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A novel fluorescent probe NIPF was synthesized by the Suzuki reaction to recognize Cu2+ and CN-. With the addition of Cu2+, NIPF exhibited strong fluorescence quenching (90 % for NIPF) with a Ksv value of 3.4 × 106 M-1 and a detection limit of 9.04 × 10-10 M. Subsequently, CN- was added to the NIPF-Cu2+ solution, and [Cu(CN)x]n- was formed due to the strong interaction between Cu2+ and CN- leading to fluorescence recovery (89 % for NIPF-Cu2+). In addition, a detection limit of 3.6 × 10-8 M was obtained by fluorescence titration. Meanwhile, it was demonstrated that the sensor achieved 93 %-105 % recovery of Cu2+ in the tested environmental samples, and the practicability of Cu2+ and CN- detection were verified using hydrogels test, with significant color changes observed under 365 nm light. Accordingly, the fluorescent probe NIPF was used to recognize Cu2+ and CN- by the "on-off-on" sensors.

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BACKGROUND: Thyroid cancer (TC) is a highly prevalent malignant tumor of the head and neck. Papillary thyroid carcinoma (PTC) is the primary pathological type of TC, accounting for more than 80% of all TCs. BRAF mutations are closely associated with PTC. However, the relationship among HT, PTC, and BRAF mutations has not yet been clarified. We aimed to investigate the BRAF mutation in Hashimoto's thyroiditis (HT) with PTC. METHODS: A total of 72 patients with multifocal PTC were included and grouped based on surgical pathology examination. Group A (n = 32) had pure multifocal PTC and Group B (n = 40) had HT with multifocal PTC. Various features were compared: BRAF mutation, multifactorial analysis of BRAF mutations, pathological features in patients with HT and multifocal PTC, and multifactorial analysis of factors affecting HT with multifocal PTC. RESULTS: Significant differences were seen in thyroid peroxidase antibody levels, central lymph node metastasis, extra-thyroidal invasion, main and non-main lesion diameters, and BRAF mutation positivity (P < 0.05). Patients with the BRAF mutation had significantly higher rates of extra-thyroidal invasion and lymph node metastasis than those without the BRAF mutation (P < 0.05). Logistic regression analysis showed that BRAF mutation and main lesion nodule diameter were independent risk factors affecting extra-thyroidal invasion and central lymph node metastasis in patients with HT and multifocal PTC (P < 0.05). DISCUSSION: BRAF mutations were more prevalent and closely associated with extra-thyroidal invasion and central lymph node metastasis in patients with HT and multifocal PTC.

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BACKGROUND: Folic acid (FA) supplementation during pregnancy aims to protect foetal development. However, maternal over-supplementation of FA has been demonstrated to cause metabolic dysfunction and increase the risk of autism, retinoblastoma, and respiratory illness in the offspring. Moreover, FA supplementation reduces the risk of congenital heart disease. However, little is known about its possible adverse effects on cardiac health resulting from maternal over-supplementation. In this study, we assessed the detrimental effects of maternal FA over-supplementation on the cardiac health of the offspring. METHODS AND RESULTS: Eight-week-old C57BL/6J pregnant mice were randomly divided into control and over-supplemented groups. The offspring cardiac function was assessed using echocardiography. Cardiac fibrosis was assessed in the left ventricular myocardium by histological analysis. Proteomic, protein, RNA, and DNA methylation analyses were performed by liquid chromatography-tandem mass spectrometry, western blotting, real-time quantitative PCR, and bisulfite sequencing, respectively. We found that maternal periconceptional FA over-supplementation impaired cardiac function with the decreased left ventricular ejection fraction in the offspring. Biochemical indices and tissue staining further confirmed impaired cardiac function in offspring caused by maternal FA over-supplementation. The combined proteomic, RNA expression, and DNA methylation analyses suggested that key genes involved in cardiac function were inhibited at the transcriptional level possibly due to increased DNA methylation. Among these, superoxide dismutase 1 was downregulated, and reactive oxygen species (ROS) levels increased in the mouse heart. Inhibition of ROS generation using the antioxidant N-acetylcysteine rescued the impaired cardiac function resulting from maternal FA over-supplementation. CONCLUSIONS: Our study revealed that over-supplementation with FA during mouse pregnancy is detrimental to cardiac function with the decreased left ventricular ejection fraction in the offspring and provides insights into the mechanisms underlying the association between maternal FA status and health outcomes in the offspring.

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Particulate nitrate is an important component of particulate matter and poses a significant threat to the ecosystem and human health. The gas-phase formation pathway of nitrate is extremely important, which mainly comprises the NO2 oxidation process triggered by OH radicals and the nitrate partitioning process. The response of nitrate to source emission reduction during different pollution periods remains unclear. Here, we applied the chemical kinetic and thermodynamics model to explore the importance oxidation process and partitioning process during different pollution periods based on high-time resolution observation data. The result indicated that with the aggravation of pollution, the partitioning process gradually ceases to be a limiting step in the formation of nitrates. The results of the influencing factor analysis indicate that NO2 concentration and aerosol pH values play a more significant role in the formation of nitrates. Specifically, during the clean period, nitrate formation is sensitive to both NO2 concentration and pH values, but during the pollution period, it becomes sensitive only to NO2 concentration. By combining source apportionment, we explored the response of nitrate formation to source emission reduction, and the results showed that the control of vehicle exhaust emissions and coal combustion sources is more effective in mitigating nitrate pollution. Additionally, this study also emphasized the importance of early prevention and control of pollution sources. This research provides scientific evidence for the precise management and control of nitrates.

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Synchrotron X-ray-based in situ metrology is advantageous for monitoring the synthesis of battery materials, offering high throughput, high spatial and temporal resolution, and chemical sensitivity. However, the rapid generation of massive data poses a challenge to on-site, on-the-fly analysis needed for real-time process monitoring. Here, a weighted lagged cross-correlation (WLCC) similarity approach is presented for automated data analysis, which merges with in situ synchrotron X-ray diffraction metrology to monitor the calcination process of the archetypal nickel-based cathode, LiNiO2. The WLCC approach, incorporating variables that account for peak shifts and width changes associated with structural transformations, enables rapid extraction of phase progression within 10 seconds from tens of diffraction patterns. Details are captured, from initial precursors to intermediates and the final layered LiNiO2, providing information for agile on-site adjustments during experiments and complementing post hoc diffraction analysis by offering insights into early-stage phase nucleation and growth. Expanding this data-powered platform paves the way for real time calcination process monitoring and control, which is pivotal to quality control in battery cathode manufacturing.

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Rationale: Understanding the immune mechanisms associated with liver transplantation (LT), particularly the involvement of tissue-resident memory T cells (TRMs), represents a significant challenge. Methods: This study employs a multi-omics approach to analyse liver transplant samples from both human (n = 17) and mouse (n = 16), utilizing single-cell RNA sequencing, bulk RNA sequencing, and immunological techniques. Results: Our findings reveal a comprehensive T cell-centric landscape in LT across human and mouse species, involving 235,116 cells. Notably, we found a substantial increase in CD8+ TRMs within rejected grafts compared to stable ones. The elevated presence of CD8+ TRMs is characterised by a distinct expression profile, featuring upregulation of tissue-residency markers (CD69, CXCR6, CD49A and CD103+/-,), immune checkpoints (PD1, CTLA4, and TIGIT), cytotoxic markers (GZMB and IFNG) and proliferative markers (PCNA and TOP2A) during rejection. Furthermore, there is a high expression of transcription factors such as EOMES and RUNX3. Functional assays and analyses of cellular communication underscore the active role of CD8+ TRMs in interacting with other tissue-resident cells, particularly Kupffer cells, especially during rejection episodes. Conclusions: These insights into the distinctive activation and interaction patterns of CD8+ TRMs suggest their potential utility as biomarkers for graft rejection, paving the way for novel therapeutic strategies aimed at enhancing graft tolerance and improving overall transplant outcomes.

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BACKGROUND: The anti-PD-L1 antibody durvalumab has been approved for use in first-line advanced biliary duct cancer (ABC). So far, predictive biomarkers of efficacy are lacking. METHODS: ABC patients who underwent gemcitabine-based chemotherapy with or without durvalumab were retrospectively enrolled, and their baseline clinical pathological indices were retrieved from medical records. Overall (OS) and progression free survival (PFS) were calculated and analyzed. The levels of peripheral biomarkers from 48 patients were detected with assay kits including enzyme-linked immunosorbent assay. Genomic alterations in 27 patients whose tumor tissues were available were depicted via targeted next-generation sequencing. RESULTS: A total of 186 ABC patients met the inclusion criteria between January 2020 and December 2022 were finally enrolled in this study. Of these, 93 patients received chemotherapy with durvalumab and the rest received chemotherapy alone. Durvalumab plus chemotherapy demonstrated significant improvements in PFS (6.77 vs. 4.99 months; hazard ratio 0.65 [95% CI 0.48-0.88]; P = 0.005), but not OS (14.29 vs. 13.24 months; hazard ratio 0.91 [95% CI 0.62-1.32]; P = 0.608) vs. chemotherapy alone in previously untreated ABC patients. The objective response rate (ORR) in patients receiving chemotherapy with and without durvalumab was 19.1% and 7.8%, respectively. Pretreatment sPD-L1, CSF1R and OPG were identified as significant prognosis predictors in patients receiving durvalumab. ADGRB3 and RNF43 mutations were enriched in patients who responded to chemotherapy plus durvalumab and correlated with superior survival. CONCLUSION: This retrospective real-world study confirmed the clinical benefit of durvalumab plus chemotherapy in treatment-naïve ABC patients. Peripheral sPD-L1 and CSF1R are promising prognostic biomarkers for this therapeutic strategy. Presence of ADGRB3 or RNF43 mutations could improve the stratification of immunotherapy outcomes, but further studies are warranted to explore the underlying mechanisms.

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Patients carrying mutations in polymerase epsilon/polymerase delta have shown positive responses to immune checkpoint inhibitors. Yet, prospective trials exploring the efficacy in those with polymerase epsilon/polymerase delta mutations are still lacking. A phase II clinical trial was initiated to evaluate the efficacy of toripalimab, a humanized IgG4K monoclonal antibody to human PD-1, in patients with advanced solid tumors with unselected polymerase epsilon/polymerase delta mutations but without microsatellite instability-high. A total of 15 patients were enrolled, 14 of whom were assessed for treatment efficacy. There was a 21.4% overall response rate, with a disease control rate of 57.1%. The median overall survival and median progression-free survival were 17.9 (95% CI 13.5-not reach) months and 2.5 (95% CI 1.4-not reach) months, respectively. For patients with exonuclease domain mutations, the objective response rate was 66.7% (2/3), with a disease control rate of 66.7% (2/3). For those with non-exonuclease domain mutations, the rates were 9.1% (1/11) and 54.5% (6/11), respectively. Notably, patients with PBRM1 gene mutations exhibited a high response rate to toripalimab at 75.0% (3/4). This study showed that neither the exonuclease domain mutations nor non-exonuclease domain mutations could fully predict the efficacy of immunotherapy, urging the need for more investigations to clarify potential immune sensitization differences within polymerase epsilon/polymerase delta mutation variants.

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Perovskite-based flexible electroluminescent (EL) devices are emerging as promising candidates in the display field due to their exceptional optoelectronic properties and potential for cost-effective production. However, simultaneously achieving high EL performance, excellent flexibility and stretchability, robust mechanical strength, and diverse applications remains a significant challenge. In this review, we provide a comprehensive overview of the latest developments in perovskite-based flexible EL devices, covering both direct-current (DC) and alternating-current (AC) electroluminescent formats. Our discussion encompasses the materials, working principles, device architectures, failure mechanisms, optimization strategies, and practical applications. Through this review, we aim to deepen our understanding of the current challenges and future directions of perovskite-based flexible light-emitting technologies, hoping to facilitate their potential commercial applications.

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OBJECTIVE: This study aimed to design and evaluate the efficacy of pyrrolidone derivatives as potential therapeutic agents against diffuse large B-cell lymphoma (DLBCL), a common and heterogeneous malignancy of the adult lymphohematopoietic system. Given the limitations of current therapies, there is a pressing need to develop new and effective drugs for DLBCL treatment. METHODS: A series of pyrrolidone derivatives were synthesized, and their antitumor activities were assessed, particularly against DLBCL cell lines. Structure-activity relationship (SAR) analysis was conducted to identify key structural components essential for activity. The most promising compound, referred to as compound 7, was selected for further mechanistic studies. The expression levels of relevant mRNA and protein were detected by RT-qPCR and Western blotting, and the expression of mitochondrial membrane potential and ROS was detected using flow cytometry for further assessment of cell cycle arrest and apoptosis. RESULTS: The compound 7 exhibited good antitumor activity among the synthesized derivatives, specifically in DLBCL cell lines. SAR analysis highlighted the critical role of α, ß-unsaturated ketones in the antitumor efficacy of these compounds. Mechanistically, compound 7 was found to induce significant DNA damage, trigger an inflammatory response, cause mitochondrial dysfunction, and disrupt cell cycle progression, ultimately leading to apoptosis of DLBCL cells. CONCLUSION: The compound 7 has good antitumor activity and can induce multiple cellular mechanisms leading to cancer cell death. These findings warrant further investigation of the compound 7 as a potential therapeutic agent for DLBCL.

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Background: Neoadjuvant therapy combining camrelizumab with chemotherapy has emerged as a promising approach for treating locally advanced esophageal squamous cell carcinoma (ESCC). However, the optimal strategy for integrating immunotherapy with chemotherapy remains to be fully defined. This single-arm phase II study aimed to evaluate the efficacy and safety of neoadjuvant therapy with camrelizumab induction followed by camrelizumab plus chemotherapy in locally advanced ESCC. Methods: Patients with clinical stage cT2-4N0M0 or cTxN1-3M0 ESCC were enrolled in the study. Patients received one dose of camrelizumab (200 mg) followed by docetaxel (75 mg/m2) and nedaplatin (75 mg/m2) plus camrelizumab (200 mg) every 3 weeks for two cycles, and then underwent surgery within 3-4 weeks. The primary endpoint was the major pathological response (MPR) rate. The secondary endpoints included the pathological complete response (pCR) rate, R0 resection rate, downstaging rate, disease-free survival (DFS), overall survival (OS), and safety. Results: In total, 55 patients were enrolled in the study between 16 April 2020 and 30 October 2021. Of these 55 patients, 53 (96.4%) completed neoadjuvant therapy, and 48 (87.3%) underwent surgery. The MPR rate was 77.1% [37/48, 95% confidence interval (CI): 62.7-88.0%]. The pCR (ypT0N0) rate was 39.6% (19/48, 95% CI: 25.8-54.7%). All the patients had R0 resections. Primary tumor downstaging occurred in 44 (91.7%) patients, and nodal downstaging occurred in 19 (39.6%) patients. The 2-year DFS rate was 68.9% (95% CI: 53.0-80.4%), and the 2-year OS rate was 74.7% (95% CI: 60.2-84.6%). Grade ≥3 treatment-related adverse events (TRAEs) were observed in 7 (12.7%) patients. Conclusions: In conclusion, neoadjuvant camrelizumab followed by camrelizumab plus chemotherapy showed promising efficacy in treating locally advanced ESCC and had a manageable safety profile.

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Objectives: Multisystem proteinopathy-1 (MSP1) is a late onset disease with >50 pathogenic variants in p97/VCP. MSP1 patients have multiple phenotypes that include inclusion body myopathy, Paget disease of the bone, amyotrophic lateral sclerosis, and frontotemporal dementia. There have been no clear genotype-phenotype correlations. We sought to identify genotype-phenotype correlations and associate these with VCP intrinsic ATPase activity. Methods: Patients with MSP1 were identified from the literature and the Cure VCP patient registry. Age at onset and at loss of ambulation were collated. VCP intrinsic ATPase activity was evaluated from recombinant purified protein. Results: Among the 5 most common pathogenic VCP variants in MSP1 patients, R155C patients had the earliest average age at onset (38.15 ± 9.78). This correlated with higher ATPase activity. Evaluation of 5 variants confirmed an inverse correlation between age at onset and ATPase activity (r = -0.94, p = 0.01). Discussion: Previous studies have reported that VCP pathogenic variants are "hyperactive." Whether this elevation in VCP ATPase activity is relevant to disease is unclear. Our study supports that in vitro VCP activity correlates with disease onset and may guide the prognosis of patients with rare or unreported variants. Moreover, it suggests that inhibition of VCP ATPase activity in MSP1 may be therapeutic.

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Based on a subanalysis of the NEOSUMMIT-01 study, it was revealed that perioperative immune checkpoint blockade (ICB) combined with chemotherapy has therapeutic effects in elderly patients with locally advanced gastric cancer, providing a new strategy for the treatment of elderly gastric cancer patients.

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Few studies have assessed the burden of mental disorders in adolescents related to bullying victimization at the global, regional, and national levels. We analyzed adolescent mental disorder disability-adjusted life years (DALYs) attributed to bullying in 204 countries, following the Global Burden of Disease study 2019 framework. The DALYs rate of adolescent for bullying-related mental disorders global increased from 110.45 (95 % uncertainty intervals (UI): 40.76, 218.62) per 100,000 in 1990 to 138.92 (95 % UI: 54.37, 268.19) per 100,000 in 2019. The largest increase in DALYs rates were obvious in low-SDI and high-SDI regions. In 2019, the DALYs rate of adolescents with bullying-related anxiety disorders was 1.4 times higher than those depressive disorders; the DALYs rate of adolescents with bullying-related mental disorder in females was 1.3 times higher than that of male, and older adolescent (15-19 years old) was 1.4 times higher than younger adolescent (10-14 years old). High-income North America had the fastest increase in DALYs rates of mental disorders related to bullying. In general, a positive correlation was observed between bullying DALY rate of adolescent and SDIs at the regional and national levels. Our study highlights significant disparities in adolescent mental health burden from bullying. Governments must implement adaptive policies to address diverse needs effectively.

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We present the application of N-difluoroacetylglucosamine (GlcNDFA) in a chemical evolution strategy to synthesize oligosaccharides. In comparison to conventional N-trifluoroacetylglucosamine, GlcNDFA exhibits superior substrate compatibility with glycosyltransferases as well as stability in aqueous environments. Using our 16-step assembly line, GlcNDFA can be used to produce homogeneous dekaparin, a heparin-like medication, with a yield of 62.2%. This underscores the significant potential of GlcNDFA as a chemical evolution precursor in the precise synthesis of structurally defined polysaccharides.

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ZNHIT3 (zinc finger HIT type containing protein 3) is an evolutionarily conserved protein required for ribosome biogenesis by mediating the assembly of small nucleolar RNAs (snoRNAs) of class C/D into ribonucleoprotein complexes (snoRNPs). Missense mutations in the gene encoding ZNHIT3 protein have been previously reported to cause PEHO syndrome, a severe neurodevelopmental disorder typically presenting after birth. We discuss here the case of two fetuses from a single family who presented with isolated hydrops during the early second trimester of pregnancy, resulting in intrauterine demise. Autopsy revealed no associated malformation. Through whole-genome quartet analysis, we identified two novel variants within the ZNHIT3 gene, both inherited from healthy parents and occurring as compound heterozygotes in both fetuses. The c.40T>C p.Cys14Arg variant originated from the father, while the c.251_254delAAGA variant was of maternal origin. Analysis of the variants in human cell culture models reveals that both variants reduce cell growth, albeit to different extents, and impact the protein's stability and function in distinct ways. The c.251_254delAAGA results in production of a stable form of ZNHIT3 that lacks a domain required for mediating snoRNP biogenesis, whereas the c.40T>C p.Cys14Arg variation behaves similarly to the previously described PEHO-associated ZNHIT3 variants that destabilize the protein. Interestingly, both variations lead to a marked decrease in specific box C/D snoRNA levels, reduced rRNA levels and cellular translation. Analysis of rRNA methylation pattern in fetus samples reveals distinct sites of hypo 2'-O-methylation. RNA-seq analysis of undifferentiated and differentiated SHSY5Y cells transfected with the ZNHIT3 variants reveals differential expression of a set of genes, many of which are associated with developmental processes and RNA binding compared to cells expressing wild-type ZNHIT3. In summary, this work extends the phenotype of PEHO syndrome to include antenatal manifestations and describe the molecular defects induced by two novel ZNHIT3 variants.

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Trichloroethylene (TCE) is a common environmental contaminant that can induce occupational dermatitis medicamentosa-like TCE (ODMLT), where the liver damage is the most common complication. The study aims to uncover the underlying mechanism of TCE-sensitization-induced liver damage by targeting specific exosomal microRNAs (miRNAs). Among the enriched serum exosomal miRNAs of ODMLT patients, miR-205-5p had a significant correlation coefficient with the liver function damage indicators. Moreover, retinoic acid receptor-related orphan receptor α (RORα) was identified as a direct target of miR-205-5p via specific binding. Further experiments showed that kupffer cells (KCs) underwent M1 phenotypic and functional changes in liver injury induced by TCE which were alleviated by reducing the expression of miR-205-5p. However, this alleviation was reversed by the RORα antagonist SR1001. In vitro experiments showed that miR-205-5p promoted M1 polarization of macrophages and enhanced the secretion of inflammatory factors by regulating RORα. An increase in RORα reversed the polarization direction of M1-type macrophages and reduced the secretion of proinflammatory factors. In addition, pretreatment of mice with SR1078, a specific RORα agonist, effectively blocked M1 polarization of KCs and reduced the severity of TCE-induced liver injury. Our study uncovers that miR-205-5p regulates KC M1 polarization by targeting RORα in immune liver injury induced by TCE sensitization, providing new insight into the molecular mechanisms and new therapeutic targets for ODMLT.

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Global energy shortages and environmental crises underscore the imperative for a circular economy to tackle resource scarcity and waste management. The circular economy model encourages the recovery and reuse of valuable materials, reducing reliance on finite natural resources and lessening the environmental impact of waste disposal. Among urban organic solid wastes, waste activated sludge (WAS) emerges as a potent reservoir of untapped resources (including various inorganic and organic ones) offering significant potential for recovery. This review delves into a comprehensive analysis of directional valorization of WAS to recover high-valued products, including the inorganic matters (i.e. phosphorus, ammonia nitrogen, and heavy metals), organic resources (i.e. extracellular polymers like alginate and protein, volatile fatty acid, methane, hydrogen, and plant growth hormones) and reutilization of WAS residues for the preparation of adsorbent materials - the biochar. Moreover, the main recovery methodologies associated influencing parameters, product application, and attendant challenges for those diverse recovered resources are unveiled. Future research are encouraged to prioritize the development of integrated multi-resource recovery approaches, the establishment of regulatory frameworks to support resource recovery and product utilization, and the systematic evaluation of disposal strategies to foster a more sustainable and resource-efficient future. This work illuminates avenues for sustainable WAS management with high-valued resource recovery towards circular economy.

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OBJECTIVE: The relationship between changes in Chinese visceral adiposity index (CVAI) and cardiometabolic diseases (CMD) in middle-aged and elderly individuals remains unclear. This study aimed to explore whether changes in the CVAI were associated with CMD incidence. METHODS: This study included 3,243 individuals aged over 45 years from the China Health and Retirement Longitudinal Study. The exposures were changes in the CVAI and cumulative CVAI from 2012 to 2015. Changes in the CVAI were classified using K-means clustering analysis, and the cumulative CVAI was calculated as follows: (CVAI2012 + CVAI2015)/2 × time (2015-2012). Multivariable logistic regression models were used to assess the relationship between different CVAI change classes and CMD incidence. Restricted cubic splines regression was used to assess the dose-response relationship between cumulative CVAI and CMD incidence. To investigate the relationship between combined exposure to each component of CAVI and CMD incidence, a weighted quantile sum regression analysis was employed. RESULTS: During the 5 years of follow-up, 776 (24%) incident CMD cases were identified. Changes in CVAI and cumulative CVAI were independently and positively associated with CMD. After adjusting for potential confounders, compared with Class 1, the adjusted ORs (95% CIs) for incident CMD were 1.18 (0.90-1.57) for Class 2, 1.40 (1.03-1.92) for Class 3, and 1.56 (1.04-2.34) for Class 4. When cumulative CVAI was categorized into quartiles, compared with Q1, the adjusted ORs (95% CIs) for incident CMD were 1.30 (1.00-1.70) for Q2, 1.34 (1.01-1.79) for Q3, and 1.63 (1.15-2.31) for Q4. In addition, cumulative CVAI in the overall population exhibited a linear association with CMD (Poverall = 0.012, Pnon-linearity = 0.287), diabetes (Poverall = 0.022, Pnon-linearity = 0.188), and stroke (Poverall = 0.002, Pnon-linearity = 0.978), but showed no significant association with heart disease (Poverall = 0.619, Pnon-linearity = 0.442). CONCLUSION: Participants with higher baseline CVAI level and a change of elevating CVAI level may suffer an increased incidence of CMD. Furthermore, our findings elucidate the underlying mechanisms of the CVAI by highlighting TG as the primary contributor to the observed associations. Long-term CVAI monitoring is of significant importance for early identification and prevention of CMD, with significant implications for clinical practice.

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Elevated CO2 levels (eCO2) pose challenges to wheat (Triticum aestivum L.) growth, potentially leading to a decline in quality and productivity. This study addresses the effects of two ambient CO2 concentrations (aCO2, daytime/nighttime = 410/450 ± 30 ppm and eCO2, 550/600 ± 30 ppm) and two nitrogen (N) supplements (without N supply-N0 and with 100 mg N supply as urea per kg soil-N100) on wheat (T. aestivum cv. Yunmai) growth, N accumulation, and soil microbial communities related to ammonia oxidization. The data showed that the N supply effectively mitigated the negative impacts of eCO2 on wheat growth by reducing intercellular CO2 concentrations while enhancing photosynthesis parameters. Notably, the N supply significantly increased N concentrations in wheat tissues and biomass production, thereby boosting N accumulation in seeds, shoots, and roots. eCO2 increased the agronomic efficiency of applied N (AEN) and the physiological efficiency of applied N (PEN) under N supply. Plant tissue N concentrations and accumulations are positively related to plant biomass production and soil NO3--N. Additionally, the N supply increased the richness and evenness of the soil microbial community, particularly Nitrososphaeraceae, Nitrosospira, and Nitrosomonas, which responded differently to N availability under both aCO2 and eCO2. These results underscore the importance and complexity of optimizing N supply and eCO2 for enhancing crop tissue N accumulation and yield production as well as activating nitrification-related microbial activities for soil inorganic N availability under future global environment change scenarios.