1 expression to reduce succinyl-CoA and POLRMT succinylation, resulting in enhanced mitobiogenesis. In line, genetic depletion of POLRMT or SUCLG1 significantly delays disease progression in mouse and humanized leukemia models. Importantly, succinyl-CoA level and POLRMT succinylation are downregulated in FLT3-mutated clinical leukemia samples, linking enhanced mitobiogenesis to cancer progression. Together, SUCLG1 connects succinyl-CoA with POLRMT succinylation to modulate mitochondrial function and cancer development.

Importance To date, there is currently no evidence-based medical support for the efficacy of topology-optimized splints in treating distal radius fractures. Objective To assess the clinical efficacy and complication rates of topology-optimized splints in the treatment of distal radius fractures after closed manual reduction. Design, Setting, and Participants This 12-week, multicenter, open-label, analyst-blinded randomized clinical trial (comprising a 6-week intervention followed by a 6-week observational phase) was carried out from December 3, 2021, to March 10, 2023, among 110 participants with distal radius fractures. Statistical analysis was performed on an intention-to-treat basis between June 3 and 30, 2023. Intervention Participants were randomly assigned to 2 groups: the intervention group received topology-optimized splint immobilization and the control group received cast immobilization after closed manual reduction for 6weeks. After this period, immobilization was removed, and wrist rehabilitation activities commenced. Main Outcomes and Measures The primary outcome was the Gartland-Werley (G-W) wrist score at 6 weeks (where higher scores indicate more severe wrist dysfunction). Secondary outcomes encompassed radiographic parameters, visual analog scale scores, swelling degree grade, complication rates, and 3 dimensions of G-W wrist scores. Results A total of 110 patients (mean [SD] age, 64.1 [12.7] years; 89 women [81%]) enrolled in the clinical trial, and complete outcome measurements were obtained for 101 patients (92%). Median G-W scores at 6 weeks were 15 (IQR, 13-18) for the splint group and 17 (IQR, 13-18) for the cast group (mean difference, −2.0 [95% CI, −3.4 to −0.6]; P = .03), indicating a statistically significant advantage for the splint group. At 12 weeks, no clinically significant differences in G-W scores between the 2 groups were observed. Complication rates, including shoulder-elbow pain and dysfunction and skin irritation, were less common in the splint group (shoulder-elbow pain and dysfunction: risk ratio, 0.28 [95% CI, 0.08-0.93]; P = .03; skin irritation: risk ratio, 0.30 [95% CI, 0.10-0.89]; P = .02). Conclusions and Relevance Findings of this randomized clinical trial suggest that patients with distal radius fractures that were managed with topology-optimized splints had better wrist functional outcomes and fewer complications at 6 weeks compared with those who received casting, with no difference at week 12. Therefore, topology-optimized splints with improved performance have the potential to be an advisable approach in the management of distal radius fractures. Trial Registration Chinese Clinical Trial Registry: ChiCTR2000036480

Protein O-glycosylation, also known as mucin-type O-glycosylation, is one of the most abundant glycosylation in mammalian cells. It is initially catalyzed by a family of polypeptide GalNAc transferases (ppGalNAc-Ts). The trimeric spike protein (S) of SARS-CoV-2 is highly glycosylated and facilitates the virus's entry into host cells and membrane fusion of the virus. However, the functions and relationship between host ppGalNAc-Ts and O-glycosylation on the S protein remain unclear. Herein, we identify 15 O-glycosites and 10 distinct O-glycan structures on the S protein using an HCD-product-dependent triggered ETD mass spectrometric analysis. We observe that the isoenzyme T6 of ppGalNAc-Ts (ppGalNAc-T6) exhibits high O-glycosylation activity for the S protein, as demonstrated by an on-chip catalytic assay. Overexpression of ppGalNAc-T6 in HEK293 cells significantly enhances the O-glycosylation level of the S protein, not only by adding new O-glycosites but also by increasing O-glycan heterogeneity. Molecular dynamics simulations reveal that O-glycosylation on the protomer-interface regions, modified by ppGalNAc-T6, potentially stabilizes the trimeric S protein structure by establishing hydrogen bonds and non-polar interactions between adjacent protomers. Furthermore, mutation frequency analysis indicates that most O-glycosites of the S protein are conserved during the evolution of SARS-CoV-2 variants. Taken together, our finding demonstrate that host O-glycosyltransferases dynamically regulate the O-glycosylation of the S protein, which may influence the trimeric structural stability of the protein. This work provides structural insights into the functional role of specific host O-glycosyltransferases in regulating the O-glycosylation of viral envelope proteins.

Diffuse large B-cell lymphoma(DLBCL)is the most common subtype of B-cell lymphoma in adult patients.Due to the clinical and molecular heterogeneity of DLBCL patients,robust biomarkers in clinical practice are still required.

Peroxymonosulfate (PMS) catalytic activation is effective to eliminate organic pollutants from water, thus the development of low-cost and efficient catalysts is significant in applications. The resource conversion of plastic wastes (PWs) into carbon nanotubes (CNTs) is a promising candidate for PMS-based advanced oxidation processes (AOPs), and also a sustainable strategy to realize plastic management and reutilization. Herein, costeffective PWs-derived N-doped CNTs (N-pCNTs) were synthesized, which displayed efficient activity for PMS activation through an electron transfer pathway (ETP) for sulfamethoxazole (SMX) degradation in high salinity water. The pyrrolic N induced the positively charged surface of N-pCNTs, favoring the electrostatic adsorption of PMS and subsequent generation of active PMS* . A galvanic oxidation process was developed to prove the electron-shuttle dominated ETP for SMX oxidation. Combined with theoretical calculations, the efficiency of ETP was determined by the potential difference between HOMO of SMX and LUMO of N-pCNTs. Such oxidation produced low-toxicity intermediates and resulted in selective degradation of specific sulfonamide antibiotics. This work reveals the feasibility of low-cost N-pCNTs catalysts from PWs serving as an appealing candidate for PMS-AOPs in water remediation, providing a new solution to alleviate environmental issues caused by PWs and also advances the understanding of ETP during PMS activation.

Remediation of soils contaminated with organic pollutants is often accomplished by chemical oxidation processes using oxidants such as persulfate or H2O2. However, it is unclear how different oxidants transform soil organic matter (SOM) and affect soil ecosystem services. Herein, two chemical oxidation technologies, Fenton reaction (FT) and base-activation of sodium persulfate (BP), were investigated to remediate diesel-polluted soils. The molecular transformation of SOM was analyzed using excitation-emission matrix fluorescence spectroscopy (EEM FS) and electrospray ionization coupled with Fourier transform ion cyclotron resonance mass spectrometry (ESI-FT-ICR-MS). Fulvic acid-like substances and lipids were consumed in both treatments, while the contents of lignin-like and tannin-like substances increased after BP treatment. The oxygen to carbon ratios (O/C), modified aromaticity index (AImod), and double bond equivalent (DBE) of SOM increased significantly in BP-treated soil, while these parameters decreased in FT-treated soil (FTS), suggesting the oxygen-containing, unsaturated and aromatic compounds were produced in BPS but removed in FTS. The increased cation exchange capacity (CEC) value (81.47 cmol/kg) and germination index of wheat seed (97%) for the SOM in BPS indicate the possible favorable effect of persulfate-based treatment on soil quality. Overall, this study advances mechanistic understanding of the effects of H2O2- and persulfate-based soil remediation technologies based on the molecular compositions of SOM and soil quality.

Nanoscale zero-valent iron (nZVI)-based advanced oxidation processes (AOPs) are limited by the rapidly formed surface layer of iron (oxyhydr) oxides. This restriction can be broken by the simultaneous activation of H2O2 and peroxydisulfate (PDS, S2O82-) over sulfidated nanoscale ZVI (S-nZVI), which displayed a synergistic effect to alleviate the drawbacks of the oxidants used alone. In this work, a biochar-supported S-nZVI (noted as S-nZVI@BC) was employed to simultaneously activate PDS and H2O2 for methyl tert-butyl ether (MTBE) degradation, and the rate constant for S-nZVI@BC/Bi-ox (Bi-ox, bi-oxidant at 1:1 molar ratio of PDS and H2O2) was 3.7-, 4.5-, and 12.8-fold higher than that of nZVI@BC/Bi-ox, S-nZVI@BC/PDS, and S-nZVI@BC/H2O2. According to electron paramagnetic resonance (EPR), X-ray photoelectric spectroscopy (XPS), and in-situ oxygen detection analyses, oxygen vacancies were generated over the shell of S-nZVI@BC during PDS activation, and the oxygen vacancy-contained surface layers promoted H2O2 adsorption and dissociation to produce surface-bound center dot OH (center dot OHads), thus significantly improving H2O2 utilization efficiency and accelerating MTBE degradation. These findings provide promising S-nZVI-based AOPs by combining H2O2 and peroxydisulfate activation for environmental remediation and bring insights for the creation of oxygen vacancy-containing materials for peroxide activation.

Thymic epithelial tumors (TETs) are rare malignant tumors, and the molecular mechanisms of both primary and recurrent TETs are poorly understood. Here we established comprehensive proteomic signatures of 15 tumors (5 recurrent and 10 non-recurrent) and 15 pair wised tumor adjacent normal tissues. We then proposed an integrative network approach for studying the proteomics data by constructing protein-protein interaction networks based on differentially expressed proteins and a machine learning-based score, followed by network modular analysis, functional enrichment annotation and shortest path inference analysis. Network modular analysis revealed that primary and recurrent TETs shared certain common molecular mechanisms, including a spliceosome module consisting of RNA splicing and RNA processing, but the recurrent TET was specifically related to the ribosome pathway. Applying the shortest path inference to the collected seed gene module identified that the ribonucleoprotein hnRNPA2B1 probably serves as a potential target for recurrent TET therapy. The drug repositioning combined molecular dynamics simulations suggested that the compound ergotamine could potentially act as a repurposing drug to treat recurrent TETs by targeting hnRNPA2B1. Our study demonstrates the value of integrative network analysis to understand proteotype robustness and its relationships with genotype, and provides hits for further research on cancer therapeutics.