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China's lowland rural rivers are facing severe eutrophication problems due to excessive phosphorus (P) from anthropogenic activities. However, quantifying P dynamics in a lowland rural river is challenging due to its complex interaction with surrounding areas. A P dynamic model (River-P) was specifically designed for lowland rural rivers to address this challenge. This model was coupled with the Environmental Fluid Dynamics Code (EFDC) and the Phosphorus Dynamic Model for lowland Polder systems (PDP) to characterize P dynamics under the impact of dredging in a lowland rural river. Based on a two-year (2020-2021) dataset from a representative lowland rural river in the Lake Taihu Basin, China, the coupled model was calibrated and achieved a model performance (R2>0.59, RMSE<0.04 mg/L) for total P (TP) concentrations. Our research in the study river revealed that (1) the time scale for the effectiveness of sediment dredging for P control was ∼300 days, with an increase in P retention capacity by 74.8 kg/year and a decrease in TP concentrations of 23% after dredging. (2) Dredging significantly reduced P release from sediment by 98%, while increased P resuspension and settling capacities by 16% and 46%, respectively. (3) The sediment-water interface (SWI) plays a critical role in P transfer within the river, as resuspension accounts for 16% of TP imports, and settling accounts for 47% of TP exports. Given the large P retention capacity of lowland rural rivers, drainage ditches and ponds with macrophytes are promising approaches to enhance P retention capacity. Our study provides valuable insights for local environmental departments, allowing a comprehensive understanding of P dynamics in lowland rural rivers. This enable the evaluation of the efficacy of sediment dredging in P control and the implementation of corresponding P control measures.

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JOURNAL/nrgr/04.03/01300535-202501000-00029/figure1/v/2024-05-14T021156Z/r/image-tiff Morphological alterations in dendritic spines have been linked to changes in functional communication between neurons that affect learning and memory. Kinesin-4 KIF21A helps organize the microtubule-actin network at the cell cortex by interacting with KANK1; however, whether KIF21A modulates dendritic structure and function in neurons remains unknown. In this study, we found that KIF21A was distributed in a subset of dendritic spines, and that these KIF21A-positive spines were larger and more structurally plastic than KIF21A-negative spines. Furthermore, the interaction between KIF21A and KANK1 was found to be critical for dendritic spine morphogenesis and synaptic plasticity. Knockdown of either KIF21A or KANK1 inhibited dendritic spine morphogenesis and dendritic branching, and these deficits were fully rescued by coexpressing full-length KIF21A or KANK1, but not by proteins with mutations disrupting direct binding between KIF21A and KANK1 or binding between KANK1 and talin1. Knocking down KIF21A in the hippocampus of rats inhibited the amplitudes of long-term potentiation induced by high-frequency stimulation and negatively impacted the animals' cognitive abilities. Taken together, our findings demonstrate the function of KIF21A in modulating spine morphology and provide insight into its role in synaptic function.

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Excess nitrites are potentially threatening to human health, so it is urgent to develop accurate and sensitive methods. The development of sensors can provide early warning of possible hazards and alert people to protect public health. This work presents an NiSx@MoS2-composite with excellent electrochemical activity, representing a key finding for highly sensitive NO2- detection and sensor development. With the assistance of NiSx@MoS2, this electrochemical sensor has excellent quantitative detection performance. It has a wide detection range (0.0001-0.0020 mg/mL) and a low detection limit (1.863*10-5 mg/mL) for NO2-. This electrochemical sensor maintains excellent specificity among numerous interferences, and it completes the accurate detection of different real food samples. Pleasingly, the electrochemical sensor has satisfactory repeatability stability, and potential for practical applications. It would demonstrate tremendous potential in scientific dietary guidance, food safety detection and other fields.

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Extracellular matrix (ECM) stiffness is a major driver of stem cell fate. However, the involvement of the three-dimensional (3D) genomic reorganization in response to ECM stiffness remains unclear. Here, we generated comprehensive 3D chromatin landscapes of mesenchymal stem cells (MSCs) exposed to various ECM stiffness. We found that there were more long-range chromatin interactions, but less compartment A in MSCs cultured on stiff ECM than those cultured on soft ECM. However, the switch from compartment B in MSCs cultured on soft ECM to compartment A in MSCs cultured on stiff ECM included genes encoding proteins primarily enriched in cytoskeleton organization. At the topologically associating domains (TADs) level, stiff ECM tends to have merged TADs on soft ECM. These merged TADs on stiff ECM include upregulated genes encoding proteins enriched in osteogenesis, such as SP1, ETS1, and DCHS1, which were validated by quantitative real-time polymerase chain reaction and found to be consistent with the increase of alkaline phosphatase staining. Knockdown of SP1 or ETS1 led to the downregulation of osteogenic marker genes, including COL1A1, RUNX2, ALP, and OCN in MSCs cultured on stiff ECM. Our study provides an important insight into the stiff ECM-mediated promotion of MSC differentiation towards osteogenesis, emphasizing the influence of mechanical cues on the reorganization of 3D genome architecture and stem cell fate.

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Background: The inflammatory response to atherosclerosis is a process that leads to coronary artery disease. Pan-immune-inflammation value (PIV) has emerged as a new and simple biomarker of inflammation. However, studies on the predictive power of PIV for major adverse cardiovascular events (MACE) or the degree of coronary artery stenosis are scarce. We aimed to explore the predictive ability of PIV for MACE and the degree of coronary artery stenosis in patients with ST-segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) during hospitalization. Methods: This study included 542 patients who were diagnosed with STEMI and who underwent PCI between 2016 and 2023 and whose PIV and other inflammatory markers were measured. Using univariate and multivariate logistic regression analysis, risk variables for MACE following PCI and severe coronary stenosis during hospitalization were assessed to create receiver operating characteristic (ROC) curves and determine the best thresholds for inflammatory markers. Spearman correlation analysis was used to evaluate the correlation of PIV and other inflammatory markers with the Gensini score (GS). Results: Compared with the systemic inflammatory index (SII), platelet-to-lymphocyte ratio (PLR), and neutrophil-to-lymphocyte ratio (NLR), the PIV may have greater predictive value in terms of the occurrence of MACE and the degree of coronary stenosis after PCI in hospitalized STEMI patients. The correlation between the PIV and GS was strong. Conclusions: PIV was superior to the SII, PLR, and NLR in predicting inpatient prognosis and severe coronary stenosis after PCI for STEMI patients.

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Background: Recent research indicates that the monocyte lymphocyte ratio (MLR), neutrophil lymphocyte ratio (NLR), platelet lymphocyte ratio (PLR), C-reactive protein (CRP), and systemic immune-inflammation index (SII) may serve as valuable predictors of early postoperative mortality in elderly individuals with hip fractures. The primary objective of the study was to examine the association between preoperative MLR, NLR, PLR, CRP, and SII levels and 3-year mortality risk in geriatric patients after hip fracture surgery. Patients and methods: The study included patients aged 65 years or older who underwent hip fracture surgery between November 2018 and November 2019. Admission levels of MLR, NLR, PLR, CRP, and SII were measured. The median follow-up period was 3.1 years. Cox proportional hazards models were used to calculate the hazard ratio (HR) for mortality with adjusting for potential covariates. Time-dependent receiver operating characteristic (ROC) curves were employed to assess the predictive capability of inflammatory indicators for mortality. Results: A total of 760 patients completed the follow-up (79.4 ± 7.8 years, 71.1% female). A higher preoperative MLR was found to be significantly associated with an increased 3-year postoperative mortality risk (HR 1.811, 95% CI 1.047-3.132, P = 0.034). However, no significant correlations were observed between preoperative NLR, PLR, CRP, SII and 3-year mortality. The areas under the ROC curve (AUCs) of MLR for predicting 30-day, 120-day, 1-year, and 3-year mortality were 0.74 (95% CI 0.53-0.95), 0.70 (95% CI 0.57-0.83), 0.67 (95% CI 0.60-0.74), and 0.61 (95% CI 0.56-0.66), respectively. Conclusion: Preoperative MLR is a useful inflammatory marker for predicting 3-year mortality in elderly hip fracture patients, but its predictive ability diminishes over time.

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This review examines combining tumor ablation therapy with immunotherapy for respiratory and digestive system tumors, particularly NSCLC and liver cancer. Despite advancements in traditional methods, they face limitations in advanced-stage tumors. Ablation techniques like RFA, MWA, and cryoablation offer minimally invasive options, while immune checkpoint inhibitors enhance the immune system's tumor-fighting ability. This review highlights their synergistic effects, clinical outcomes, and future research directions, including optimizing protocols, exploring new combinations, uncovering molecular mechanisms, advancing precision medicine, and improving accessibility. Combined therapy is expected to improve efficacy and patient outcomes significantly.

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Polysaccharides, which are well-known natural macromolecules, have been recognized for their protective effects on neurons and their influence on extracellular dopamine levels in the brain. It is crucial to investigate the impact of plant polysaccharides on neurotransmission, particularly regarding the vesicular storage and exocytosis of neurotransmitters. In this study, we demonstrated the possibility of studying how the polysaccharide from Glochidion eriocarpum Champ.(GPS) affects vesicle dopamine content and the dynamics of exocytosis in pheochromocytoma (PC12) cells using single-cell amperometry (SCA) and intracellular vesicle impact electrochemical cytometry (IVIEC). Our results unambiguously demonstrate that GPS effectively enhances vesicular neurotransmitter content and alters the dynamics of exocytosis, favoring a smaller fraction of content released in exocytotic release, thereby inducing the partial release mode. These significant effects are attributed to GPS's efficient elevation of calcium influx, significant alteration in the composition of exocytosis-related membrane lipids, and enhancement of free radical scavenging ability. These findings not only establish GPS as a promising candidate for preventive or therapeutic interventions against neurodegenerative disorders but also reiterate the importance of screening native neurologic drugs with single-vesicle electrochemical approaches, the combination of SCA and IVIEC, from a neurotransmitter-centric perspective.

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PURPOSE: An MRI-based risk calculator (RC) has been recommended for diagnosing clinically significant prostate cancer (csPCa). PSMA PET/CT can detect lesions that are not visible on MRI, and the addition of PSMA PET/CT to MRI may improve diagnostic performance. The aim of this study was to incorporate the PRIMARY score or SUVmax derived from [68Ga]Ga-PSMA-11 PET/CT into the RC and compare these models with MRI-based RC to assess whether this can further reduce unnecessary biopsies. METHODS: A total of 683 consecutive biopsy-naïve men who underwent both [68Ga]Ga-PSMA-11 PET/CT and MRI before biopsy were temporally divided into a development cohort (n = 552) and a temporal validation cohort (n = 131). Three logistic regression RCs were developed and compared: MRI-RC, MRI-SUVmax-RC and MRI-PRIMARY-RC. Discrimination, calibration, and clinical utility were evaluated. The primary outcome was the clinical utility of the risk calculators for detecting csPCa and reducing the number of negative biopsies. RESULTS: The prevalence of csPCa was 47.5% (262/552) in the development cohort and 41.9% (55/131) in the temporal validation cohort. In the development cohort, the AUC of MRI-PRIMARY-RC was significantly higher than that of MRI-RC (0.924 vs. 0.868, p < 0.001) and MRI-SUVmax-RC (0.924 vs. 0.904, p = 0.002). In the temporal validation cohort, MRI-PRIMARY-RC also showed the best discriminative ability with an AUC of 0.921 (95% CI: 0.873-0.969). Bootstrapped calibration curves revealed that the model fit was acceptable. MRI-PRIMARY-RC exhibited near-perfect calibration within the range of 0-40%. DCA showed that MRI-PRIMARY-RC had the greatest net benefit for detecting csPCa compared with MRI-RC and MRI-SUVmax-RC at a risk threshold of 5-40% for csPCa in both the development and validation cohorts. CONCLUSION: The addition of the PRIMARY score to MRI-based multivariable model improved the accuracy of risk stratification prior to biopsy. Our novel MRI-PRIMARY prediction model is a promising approach for reducing unnecessary biopsies and improving the early detection of csPCa.

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INTRODUCTION: The aim of this study was to identify perioperative risk factors of laryngeal symptoms and to develop an implementable risk prediction model for Chinese hospitalized patients undergoing coronary artery bypass grafting (CABG). METHODS: A total of 1476 Chinese CABG patients admitted to Wuhan Asian Heart Hospital from January 2020 to June 2022 were included and then divided into a modeling cohort and a verification cohort. Univariate analysis was used to identify laryngeal symptoms risk factors, and multivariate logistic regression was applied to construct a prediction model for laryngeal symptoms after CABG. Discrimination and calibration of this model were validated based on the area under the receiver operating characteristic (ROC) curve and the Hosmer-Lemeshow (H-L) test, respectively. RESULTS: The incidence of laryngeal symptoms in patients who underwent CABG was 6.48%. Four independent risk factors were included in the model, and the established aryngeal complications risk calculation formula was Logit (P) = -4.525 + 0.824 × female + 2.09 × body mass index < 18.5 Kg/m2 + 0.793 × transesophageal echocardiogram + 1.218 × intensive care unit intubation time. For laryngeal symptoms, the area under the ROC curve was 0.769 in the derivation cohort (95% confidence interval [CI]: 0.698-0.840) and 0.811 in the validation cohort (95% CI: 0.742-0.879). According to the H-L test, the P-values in the modeling group and the verification group were 0.659 and 0.838, respectively. CONCLUSION: The prediction model developed in this study can be used to identify high-risk patients for laryngealsymptoms undergoing CABG, and help clinicians implement the follow-up treatment.

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Heat stress at the flowering stage significantly impacts rice grain yield, yet the number of identified genes associated with rice heat tolerance at this crucial stage remains limited. This study focuses on elucidating the function of the heat-induced gene reduced heat stress tolerance 1 (OsRHS). Overexpression of OsRHS leads to reduced heat tolerance, while RNAi silencing or knockout of OsRHS enhances heat tolerance without compromising yield, as assessed by the seed setting rate. OsRHS is localized in the cytoplasm and mainly expressed in the glume and anther of spikelet. Moreover, OsRHS was found to interact with the HSP protein cHSP70-4, and the knockout of cHSP70-4 resulted in increased heat tolerance. Complementation assays revealed that the knockout of cHSP70-4 could restore the compromised heat tolerance in OsRHS overexpression plants. Additional investigation reveals that elevated temperatures can amplify the bond between OsRHS and cHSP70-4 within rice. Furthermore, our findings indicate that under heat stress conditions during the flowering stage, OsRHS plays a negative regulatory role in the expression of many stress-related genes. These findings unveil the crucial involvement of OsRHS and cHSP70-4 in modulating heat tolerance in rice and identify novel target genes for enhancing heat resilience during the flowering phase in rice.

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Cancer is a significant cause of death around the world, and for many varieties, treatment is not successful. Therefore, there is a need for the development of innovative, efficacious, and precisely targeted treatments. Here, we develop a series of Au(I) complexes (1-4) through rational manipulation of ligand structures, thereby achieving tumor cell specific targeting and orchestrated tumor eradication via chemo-phototherapy and induced immunogenic cell death. A comprehensive exploration based on in vitro and in vivo female mice experimentation shows that complex 4 exhibits proficiency in specific tumor imaging, endoplasmic reticulum targeting, and has robust therapeutic capabilities. Mechanistic elucidation indicates that the anticancer effect derives from the synergistic actions of thioredoxin reductase inhibition, highly efficient reactive oxygen species production and immunogenic cell death. This work presents a report on a robust Au(I) complex integrating three therapeutic modalities within a singular system. The strategy presented in this work provides a valuable reference for the development of high-performance therapeutic agents.

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The use of a filling block can improve the initial stability of the fixation plate in the open wedge high tibial osteotomy (OWHTO), and promote bone healing. However, the biomechanical effects of filling block structures and materials on OWHTO remain unclear. OWHTO anatomical filling block model was designed and built. The finite element analysis method was adopted to study the influence of six filling block structure designs and four different materials on the stress of the fixed plate, tibia, screw, and filling block, and the micro-displacement at the wedge gap of the OWHTO fixation system. After the filling block was introduced in the OWHTO, the maximum von Mises stress of the fixation plate was reduced by more than 30%, the maximum von Mises stress of the tibia decreased by more than 15%, and the lateral hinge decreased by 81%. When the filling block was designed to be filled in the posterior position of the wedge gap, the maximum von Mises stress of the fixation system was 97.8 MPa, which was smaller than other filling methods. The minimum micro-displacement of osteotomy space was -2.9 µm, which was larger than that of other filling methods. Compared with titanium alloy and tantalum metal materials, porous hydroxyapatite material could obtain larger micro-displacement in the osteotomy cavity, which is conducive to stimulating bone healing. The results demonstrate that OWHTO with a filling block can better balance the stress distribution of the fixation system, and a better fixation effect can be obtained by using a filling block filled in the posterior position. Porous HA used as the material of the filling block can obtain a better bone healing effect.

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Although targeting the androgen signaling pathway by androgen receptor (AR) inhibitors, including enzalutamide, has shown therapeutic effectiveness, inevitable emergence of acquired resistance remains a critical challenge in the treatment of advanced prostate cancer (PCa). Recognizing targetable genomic aberrations that trigger endocrine treatment failure holds great promise for advancing therapeutic interventions. Here, we characterized PLXNA1, amplified in a subset of PCa patients, as a contributor to enzalutamide resistance (ENZR). Elevated PLXNA1 expression facilitated PCa proliferation under enzalutamide treatment due to AKT signaling activation. Mechanistically, PLXNA1 recruited NRP1 forming a PLXNA1-NRP1 complex, which in turn potentiated the phosphorylation of the AKT. Either inhibiting PLXNA1-NRP1 complex with an NRP1 inhibitor, EG01377, or targeting PLXNA1-mediated ENZR with AKT inhibitors, abolished the pro-resistance phenotype of PLXNA1. Taken together, combination of AKT inhibitor and AR inhibitors presents a promising therapeutic strategy for PCa, especially in advanced PCa patients exhibiting PLXNA1 overexpression.

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BACKGROUND AND PURPOSE: Atherosclerosis is the basis of cardiovascular disease. Ferroptosis is a form of programmed cell death characterized by lipid peroxidation, which contributes to atherogenesis. The plant extract PNS (Panax notoginseng saponins), containing the main active ingredients of Panax notoginseng, exhibits anti-atherogenic properties. Herein, we determined whether PNS and its major components could attenuate atherosclerosis by suppressing ferroptosis and revealed the underlying mechanism(s). EXPERIMENTAL APPROACH: The anti-atherogenic effects of PNS and their association with inhibition of ferroptosis was determined in apoE-/- mice. In vitro, the anti-ferroptotic effect and mechanism(s) of PNS components were demonstrated in the presence of ferroptosis inducers. Expression of ferroptosis markers and the ubiquitination of Keap1 were evaluated in USP2-/- macrophages. Finally, the anti-atherogenic effect of USP2 knockout was determined by using USP2-/- mice treated with high-fat diet (HFD) and AAV-PCSK9. KEY RESULTS: PNS inhibited ferroptosis and atherosclerosis in vivo. PNS suppressed ferroptosis and ferroptosis-aggravated foam cell formation and inflammation in vitro. Mechanistically, PNS and its components activated Nrf2 by antagonizing Keap1, which was attributed to the inhibition of USP2 expression. USP2 knockout antagonized ferroptosis and ferroptosis-aggravated foam cell formation and inflammation, thus mitigating atherosclerosis. USP2 knockout abolished inhibitory effects of PNS on foam cell formation and inflammation in vitro. CONCLUSION AND IMPLICATIONS: PNS reduced USP2-mediated Keap1 de-ubiquitination and promoted Keap1 degradation, thereby activating Nrf2, improving iron metabolism and reducing lipid peroxidation, thus contributing to an anti-atherosclerotic outcome. Our study revealed the mechanism(s) underlying inhibition of ferroptosis and atherosclerosis by PNS.

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BACKGROUND: NUP98 rearrangements (NUP98-r) are rare but overrepresented mutations in pediatric acute myeloid leukemia (AML) patients. NUP98-r is often associated with chemotherapy resistance and a particularly poor prognosis. Therefore, characterizing pediatric AML with NUP98-r to identify aberrations is critically important. METHODS: Here, we retrospectively analyzed the clinicopathological features, genomic and transcriptomic landscapes, treatments, and outcomes of pediatric patients with AML. RESULTS: Nine patients with NUP98-r mutations were identified in our cohort of 142 patients. Ten mutated genes were detected in patients with NUP98-r. The frequency of FLT3-ITD mutations differed significantly between the groups harboring NUP98-r and those without NUP98-r (P = 0.035). Unsupervised hierarchical clustering via RNA sequencing data from 21 AML patients revealed that NUP98-r samples clustered together, strongly suggesting a distinct subtype. Compared with that in the non-NUP98-r fusion and no fusion groups, CMAHP expression was significantly upregulated in the NUP98-r samples (P < 0.001 and P = 0.001, respectively). Multivariate Cox regression analyses demonstrated that patients harboring NUP98-r (P < 0.001) and WT1 mutations (P = 0.030) had worse relapse-free survival, and patients harboring NUP98-r (P < 0.008) presented lower overall survival. CONCLUSIONS: These investigations contribute to the understanding of the molecular characteristics, risk stratification, and prognostic evaluation of pediatric AML patients.

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Histopathology image evaluation is indispensable for cancer diagnoses and subtype classification. Standard artificial intelligence methods for histopathology image analyses have focused on optimizing specialized models for each diagnostic task1,2. Although such methods have achieved some success, they often have limited generalizability to images generated by different digitization protocols or samples collected from different populations3. Here, to address this challenge, we devised the Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model, a general-purpose weakly supervised machine learning framework to extract pathology imaging features for systematic cancer evaluation. CHIEF leverages two complementary pretraining methods to extract diverse pathology representations: unsupervised pretraining for tile-level feature identification and weakly supervised pretraining for whole-slide pattern recognition. We developed CHIEF using 60,530 whole-slide images spanning 19 anatomical sites. Through pretraining on 44 terabytes of high-resolution pathology imaging datasets, CHIEF extracted microscopic representations useful for cancer cell detection, tumour origin identification, molecular profile characterization and prognostic prediction. We successfully validated CHIEF using 19,491 whole-slide images from 32 independent slide sets collected from 24 hospitals and cohorts internationally. Overall, CHIEF outperformed the state-of-the-art deep learning methods by up to 36.1%, showing its ability to address domain shifts observed in samples from diverse populations and processed by different slide preparation methods. CHIEF provides a generalizable foundation for efficient digital pathology evaluation for patients with cancer.

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Dark tea (DT) holds a rich cultural history in China and has gained sizeable consumers due to its unique flavor and potential health benefits. In this study, headspace solid-phase microextraction (HS-SPME) combined with gas chromatography-mass spectrometry (GC-MS), relative odor activity value (ROAV), and chemometrics approaches were used to detect and analyze aroma compounds differences among five dark teas from different geographical regions. The results revealed that the five DTs from different geographical regions differed in types, quantities, and relative concentrations of volatile compounds. A total of 1372 volatile compounds of were identified in the 56 DT samples by HS-SPME-GC-MS. Using ROAV and chemometrics approaches, based on ROAV>1 and VIP>1. Eighteen key aroma compounds can be used as potential indicators for DT classification, including dihydroactinidiolide, linalool, 1,2,3-trimethoxybenzene, geranyl acetone, 1,2,4-trimethoxybenzene, cedrol, 3,7-dimethyl-1,5,7-octatrien-3-ol, ß-ionone, 4-ethyl-1,2-dimethoxybenzene, methyl salicylate, α-ionone, geraniol, linalool oxide I, linalool oxide II, 6-methyl-5-hepten-2-one, α-terpineol, 1,2,3-trimethoxy-5-methylbenzene, and 1,2-dimethoxybenzene. These compounds provide a certain theoretical basis for distinguishing the differences in five DTs from different geographical regions. This study provides a potential method for identifying the volatile substances in DTs and elucidating the differences in key aroma compounds. Abbreviations: DT, dark tea; FZT, Fuzhuan tea; LPT, Guangxi Liupao tea; QZT, Hubei Qingzhuan tea; TBT, Sichuan Tibetan tea; PET, Yunnan Pu-erh tea; ROAV, Relative odor activity value; OT, Odor threshold; HS-SPME, Headspace solid-phase microextraction; GC-MS, Gas chromatography-mass spectrometry; PCA, Principal components analysis; PLS-DA, Partial least squares-discriminant analysis; HCA, Hierarchical clustering analysis.

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