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Small cell lung cancer (SCLC) is characterized by rapid progression and low survival rates. Therefore, novel therapeutic agents are urgently needed for this disease. Capsaicin, the active ingredient of chilli peppers, displays anti-proliferative activity in prostate and epidermoid cancer in vitro. However, the anti-proliferative activity of capsaicin has not been studied in human SCLCs. The present manuscript fills this void of knowledge and explores the anti-proliferative effect of capsaicin in SCLC in vitro and in vivo.BrdU assays and PCNA ELISAs showed that capsaicin displays robust anti-proliferative activity in four human SCLC cell lines. Furthermore, capsaicin potently suppressed the growth of H69 human SCLC tumors in vivo as ascertained by CAM assays and nude mice models. The second part of our study attempted to provide insight into molecular mechanisms underlying the anti-proliferative activity of capsaicin. We found that the anti-proliferative activity of capsaicin is correlated with a decrease in the expression of E2F-responsive proliferative genes like cyclin E, thymidylate synthase, cdc25A and cdc6, both at mRNA and protein levels. The transcription factor E2F4 mediated the anti-proliferative activity of capsaicin. Ablation of E2F4 levels by siRNA methodology suppressed capsaicin-induced G1 arrest. ChIP assays demonstrated that capsaicin caused the recruitment of E2F4 and p130 on E2F-responsive proliferative promoters, thereby inhibiting cell proliferation.Our findings suggest that the anti-proliferative effects of capsaicin could be useful in the therapy of human SCLCs.

Abstract Single-cell technology depicts integrated tumor profiles including both tumor cells and tumor microenvironments, which theoretically enables more robust diagnosis than traditional diagnostic standards based on only pathology. However, the inherent challenges of single-cell RNA sequencing (scRNA-seq) data, such as high dimensionality, low signal-to-noise ratio (SNR), sparse and non-Euclidean nature, pose significant obstacles for traditional diagnostic approaches. The diagnostic value of single-cell technology has been largely unexplored despite the potential advantages. Here, we present a graph neural network-based framework tailored for molecular diagnosis of primary liver tumors using scRNA-seq data. Our approach capitalizes on the biological plausibility inherent in the intercellular communication networks within tumor samples. By integrating pathway activation features within cell clusters and modeling unidirectional inter-cellular communication, we achieve robust discrimination between malignant tumors (including hepatocellular carcinoma, HCC, and intrahepatic cholangiocarcinoma, iCCA) and benign tumors (focal nodular hyperplasia, FNH) by scRNA data of all tissue cells and immunocytes only. The efficacy to distinguish iCCA from HCC was further validated on public datasets. Through extending the application of high-throughput scRNA-seq data into diagnosis approaches focusing on integrated tumor microenvironment profiles rather than a few tumor markers, this framework also sheds light on minimal-invasive diagnostic methods based on migrating/circulating immunocytes.

Abstract Background Arecae Semen is a traditional herbal medicine widely used in the medical service and food industry, but in recent years, the carcinogenesis of edible Arecae Semen chewing has aroused comprehensive attention, therefore it is necessary to evaluate its medicinal properties. Increasing evidence has shown that Arecae Semen Compounds (ASC) possess antidepressant ability. This study aimed to evaluate the effectiveness and safety of ASC in the treatment of depression. Methods We retrieved articles in eight databases from their inception to May 2024. Randomized controlled trials (RCTs) comparing the effects of ASC alone or combined with routine treatment in patients with depression were identified. The Cochrane risk of bias (ROB) tool (ROB 2) was used for assessing the ROB in the included trials. Grading of Recommendations Assessment, Development, and Evaluation (GRADE) was used to assess the certainty of the evidence for the review outcomes. The outcomes included Hamilton depression rating scale (HAMD) scores, depression-related symptoms, serum dopamine levels, and adverse events. Stata 14.0 was used for data analysis calculating standardized mean difference (SMD) for continuous outcomes and relative risk (RR) for binary outcomes, both with 95% confidence intervals (CI). Results Nine RCTs involving 787 patients were included in this review. ASC lowered HAMD scores (SMD − 3.43, 95% CI − 5.24 to − 1.61; I 2 = 95.2%, P

Abstract Sepsis-induced cardiomyopathy (SIC) is described as a reversible myocardial depression that occurs in patients with septic shock. Increasing evidence shows that microRNA-194-5p (miR-194-5p) participates in the regulation of oxidative stress, mitochondrial dysfunction, and apoptosis and its expression is associated with the occurrence and progression of cardiovascular disease; however, the effects of miR-194-5p in SIC are still unclear. This study explores whether miR-194-5p could modulate SIC by affecting oxidative stress, mitochondrial function, and apoptosis. Experimental septic mice were induced by intraperitoneal injection of lipopolysaccharide (LPS) in C57BL/6J mice. The biological role of miR-194-5p in SIC in vivo was investigated using cardiac echocardiography, ELISA, western blot, qRT-PCR, transmission electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay, bioinformatics analysis, and dual-luciferase reporter gene assay. Our major finding is that miR-194-5p antagomir mitigates sepsis-induced cardiac dysfunction, inflammation, oxidative stress, apoptosis and mitochondrial dysfunction in the hearts of septic mice, while miR-194-5p agomir triggers the opposite effects. Furthermore, dual-specificity phosphatase 9 (DUSP9) is a direct target of miR-194-5p and the cardioprotective effects of miR-194-5p antagomir on cardiac dysfunction, inflammation, apoptosis, mitochondrial dysfunction and oxidative stress are abolished through inhibiting DUSP9. Therefore, miR-194-5p inhibition could mitigate SIC via DUSP9 in vivo and the novel miR-194-5p/DUSP9 axis might be the potential treatment targets for SIC patients.

Abstract The dose–response of intravenous lidocaine in preventing postoperative vomiting (POV) in children remains unclear. This study investigated whether intravenous lidocaine dose-dependently decreased POV risk within 24 h postoperatively in children undergoing tonsillectomy (with or without adenoidectomy) without severe complications. Patients aged 3–12 years (American Society of Anesthesiologists grade I–II) scheduled for elective tonsillectomy (with or without adenoidectomy) were enroled from December 2021 to March 2022. They were randomly grouped according to the lidocaine dose (A [0 mg kg−1], B [1 mg kg−1], C [1.5 mg kg−1], and D [2 mg kg−1]) and were administered the same induction protocol (sufentanil, propofol, and suxamethonium chloride). Anaesthesia was maintained with sevoflurane. The incidence of POV within 24 h postoperatively was 46, 40, 36, and 20% in groups A, B, C, and D, respectively, with significant differences between groups D and A. Postoperative analgesic rescues in groups A, B, C, and D were 62, 36, 34, and 16%, respectively, with significant differences between groups D and B, C and A, and D and A. No severe adverse events were reported. Intravenous lidocaine has a dose-dependent effect on reducing the risk of POV in children undergoing tonsillectomy (with or without adenoidectomy) without serious adverse events. Trial registration: Chinese Clinical Trial Registry, ChiCTR2100053006.

Abstract Third-generation EGFR tyrosine kinase inhibitors (TKIs), exemplified by osimertinib, have demonstrated promising clinical efficacy in the treatment of non-small cell lung cancer (NSCLC). Our previous work has identified ASK120067 as a novel third-generation EGFR TKI with remarkable antitumor effects that has undergone New Drug Application (NDA) submission in China. Despite substantial progress, acquired resistance to EGFR-TKIs remains a significant challenge, impeding the long-term effectiveness of therapeutic approaches. In this study, we conducted a comprehensive investigation utilizing high-throughput proteomics analysis on established TKI-resistant tumor models, and found a notable upregulation of branched-chain amino acid transaminase 1 (BCAT1) expression in both osimertinib- and ASK120067-resistant tumors compared with the parental TKI-sensitive NSCLC tumors. Genetic depletion or pharmacological inhibition of BCAT1 impaired the growth of resistant cells and partially re-sensitized tumor cells to EGFR TKIs. Mechanistically, upregulated BCAT1 in resistant cells reprogrammed branched-chain amino acid (BCAA) metabolism and promoted alpha ketoglutarate (α-KG)-dependent demethylation of lysine 27 on histone H3 (H3K27) and subsequent transcriptional derepression of glycolysis-related genes, thereby enhancing glycolysis and promoting tumor progression. Moreover, we identified WQQ-345 as a novel BCAT1 inhibitor exhibiting antitumor activity both in vitro and in vivo against TKI-resistant lung cancer with high BCAT1 expression. In summary, our study highlighted the crucial role of BCAT1 in mediating resistance to third-generation EGFR-TKIs through epigenetic activation of glycolysis in NSCLC, thereby supporting BCAT1 as a promising therapeutic target for the treatment of TKI-resistant NSCLC.

Abstract The precise forecasting of air quality is of great significance as an integral component of early warning systems. This remains a formidable challenge owing to the limited information of emission source and the considerable uncertainties inherent in dynamic processes. To improve the accuracy of air quality forecasting, this work proposes a new spatiotemporal hybrid deep learning model based on variational mode decomposition (VMD), graph attention networks (GAT) and bi-directional long short-term memory (BiLSTM), referred to as VMD–GAT–BiLSTM, for air quality forecasting. The proposed model initially employ a VMD to decompose original PM2.5 data into a series of relatively stable sub-sequences, thus reducing the influence of unknown factors on model prediction capabilities. For each sub-sequence, a GAT is then designed to explore deep spatial relationships among different monitoring stations. Next, a BiLSTM is utilized to learn the temporal features of each decomposed sub-sequence. Finally, the forecasting results of each decomposed sub-sequence are aggregated and summed as the final air quality prediction results. Experiment results on the collected Beijing air quality dataset show that the proposed model presents superior performance to other used methods on both short-term and long-term air quality forecasting tasks.

Abstract The study aims to investigate the predictive capability of machine learning algorithms for omental metastasis in locally advanced gastric cancer (LAGC) and to compare the performance metrics of various machine learning predictive models. A retrospective collection of 478 pathologically confirmed LAGC patients was undertaken, encompassing both clinical features and arterial phase computed tomography images. Radiomic features were extracted using 3D Slicer software. Clinical and radiomic features were further filtered through lasso regression. Selected clinical and radiomic features were used to construct omental metastasis predictive models using support vector machine (SVM), decision tree (DT), random forest (RF), K-nearest neighbors (KNN), and logistic regression (LR). The models’ performance metrics included accuracy, area under the curve (AUC) of the receiver operating characteristic curve, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). In the training cohort, the RF predictive model surpassed LR, SVM, DT, and KNN in terms of accuracy, AUC, sensitivity, specificity, PPV, and NPV. Compared to the other four predictive models, the RF model significantly improved PPV. In the test cohort, all five machine learning predictive models exhibited lower PPVs. The DT model demonstrated the most significant variation in performance metrics relative to the other models, with a sensitivity of 0.231 and specificity of 0.990. The LR-based predictive model had the lowest PPV at 0.210, compared to the other four models. In the external validation cohort, the performance metrics of the predictive models were generally consistent with those in the test cohort. The LR-based model for predicting omental metastasis exhibited a lower PPV. Among the machine learning algorithms, the RF predictive model demonstrated higher accuracy and improved PPV relative to LR, SVM, KNN, and DT models.

Abstract As countries attach importance to environmental protection, clean energy has become a hot topic. Among them, solar energy, as one of the efficient and easily accessible clean energy sources, has received widespread attention. An essential component in converting solar energy into electricity are solar cells. However, a major optimization difficulty remains in precisely and effectively calculating the parameters of photovoltaic (PV) models. In this regard, this study introduces an improved rime optimization algorithm (RIME), namely ERINMRIME, which integrates the Nelder-Mead simplex (NMs) with the environment random interaction (ERI) strategy. In the later phases of ERINMRIME, the ERI strategy serves as a complementary mechanism for augmenting the solution space exploration ability of the agent. By facilitating external interactions, this method improves the algorithm’s efficacy in conducting a global search by keeping it from becoming stuck in local optima. Moreover, by incorporating NMs, ERINMRIME enhances its ability to do local searches, leading to improved space exploration. To evaluate ERINMRIME's optimization performance on PV models, this study conducted experiments on four different models: the single diode model (SDM), the double diode model (DDM), the three-diode model (TDM), and the photovoltaic (PV) module model. The experimental results show that ERINMRIME reduces root mean square error for SDM, DDM, TDM, and PV module models by 46.23%, 59.32%, 61.49%, and 23.95%, respectively, compared with the original RIME. Furthermore, this study compared ERINMRIME with nine improved classical algorithms. The results show that ERINMRIME is a remarkable competitor. Ultimately, this study evaluated the performance of ERINMRIME across three distinct commercial PV models, while considering varying irradiation and temperature conditions. The performance of ERINMRIME is superior to existing similar algorithms in different irradiation and temperature conditions. Therefore, ERINMRIME is an algorithm with great potential in identifying and recognizing unknown parameters of PV models.

Objective To analyze the application of serological test results in the diagnosis and treatment of anti-M-induced hemolytic disease of the fetus and newborn(HDFN), and to explore HDFN prevention strategies. Methods The serological test results of 12 cases of HDFN caused by anti-M diagnosed in our laboratory from January 2017 to December 2023 were retrospectively analyzed, including blood group identification of mothers and children, serum total bilirubin/hemoglobin/antibody titer test, and three hemolysis tests in newborns. Clinical data of the children and mothers were collected, including pregnancy history, blood transfusion history, prenatal antibody testing, history of intrauterine blood transfusion and gestational week of delivery, and the prognosis of the children was followed up. Results All 12 cases of fetal neonatal hemolytic disease due to anti-M were RhD+ MN phenotype newborn born to RhD+ NN mother, with maternal- fetal incompatiblility in MN blood groups. In the ABO blood group system, ABO incompatibility between mother and child accounted for 41.7%(5/12).None of the mothers had a history of blood transfusion, and the median titer of the test at 4℃ was 32, and the median titer at 37℃ was 4. The mothers of 3 cases had a history of multiple intrauterine blood transfusions, with an incidence of 25%(3/12). One case had an abnormal first pregnancy, with an incidence of 8.3%(1/12), and seven cases had an abnormal pregnancy with a miscarriage, with an incidence of abnormal pregnancy and birth history of 58.3%(7/12). There were 6 cases of premature labor, with an incidence of 50%(6/12). The mothers in three cases underwent regular obstetric examination and the specificity of the antibodies was determined, accounting for 25%(3/12). Twelve children had free antibodies with a median titer of 6 at 4℃ and 2 at 37℃. Two children had anti-M antibodies that were not reactive at 37℃, with a negative rate of 16.7%(2/12). The positive rate of DAT and elution test was respectively 8.3%(1/12) and 16.7%(2/12) in the children. The median minimum hemoglobin value was 75 g/L, and all 12 children received blood transfusions. The median peak total bilirubin value was 157.5 μmol/L, and none of them reached the threshold for blood exchange. The rate of delayed anemia was 16.7%(2/12), the postnatal mortality rate was 8.3%(1/12), and 11 children was free of growth and neurodevelopmental delay in prognosis. Conclusion Anti-M can cause severe HDFN, which can also occur in primigravida. The intensity of antibody titer does not correlate with the severity of the disease, and it is prone to cause delayed anemia, which should be monitored regularly according to the serological characteristics of anti-M and clinical symptoms, and should be treated timely.

Abstract Image segmentation techniques play a vital role in aiding COVID-19 diagnosis. Multi-threshold image segmentation methods are favored for their computational simplicity and operational efficiency. Existing threshold selection techniques in multi-threshold image segmentation, such as Kapur based on exhaustive enumeration, often hamper efficiency and accuracy. The whale optimization algorithm (WOA) has shown promise in addressing this challenge, but issues persist, including poor stability, low efficiency, and accuracy in COVID-19 threshold image segmentation. To tackle these issues, we introduce a Latin hypercube sampling initialization-based multi-strategy enhanced WOA (CAGWOA). It incorporates a COS sampling initialization strategy (COSI), an adaptive global search approach (GS), and an all-dimensional neighborhood mechanism (ADN). COSI leverages probability density functions created from Latin hypercube sampling, ensuring even solution space coverage to improve the stability of the segmentation model. GS widens the exploration scope to combat stagnation during iterations and improve segmentation efficiency. ADN refines convergence accuracy around optimal individuals to improve segmentation accuracy. CAGWOA's performance is validated through experiments on various benchmark function test sets. Furthermore, we apply CAGWOA alongside similar methods in a multi-threshold image segmentation model for comparative experiments on lung X-ray images of infected patients. The results demonstrate CAGWOA's superiority, including better image detail preservation, clear segmentation boundaries, and adaptability across different threshold levels.

Objectives: The study aimed to investigate the relationship between blood pressure (BP) levels and mortality among critically ill older adults in the intensive care unit (ICU), establish optimal BP target for this population, and assess the mediating effect of severe malnutrition on BP-related mortality. Methods: Data were extracted from the Medical Information Mart for Intensive Care IV version 2.2 database, focusing on critically ill patients aged 80 years and older. The analysis included various BP parameters, such as systolic BP (SBP), diastolic BP (DBP), and mean arterial pressure (MAP). Results: The study cohort comprised 14,660 critically ill patients, of whom 1558 (10.6 %) experienced ICU mortality and 2493 (17.0 %) experienced in-hospital mortality. Lower BP levels (SBP ≤ 112 mmHg; DBP ≤ 53 mmHg; MAP ≤65 mmHg), were associated with an increased risk of both ICU and in-hospital mortality. Notably, only reduced SBP levels were linked to a higher risk of 1-year mortality, with an adjusted hazard ratio 1.13 (95 % confidence interval 1.05 to 1.23). Additionally, severe malnutrition was identified as a mediator in the relationship between low BP levels and ICU mortality, with BP levels positively correlated with prognostic nutritional indexes. Conclusion: Among critically ill older adults, lower BP levels are significantly associated with higher risks of ICU and in-hospital mortality, while reduced SBP levels are linked to 1-year mortality. These findings emphasize the importance of assessing nutritional status in older ICU patients with low BP levels to potentially mitigate mortality risk.

Aims: The relationship between sarcopenia and cognitive impairment in older adults remains contentious. This study investigates this association and examines the long-term prognosis for individuals with both conditions. Methods: Utilizing data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014, this study focuses on the correlation between sarcopenia and cognitive impairment, as well as the extended prognosis for individuals managing these conditions. Results: The study cohort comprised 2890 participants, with 648 (22.4 %) diagnosed with sarcopenia. Multivariable logistic regression analysis identified a significant association between sarcopenia and an increased risk of cognitive impairment (adjusted odds ratio [aOR]: 1.68, 95 % confidence interval [CI]: 1.30–2.17). Over a median follow-up period of 48 months, 200 individuals (6.9 %) succumbed to cardiovascular and cerebrovascular diseases (CCVDs), including hypertension, congestive heart failure, coronary artery disease, and stroke, as well as Alzheimer's disease (AD). Participants had comorbid conditions such as CCVDs and diabetes mellitus. Kaplan–Meier survival analysis and the Cox proportional hazards model indicated that individuals with both sarcopenia and cognitive impairment had the highest mortality risk from CCVDs and AD (adjusted hazard ratio [aHR]: 2.73, 95 % CI: 1.48–5.02). Individuals with sarcopenia and comorbidities exhibited a higher mortality risk from CCVDs or AD compared to those without sarcopenia but with comorbidities (aHR: 2.71, 95 % CI: 1.37–5.37). Conclusion: Sarcopenia is independently associated with cognitive impairment. Older adults with both sarcopenia and cognitive impairment or concurrent comorbidities face increased mortality risks from CCVDs or AD compared to their healthy counterparts. Clinical implication: • Sarcopenia is associated with cognitive impairment. • Cognitive impairment and comorbidities increased the risk of mortality from CCVDs and AD for sarcopenia patients.

Abstract With the continuous development of the economy and society, along with the sustained population growth, the issue of water resources carrying capacity in China has attracted increasing attention. This paper constructs a model for evaluating the provincial water resources carrying capacity in China from four dimensions: water, economy, society, and ecology. Utilizing this model, we analyze the spatiotemporal variations in water resources carrying capacity among 31 provinces in China from 2005 to 2021. Additionally, we delve into the coupling coordination and influencing factors of water resources carrying capacity. The study reveals an overall increasing trend in China’s water resources carrying capacity index, with the ecological indicator exhibiting the most significant growth while the water resources sub-indicator lags behind. There are notable regional differences, with higher water resources carrying capacity observed in the eastern coastal areas and relatively lower capacity in the western regions. The ecological criterion becomes a core factor constraining water resources carrying capacity from 2005 to 2015, gradually giving way to the prominence of the social criterion since 2015. The coordination degree is relatively higher in the eastern regions, more scattered in the western regions, and relatively stable in the central regions. Based on the research findings, a series of recommendations are proposed, including strengthening environmental protection policies, optimizing water resources management mechanisms, improving water use efficiency, and promoting economic structural diversification. These suggestions aim to facilitate the sustainable development of water resources carrying capacity in China.

Abstract China’s rural reform is reliant on farmers' cooperatives as a key organization vehicle. It plays an important role in promoting rural revitalization. Such as, realizing the organic connection between small farmers and agricultural modernization. This study used the nearest neighbor index and kernel density estimation to analyze the spatial distribution and structural characteristics of farmer cooperatives in Hunan Province. It revealed the spatial differentiation law of cooperatives. Also using geographical detectors to figure out the main factors that affect the spatial distribution. The results show that: ① Hunan Farmers Cooperatives show significant spatial agglomeration. The overall spatial distribution shows the spatial characteristics of "one core, one circle, and multiple points". And the spatial distribution pattern of "large agglomeration, finger-shaped radiation distribution". Among them, the distribution of provincial demonstration cooperatives is relatively balanced. ② Cooperatives in six types of industries, such as planting, forestry, and feeding, showed agglomeration distribution. Different industrial cooperatives spread out in different ways, such as in an anti-"L" shape, a dual-core shape, or a one-center area. ③ The 24 influence factors selected from the five dimensions of the natural environment, social economic basis, production basis, output capacity, and facility basis have high, general, and weak influence on cooperatives' spatial distribution. The development and distribution of cooperatives mainly depend on resource endowment, social and economic development level, and market dependence. The spatial distribution heterogeneity of different professional cooperatives is mainly affected by slope, per capita disposable income of rural residents, road density, and other factors. ④ The progression of farmer cooperatives in Hunan Province should prioritize high-quality development, emphasizing the need for innovative approaches and transformative strategies within rural industrial organizations. It is imperative to optimize the spatial distribution of cooperatives, strategically contributing to the establishment of a novel framework for modern agricultural development in Hunan Province. Additionally, there is a critical emphasis on spearheading collaborative initiatives among cooperatives of varied industrial types, aimed at fostering the integrated development of rural primary, secondary, and tertiary industries.

Abstract Soil sickness a severe problem in tobacco production, leading to soil-borne diseases and reduce in tobacco yield. This occurs as a result of the interaction between root exudates and rhizosphere microorganisms, which is however, little studied until now. By combining the field investigation and pot experiment, we found the output yield consistently decreased during the first 10 years of continuous cropping in a tobacco field, but increased at the 15th year (15Y). The root exudate and rhizosphere bacterial community was further analyzed to reveal the underlying mechanism of the suppressive soil formation. Root exudate of 15Y tobacco enriched in amino acids and derivatives, while depleted in the typical autotoxins including phenolic acids and alkaloids. This was correlated to the low microbial diversity in 15Y, but also the changes in community composition and topological properties of the co-occurrence network. Especially, the reduced autotoxins were associated with low Actinobacteria abundance, low network complexity and high network modularity, which significantly correlated with the recovered output yield in 15Y. This study revealed the coevolution of rhizosphere microbiota and root exudate as the soil domesticated by continuous cropping of tobacco, and indicated a potential role of the autotoxins and theirs effect on the microbial community in the formation of suppressive soil.

Abstract Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

Objective To explore the relationship between pulmonary function, physical activity, and health-related quality of life (QoL) in resected lung cancer patients based on the International Classification of Functioning, Disability, and Health (ICF) framework developed by the World Health Organization to describe health and health-related states. Methods A quantitative study was designed with postoperative lung cancer survivors to assess personal characteristics. We also assessed functional impairment related to the lung using forced vital capacity (FVC) and forced expiratory volume at 1 second (FEV1), activity limitations using maximal oxygen consumption (VO2max), anaerobic threshold (AT) and 6-minute walking distance (6MWD), and participation restriction using the 36-item Short Form Health Survey V1 (SF-36). Data analyses were conducted using the multivariate method and SmartPLS to examine path coefficient among the measures. Results Forty-one patients were enrolled in this study. FVC and FEV1 were poorly correlated with QoL, and 6MWD, AT, or VO2max were positively associated with QoL. AT or VO2max showed a significant (p

Abstract Background Most studies on the impact of the COVID-19 pandemic on depression burden focused on the earlier pandemic phase specific to lockdowns, but the longer-term impact of the pandemic is less well-studied. In this population-based cohort study, we examined the short-term and long-term impacts of COVID-19 on depression incidence and healthcare service use among patients with depression. Methods Using the territory-wide electronic medical records in Hong Kong, we identified all patients aged ≥ 10 years with new diagnoses of depression from 2014 to 2022. We performed an interrupted time-series (ITS) analysis to examine changes in incidence of medically attended depression before and during the pandemic. We then divided all patients into nine cohorts based on year of depression incidence and studied their initial and ongoing service use patterns until the end of 2022. We applied generalized linear modeling to compare the rates of healthcare service use in the year of diagnosis between patients newly diagnosed before and during the pandemic. A separate ITS analysis explored the pandemic impact on the ongoing service use among prevalent patients with depression. Results We found an immediate increase in depression incidence (RR = 1.21, 95% CI: 1.10–1.33, p

Abstract. Background:. The serum vitamin D level varies widely by population, and studies have linked vitamin D levels with the risk of type 2 diabetes mellitus (T2DM). However, the relationship is inconsistent and the impact of vitamin D on T2DM among East Chinese adults is unclear. The study aimed to investigate the association between serum 25-hydroxyvitamin D (25[OH]D) levels and the risk of T2DM and evaluated whether the association is modified by genetic predisposition. Methods:. In the Survey on Prevalence in East China for Metabolic Diseases and Risk Factors (SPECT-China) cohort, 1862 participants free of T2DM at baseline were included. A weighted genetic risk score was calculated with 28 variants associated with T2DM. Hierarchical logistic models were used to examine the association of serum 25(OH)D and genetic risk with T2DM. Results:. After a 5-year follow-up, 132 cases of T2DM were documented. We observed no significant association between quartiles of serum 25(OH)D and T2DM risk after multivariable adjustment (χ2 = 0.571, Pfor trend = 0.426). Compared to those in the lowest quartile of 25(OH)D, the odds ratios (ORs) (95% confidence interval [CI]) for participants with increased quartiles were 1.29 (0.74–2.25), 1.35 (0.77–2.36), and 1.27 (0.72–2.24), respectively. We observed a positive association of glycated hemoglobin (HbA1c) with 25(OH)D at baseline (β = 1.752, P = 0.001) and after follow-up (β = 1.385, P = 0.003), and a negative association of ln conversion homeostasis model assessment (HOMA)-β with 25(OH)D at baseline (β = -0.982, P = 0.021). There was no significant interaction between 25(OH)D and diabetes genetic predisposition on the risk of T2DM (χ2 = 2.710, Pfor interaction = 0.100). The lowest OR (95% CI) of T2DM was among participants with low genetic risk and the highest quartile of 25(OH)D (0.17 [0.05–0.62]). Conclusion:. Serum 25(OH)D may be irrelevant to the risk of incident T2DM among East Chinese adults regardless of genetic predisposition.

Abstract Modern medicine has produced large genetic datasets of high dimensions through advanced gene sequencing technology, and processing these data is of great significance for clinical decision-making. Gene selection (GS) is an important data preprocessing technique that aims to select a subset of feature information to improve performance and reduce data dimensionality. This study proposes an improved wrapper GS method based on forensic-based investigation (FBI). The method introduces the search mechanism of the slime mould algorithm in the FBI to improve the original FBI; the newly proposed algorithm is named SMA_FBI; then GS is performed by converting the continuous optimizer to a binary version of the optimizer through a transfer function. In order to verify the superiority of SMA_FBI, experiments are first executed on the 30-function test set of CEC2017 and compared with 10 original algorithms and 10 state-of-the-art algorithms. The experimental results show that SMA_FBI is better than other algorithms in terms of finding the optimal solution, convergence speed, and robustness. In addition, BSMA_FBI (binary version of SMA_FBI) is compared with 8 binary algorithms on 18 high-dimensional genetic data from the UCI repository. The results indicate that BSMA_FBI is able to obtain high classification accuracy with fewer features selected in GS applications. Therefore, SMA_FBI is considered an optimization tool with great potential for dealing with global optimization problems, and its binary version, BSMA_FBI, can be used for GS tasks.

Abstract Background Thyroid nodule (TN) patients in China are subject to overdiagnosis and overtreatment. The implementation of existing technologies such as thyroid ultrasonography has indeed contributed to the improved diagnostic accuracy of TNs. However, a significant issue persists, where many patients undergo unnecessary biopsies, and patients with malignant thyroid nodules (MTNs) are advised to undergo surgery therapy. Methods This study included a total of 293 patients diagnosed with TNs. Differential methylation haplotype blocks (MHBs) in blood leukocytes between MTNs and benign thyroid nodules (BTNs) were detected using reduced representation bisulfite sequencing (RRBS). Subsequently, an artificial intelligence blood leukocyte DNA methylation (BLDM) model was designed to optimize the management and treatment of patients with TNs for more effective outcomes. Results The DNA methylation profiles of peripheral blood leukocytes exhibited distinctions between MTNs and BTNs. The BLDM model we developed for diagnosing TNs achieved an area under the curve (AUC) of 0.858 in the validation cohort and 0.863 in the independent test cohort. Its specificity reached 90.91% and 88.68% in the validation and independent test cohorts, respectively, outperforming the specificity of ultrasonography (43.64% in the validation cohort and 47.17% in the independent test cohort), albeit with a slightly lower sensitivity (83.33% in the validation cohort and 82.86% in the independent test cohort) compared to ultrasonography (97.62% in the validation cohort and 100.00% in the independent test cohort). The BLDM model could correctly identify 89.83% patients whose nodules were suspected malignant by ultrasonography but finally histological benign. In micronodules, the model displayed higher specificity (93.33% in the validation cohort and 92.00% in the independent test cohort) and accuracy (88.24% in the validation cohort and 87.50% in the independent test cohort) for diagnosing TNs. This performance surpassed the specificity and accuracy observed with ultrasonography. A TN diagnostic and treatment framework that prioritizes patients is provided, with fine-needle aspiration (FNA) biopsy performed only on patients with indications of MTNs in both BLDM and ultrasonography results, thus avoiding unnecessary biopsies. Conclusions This is the first study to demonstrate the potential of non-invasive blood leukocytes in diagnosing TNs, thereby making TN diagnosis and treatment more efficient in China.

Background Minichromosome maintenance complex component 3 (MCM3) plays a key role in various tumours. However, it remains largely unknown what the specific role and clinical significance of MCM3 in pancreatic adenocarcinoma (PAAD) are.Materials and Methods We integrated high-throughput data from PAAD worldwide to analyse the expression level of MCM3 mRNA. We used immunohistochemistry to analyse MCM3 protein expression levels in 145 cases in the PAAD group and 29 cases in the non-PAAD group. We also mainly analysed the necessity of MCM3 for PAAD growth based on CRISPR screen data. In addition, we used enrichment analysis and protein–protein interaction networks to explore the molecular mechanism of MCM3 in PAAD. We also analysed the correlation between MCM3 expression, components of the immune microenvironment in PAAD tissue and clinical prognosis.Results In PAAD, we observed for the first time that MCM3 was significantly highly expressed at both the mRNA (SMD = 0.67, 95% CI: 0.38 ∼ 0.96) and the protein level (p

AbstractAim: This comprehensive review aims to explore the potential applications of Gastrin-releasing peptide receptor (GRPR) in the diagnosis and treatment of prostate cancer. Additionally, the study investigates the role of GRPR in prognostic assessment for individuals afflicted with prostate cancer.Methods: The review encompasses a thorough examination of existing literature and research studies related to the upregulation of GRPR in various tumor types, with a specific focus on prostate. The review also evaluates the utility of GRPR as a molecular target in prostate cancer research, comparing its significance to the well-established Prostate-specific membrane antigen (PSMA). The integration of radionuclide-targeted therapy with GRPR antagonists is explored as an innovative therapeutic approach for individuals with prostate cancer.Results: Research findings suggest that GRPR serves as a promising molecular target for visualizing low-grade prostate cancer. Furthermore, it is demonstrated to complement the detection of lesions that may be negative for PSMA. The integration of radionuclide-targeted therapy with GRPR antagonists presents a novel therapeutic paradigm, offering potential benefits for individuals undergoing treatment for prostate cancer.Conclusions: In conclusion, this review highlights the emerging role of GRPR in prostate cancer diagnosis and treatment. Moreover, the integration of radionuclide-targeted therapy with GRPR antagonists introduces an innovative therapeutic approach that holds promise for improving outcomes in individuals dealing with prostate cancer. The potential prognostic value of GRPR in assessing the disease’s progression adds another dimension to its clinical significance in the realm of urology.

Objective Collect the characteristics of patients’ baseline data, and explore the predictive factors of late recurrence of atrial fibrillation (AF) after catheter ablation according to whether late recurrence or not. The purpose of this study was to determine the significance of the APPLE score in conjunction with the monocyte–high-density lipoprotein cholesterol ratio (MHR) in predicting the late recurrence of AF after catheter ablation in patients with AF.Methods Baseline data were collected to explore the predictors of late recurrence after AF catheter ablation. The receiver operating characteristic (ROC) curve and the area under the curve (AUC) were used to compare the predictive value of MHR, the APPLE score and their combined variables in the late recurrence of AF after catheter ablation.Results This is a retrospective study. A total of 438 patients were followed-up, including 303 cases of paroxysmal AF, 135 cases of persistent AF (28 cases of long-term persistent AF) and 115 cases of late recurrence. The Cox multivariate regression analysis revealed that MHR, the APPLE score and early recurrence were independent predictors of the late recurrence of AF. The AUC of the combined variables for predicting late recurrence after catheter ablation in patients with AF was higher than that of MHR and the APPLE score (p

Background Global public health is seriously threatened by the escalating issue of antimicrobial resistance (AMR). Antimicrobial peptides (AMPs), pivotal components of the innate immune system, have emerged as a potent solution to AMR due to their therapeutic potential. Employing computational methodologies for the prompt recognition of these antimicrobial peptides indeed unlocks fresh perspectives, thereby potentially revolutionizing antimicrobial drug development. Methods In this study, we have developed a model named as deepAMPNet. This model, which leverages graph neural networks, excels at the swift identification of AMPs. It employs structures of antimicrobial peptides predicted by AlphaFold2, encodes residue-level features through a bi-directional long short-term memory (Bi-LSTM) protein language model, and constructs adjacency matrices anchored on amino acids’ contact maps. Results In a comparative study with other state-of-the-art AMP predictors on two external independent test datasets, deepAMPNet outperformed in accuracy. Furthermore, in terms of commonly accepted evaluation matrices such as AUC, Mcc, sensitivity, and specificity, deepAMPNet achieved the highest or highly comparable performances against other predictors. Conclusion deepAMPNet interweaves both structural and sequence information of AMPs, stands as a high-performance identification model that propels the evolution and design in antimicrobial peptide pharmaceuticals. The data and code utilized in this study can be accessed at https://github.com/Iseeu233/deepAMPNet.

Summary: Background: Bivalent SARS-CoV-2 vaccines were developed to counter increasing susceptibility to emerging SARS-CoV-2 variants. We evaluated the durability of immunity and protection following first bivalent vaccination among nursing home residents. Methods: We evaluated anti-spike and neutralization titers from blood in 653 community nursing home residents before and after each monovalent booster, and a bivalent vaccine. Concurrent clinical outcomes were evaluated using electronic health record data from a separate cohort of 3783 residents of Veterans Affairs (VA) nursing homes who had received at least the primary series monovalent vaccination. Using target trial emulation, we compared VA residents who did and did not receive the bivalent vaccine to measure vaccine effectiveness against infection, hospitalization, and death. Findings: In the community cohort, Omicron BA.5 neutralization activity rose after each monovalent and bivalent booster vaccination regardless of prior infection history. Titers declined over time but six months post-bivalent vaccination, BA.5 neutralization persisted at detectable levels in 75% of infection-naive and 98% of prior-infected individuals. In the VA nursing home cohort, bivalent vaccine added effectiveness to monovalent booster vaccination by 18.5% for infection (95% confidence interval (CI) −5.6, 34.0%), and 29.2% for hospitalization or death (95% CI −14.2, 56.2%) over five months. Interpretation: The level of protection declined after bivalent vaccination over a 6 month period and may open a window of added vulnerability before the next updated vaccine becomes available, suggesting a subset of nursing home residents may benefit from an additional vaccination booster. Funding: CDC, NIH, VHA.

Abstract Introduction Salusins, which are translated from the alternatively spliced mRNA of torsin family 2 member A (TOR2A), play a vital role in regulation of various cardiovascular diseases. However, it remains unclear precisely regarding their roles in hypertrophic cardiomyopathy (HCM). Therefore, this study was conducted to explore therapeutic effect and the underlying mechanisms of salusins on HCM. Material and methods In vivo experiments, Sprague–Dawley rats were used to induce HCM model by angiotensin (Ang) II infusion for 4 weeks. The rats were randomly divided into four groups, namely, Saline + Control shRNA (n = 7), Ang II + Control shRNA (n = 8), Saline + TOR2A shRNA (n = 7), and Ang II + TOR2A shRNA groups (n = 8). After HCM induction, doppler echocardiography is recommended to evaluate heart function. In vitro experiments, primary neonatal rat cardiomyocytes (NRCMs) and cardiac fibroblasts (NRCFs) were obtained from newborn rats, and were treated with Ang II (10–6 M) for 24 h. Results After treatment with Ang II, levels of salusin-α and salusin-β were elevated in serum and cardiac tissues of rats and in the neonatal rat cardiomyocytes and cardiac fibroblasts. Downregulation of salusins alleviated the Ang II-induced cardiac hypertrophy by suppressing the increased atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) and beta-myosin heavy chain (β-MHC) and cardiac fibrosis by blocking collagen I, collagen III and transforming growth factor-beta (TGF-β), and it also attenuated oxidative stress by suppressing the increased reactive oxygen species (ROS) and malondialdehyde (MDA) levels and reversing the decreased superoxide dismutase (SOD) activity and autophagy by inhibiting the increased microtubule-associated protein light chain 3B (LC3B), Beclin1, autophagy related gene (Atg) 3 and Atg5 in the cardiac tissues of Ang II-infused rats and in the Ang II-treated NRCMs. Conclusions All these findings suggest that the levels of salusins were elevated in the HCM, and targeting of salusins contributes to alleviation of cardiac hypertrophy and fibrosis probably via attenuating oxidative stress and autophagy. Accordingly, targeting of salusins may be a strategy for HCM therapy.

Abstract Background Lipids are regulators of insulitis and β-cell death in type 1 diabetes development, but the underlying mechanisms are poorly understood. Here, we investigated how the islet lipid composition and downstream signaling regulate β-cell death. Methods We performed lipidomics using three models of insulitis: human islets and EndoC-βH1 β cells treated with the pro-inflammatory cytokines interlukine-1β and interferon-γ, and islets from pre-diabetic non-obese mice. We also performed mass spectrometry and fluorescence imaging to determine the localization of lipids and enzyme in islets. RNAi, apoptotic assay, and qPCR were performed to determine the role of a specific factor in lipid-mediated cytokine signaling. Results Across all three models, lipidomic analyses showed a consistent increase of lysophosphatidylcholine species and phosphatidylcholines with polyunsaturated fatty acids and a reduction of triacylglycerol species. Imaging assays showed that phosphatidylcholines with polyunsaturated fatty acids and their hydrolyzing enzyme phospholipase PLA2G6 are enriched in islets. In downstream signaling, omega-3 fatty acids reduce cytokine-induced β-cell death by improving the expression of ADP-ribosylhydrolase ARH3. The mechanism involves omega-3 fatty acid-mediated reduction of the histone methylation polycomb complex PRC2 component Suz12, upregulating the expression of Arh3, which in turn decreases cell apoptosis. Conclusions Our data provide insights into the change of lipidomics landscape in β cells during insulitis and identify a protective mechanism by omega-3 fatty acids. Video Abstract

Abstract Vaccines have proven effective in protecting populations against COVID-19, including the recombinant COVID-19 vaccine (Sf9 cells), the first approved recombinant protein vaccine in China. In this positive-controlled trial with 85 adult participants (Sf9 cells group: n = 44; CoronaVac group: n = 41), we evaluated the safety, immunogenicity, and protective effectiveness of a heterologous boost with the Sf9 cells vaccine in adults who had been vaccinated with the inactivated vaccine, and found a post-booster adverse events rate of 20.45% in the Sf9 cells group and 31.71% in the CoronaVac group (p = 0.279), within 28 days after booster injection. Neither group reported any severe adverse events. Following the Sf9 cells vaccine booster, the geometric mean titer (GMT) of binding antibodies to the receptor-binding domain of prototype SARS-CoV-2 on day 28 post-booster was significantly higher than that induced by the CoronaVac vaccine booster (100,683.37 vs. 9,451.69, p

Abstract Background Although great progress has been made in anti-cancer therapy, the prognosis of laryngeal squamous cell carcinoma (LSCC) patients remains unsatisfied. Quantities of studies demonstrate that glycolytic reprograming is essential for the progression of cancers, where triosephosphate isomerase 1 (TPI1) serves as a catalytic enzyme. However, the clinicopathological significance and potential biological functions of TPI1 underlying LSCC remains obscure. Methods We collected in-house 82 LSCC tissue specimens and 56 non-tumor tissue specimens. Tissue microarrays (TMA) and immunohistochemical (IHC) experiments were performed. External LSCC microarrays and bulk RNA sequencing data were integrated to evaluate the expression of TPI1. We used a log-rank test and the CIBERSORT algorithm to assess the prognostic value of TPI1 and its association with the LSCC microenvironment. Malignant laryngeal epithelial cells and immune-stromal cells were identified using inferCNV and CellTypist. We conducted a comprehensive analysis to elucidate the molecular functions of TPI1 in LSCC tissue and single cells using Pearson correlation analysis, high dimensional weighted gene co-expression analysis, gene set enrichment analysis, and clustered regularly interspaced short palindromic repeats (CRISPR) screen. We explored intercellular communication patterns between LSCC single cells and immune-stromal cells and predicted several therapeutic agents targeting TPI1. Results Based on the in-house TMA and IHC analysis, TPI1 protein was found to have a strong positive expression in the nucleus of LSCC cells but only weakly positive activity in the cytoplasm of normal laryngeal cells (p

Abstract Background Complement component 3a and its receptor (C3a/C3aR) and the nucleotide-binding oligomerization domain-like receptor protein-3 (NLRP3) inflammasome contribute to epithelial-mesenchymal transition (EMT). However, the relationship between C3a/C3aR and the NLRP3 inflammasome in EMT remains unclear. This study aimed to elucidate the roles of C3a/C3aR and the NLRP3 inflammasome involved in TGF-β-induced EMT. Method Mouse renal tubular epithelial cells (TCMK-1) were exposed to C3a and TGF-β for 48 h. C3aR antagonist, MCC950, an inhibitor of the NLRP3 inflammasome and PD98059, an inhibitor of ERK signaling, were respectively applied to pretreat the cells at 30 min before C3a and TGF-β administration.The cells were collected for western blot, immunofluorescence staining and ELISA. Unilateral ureteral obstruction (UUO) models were established using male C57BL/6 wild-type (WT) mice and age-matched C3aR-deficient mice. MCC950 was intraperitoneally injected in UUO mice. Kidney samples were collected for immunohistochemistry staining. Results In vitro, C3a synergized with TGF-β to promote EMT and the activation of the NLRP3 inflammasome. Inhibition of C3aR attenuated EMT and the activation of the NLRP3 inflammasome. Inhibition of the NLRP3 inflammasome alleviated EMT but didn’t affect the expression of C3aR. Inhibition of ERK signaling inhibited the activation of the NLRP3 inflammasome. In vivo, the expression of IL-1β was significantly higher in UUO mice compared to the sham-operated mice. C3aR deficiency and inhibition of the NLRP3 Inflammasome contributed to decreased IL-1β in UUO mice. Conclusion Our data revealed that C3a/C3aR synergies with TGF-β to activate the NLRP3 inflammasome to promote epithelial-mesenchymal transition of renal tubular epithelial cells through ERK signaling, and the way in which C3aR activates the inflammasome is to promote the assembly of the NLRP3 inflammasome.

Abstract This study aimed to predict the outcome of patient specific quality assurance (PSQA) in IMRT for breast cancer using complexity metrics, such as MU factor, MAD, CAS, MCS. Several breast cancer plans were considered, including LBCS, RBCS, LBCM, RBCM, left breast, right breast and the whole breast for both Edge and TrueBeam LINACS. Dose verification was completed by Portal Dosimetry (PD). The receiver operating characteristic (ROC) curve was employed to determine whether the treatment plans pass or failed. The area under the curve (AUC) was used to assess the classification performance. The correlation of PSQA and complexity metrics was examined using Spearman’s rank correlation coefficient (R s ). For LINACS, the most suitable complexity metric was found to be the MU factor (Edge R s = − 0.608, p

Abstract Background Advanced prostate cancer (PCa) will develop into castration-resistant prostate cancer (CRPC) and lead to poor prognosis. As the primary subtype of CRPC, CRPC-AR accounts for the major induction of PCa heterogeneity. CRPC-AR is mainly driven by 25 transcription factors (TFs), which we speculate may be the key factors driving PCa toward CRPC. Therefore, it is necessary to clarify the key regulator and its molecular mechanism mediating PCa progression. Methods Firstly, we downloaded transcriptomic data and clinical information from TCGA-PRAD. The characteristic gene cluster was identified by PPI clustering, GO enrichment, co-expression correlation and clinical feature analyses for 25 TFs. Then, the effects of 25 TFs expression on prognosis of PCa patients was analyzed using univariate Cox regression, and the target gene was identified. The expression properties of the target gene in PCa tissues were verified using tissue microarray. Meanwhile, the related mechanistic pathway of the target gene was mined based on its function. Next, the target gene was silenced by small interfering RNAs (siRNAs) for cellular function and mechanistic pathway validation. Finally, CIBERSORT algorithm was used to analyze the infiltration levels of 22 immune cells in PCa patients with low and high expression of target gene, and validated by assaying the expression of related immunomodulatory factor. Results We found that HOX family existed independently in 25 TFs, among which HOXC10, HOXC12 and HOXC13 had unique clinical features and the PCa patients with high HOXC13 expression had the worst prognosis. In addition, HOXC13 was highly expressed in tumor tissues and correlated with Gleason score and pathological grade. In vitro experiments demonstrated that silencing HOXC13 inhibited 22RV1 and DU145 cell function by inducing cellular DNA damage and activating cGAS/STING/IRF3 pathway. Immune infiltration analysis revealed that high HOXC13 expression suppressed infiltration of γδ T cells and plasma cells and recruited M2 macrophages. Consistent with these results, silencing HOXC13 up-regulated the transcriptional expression of IFN-β, CCL2, CCL5 and CXCL10. Conclusion HOXC13 regulates PCa progression by mediating the DNA damage-induced cGAS/STING/IRF3 pathway and remodels TIME through regulation of the transcription of the immune factors IFN-β, CCL2, CCL5 and CXCL10.

Acrylamide (AA) can be formed during the thermal processing of carbohydrate-rich foods. Deoxynivalenol (DON), a mycotoxin produced by Fusarium spp., contaminates many cereal-based products. In addition to potential co-exposure through a mixed diet, co-occurrence of AA and DON in thermally processed cereal-based products is also likely, posing the question of combinatory toxicological effects. In the present study, the effects of AA (0.001–3 mM) and DON (0.1–30 µM) on the cytotoxicity, gene transcription, and expression of major cytochrome P450 (CYP) enzymes were investigated in differentiated human hepatic HepaRG cells. In the chosen ratios of AA–DON (10:1; 100:1), cytotoxicity was clearly driven by DON and no overadditive effects were observed. Using quantitative real-time PCR, about twofold enhanced transcript levels of CYP1A1 were observed at low DON concentrations (0.3 and 1 µM), reflected by an increase in CYP1A activity in the EROD assay. In contrast, CYP2E1 and CYP3A4 gene transcription decreased in a concentration-dependent manner after incubation with DON (0.01–0.3 µM). Nevertheless, confocal microscopy showed comparably constant protein levels. The present study provided no indication of an induction of CYP2E1 as a critical step in AA bioactivation by co-occurrence with DON. Taken together, the combination of AA and DON showed no clear physiologically relevant interaction in HepaRG cells.

Background Contextual cueing refers to the phenomenon in which individuals utilize frequently encountered environmental contexts, comprised of distractors, as cues to expedite a target search. Due to the conflict between the widespread occurrence of contextual cue transfer and the observed impact of changing the identity of distractors on contextual cue learning, the content of contextual cue representations remains contentious. Considering the independent nature of contextual cue learning and expression, our proposition is twofold: (1) Contextual cue representations are stimulus-specific, and (2) their expression is highly flexible. Methods To validate the model, two experiments were conducted. Experiment 1 aimed to confirm the hypothesis that contextual cue representations are stimulus-specific. We manipulated the identity consistency of distractors within repeated scenes during contextual cue learning. Difficulty in contextual cue learning under the identity-changing condition would suggest the necessity of identity within contextual cue representation, indicating the stimulus-specific nature of these representations. Experiment 2 was designed to affirm the conclusion of Experiment 1 and explore the flexibility in the expression of contextual cue representations. This experiment comprised two phases: learning and testing. During the learning phase, participants were exposed to two sets of repeated scenes in different colors under two learning conditions: load and no-load. Working memory load was introduced to interfere with the expression to prevent it from becoming automatic. In the subsequent testing phase, the colors of the two scene sets were interchanged to impede retrieval based on identity. If both load and no-load conditions demonstrate similar levels of contextual cue effects during the testing phase, it implies the flexibility in the expression of contextual cue representations and confirms the conclusion of Experiment 1. Results In Experiment 1, a notable contextual cue learning effect was observed under the identity-consistent condition (p = 0.001). However, this effect was not evident under the identity-changing condition (p = 0.286). This finding strongly supports the stimulus-specific nature of contextual cue representation. In Experiment 2, the contextual cueing effect appeared but did not show a significant difference between the two conditions (t(23) = 0.02, p = 0.987, BF10 = 0.215), indicating the cognitive system’s ability to flexibly redefine retrieval cues. This adaptability aligns with our hypothesis and confirms the high flexibility in the expression process of contextual cue representations and confirms the conclusion of Experiment 1.