[Level and health evaluation of rare earth elements in human blood and hair in the mining areas in Northwest Hubei].

OBJECTIVE: To investigate the content of rare earth elements(REs)in blood and hair of residents in a RE mining area in Northwest Hubei, and evaluate the impact of REs on the health status of local residents. METHODS: A total of 191 residents from the core area of RE mining areas and 186 residents from non RE mining areas, aged 20-69, were selected. The content of REs in the blood and hair of the survey subjects was measured using inductively coupled plasma mass spectrometry, and compared with existing literature values. At the same time, blood tests and questionnaire surveys will be conducted on the health status of residents to examine whether human RE enrichment can lead to endemic diseases. RESULTS: The average total content of REs in the blood of residents in the mining area was 60.22 ng/mL, which was 3.35 times that of the control area; The average total content of REs in hair was 1197.91 ng/g, which was 6.32 times higher than the control area. As age increasing, the abundance of REs in the blood and hair of both men and women in mining areas increased. The proportion of Yttrium and Scandium in the blood and hair were much higher than that in the soil. Compared to hair, Yttrium and Scandium were more easily enriched in the blood. There was no significant difference in the probability of fatty liver, hepatitis B, hypoglycemia, hypotension, hypertension and heart disease and the average life span between residents in RE mining areas and those in the control area. CONCLUSION: The high daily average dietary intake of REs in residents leads to a relatively large accumulation of REs in human blood and hair, but no significant and substantial human health damage has been found at present.

Anthocyanins from blueberry ameliorated arsenic-induced memory impairment, oxidative stress, and mitochondrial-biosynthesis imbalance in rat hippocampal neurons.

In this study, blueberry anthocyanins extract (BAE) was used to investigate its protective effect on arsenic-induced rat hippocampal neurons damage. Arsenic exposure resulted in elevated levels of oxidative stress, decreased antioxidant capacity and increased apoptosis in rat hippocampal brain tissue and mitochondria. Immunohistochemical results showed that arsenic exposure also significantly decreased the expression of mitochondrial biosynthesis-related factors PGC-1α and TFAM. Treatment with BAE alleviated the decrease in antioxidant capacity, mitochondrial biogenesis related protein PGC-1α/NRF2/TFAM expression, and ATP production of arsenic induced hippocampal neurons in rats, and improved cognitive function in arsenic damaged rats. This study provides new insights into the detoxification effect of anthocyanins on the nervous system toxicity caused by metal exposure in the environment, indicating that anthocyanins may be a natural antioxidant against the nervous system toxicity caused by environmental metal exposure.

Influencing factors of corticomuscular coherence in stroke patients.

Stroke, also known as cerebrovascular accident, is an acute cerebrovascular disease with a high incidence, disability rate, and mortality. It can disrupt the interaction between the cerebral cortex and external muscles. Corticomuscular coherence (CMC) is a common and useful method for studying how the cerebral cortex controls muscle activity. CMC can expose functional connections between the cortex and muscle, reflecting the information flow in the motor system. Afferent feedback related to CMC can reveal these functional connections. This paper aims to investigate the factors influencing CMC in stroke patients and provide a comprehensive summary and analysis of the current research in this area. This paper begins by discussing the impact of stroke and the significance of CMC in stroke patients. It then proceeds to elaborate on the mechanism of CMC and its defining formula. Next, the impacts of various factors on CMC in stroke patients were discussed individually. Lastly, this paper addresses current challenges and future prospects for CMC.

Roles of Nucleolar Factor RCL1 in Itraconazole Resistance of Clinical Candida albicans Under Different Stress Conditions.

Purpose: RNA terminal phosphate cyclase like 1 (RCL1) undergoes overexpression during the immune response of Candida albicans following drug treatment. This study aims to investigate the expression levels of RCL1 in C. albicans under various stress conditions. Methods: Fifteen itraconazole (ITR)-resistant strains of clinical C. albicans, and one standard strain were employed for RCL1 sequencing, and mutations in RCL1 were analyzed. Subsequently, 14 out of the 15 ITR-resistant clinical strains and 14 clinical strains sensitive to ITR, fluconazole (FCA) as well as voriconazole (VRC) were cultured under diverse conditions. The expression of RCL1 ITR-resistant and sensitive C. albicans was then assessed using real-time quantitative PCR (RT-qPCR) assays. Results: Compared to the standard strain, three missense mutations (C6A, G10A, and A11T) were identified in the RCL1 gene of ITR-resistant C. albicans through successful forward sequencing. Additionally, using successful reverse sequencing, one synonymous mutation (C1T) and four missense mutations (C1T, A3T, A7G, and T8G) were found in the RCL1 gene of ITR-resistant C. albicans. RCL1 expression was significantly higher in ITR-resistant C. albicans than in sensitive strains under standard conditions (37°C, 0.03% CO2, pH 4.0). Low temperature (25°C) increased RCL1 expression in sensitive C. albicans while decreasing it in ITR-resistant strains. Elevated CO2 concentrations (5% CO2) had a negligible effect on RCL1 expression in sensitive C. albicans, but effectively reduced RCL1 level in ITR-resistant strains. Furthermore, a medium with a pH of 7 decreased the expression of RCL1 in both resistant and sensitive C. albicans. Conclusion: This study demonstrated that RCL1 mutations in ITR-resistant C. albicans, and variations in culture conditions significantly influence RCL1 expression in both ITR-resistant and sensitive C. albicans, thereby inducing alterations in the dimorphism of C. albicans.

Current advances and development strategies of targeting son of sevenless 1 (SOS1) in drug discovery.

The Son of Sevenless 1 (SOS1) guanine nucleotide exchange factor, prevalent across eukaryotic species, plays a pivotal role in facilitating the attachment of RAS protein to GTP, thereby regulating the activation of intracellular RAS proteins. This regulation is part of a feedback mechanism involving SOS1, which allows both activators and inhibitors of SOS1 to exert control over downstream signaling pathways, demonstrating potential anti-tumor effects. Predominantly, small molecule modulators that target SOS1 focus on a hydrophobic pocket within the CDC25 protein domain. The effectiveness of these modulators largely depends on their ability to interact with specific amino acids, notably Phe890 and Tyr884. This interaction is crucial for influencing the protein-protein interaction (PPI) between RAS and the catalytic domain of SOS1. Currently, most small molecule modulators targeting SOS1 are in the preclinical research phase, with a few advancing to clinical trials. This progression raises safety concerns, making the assurance of drug safety a primary consideration alongside the enhancement of efficacy in the development of SOS1 modulators. This review encapsulates recent advancements in the chemical categorization of SOS1 inhibitors and activators. It delves into the evolution of small molecule modulation targeting SOS1 and offers perspectives on the design of future generations of selective SOS1 small molecule modulators.

Research progress of DDR1 inhibitors in the treatment of multiple human diseases.

Discoidin domain receptor 1 (DDR1) is a collagen-activated receptor tyrosine kinase (RTK) and plays pivotal roles in regulating cellular functions such as proliferation, differentiation, invasion, migration, and matrix remodeling. DDR1 is involved in the occurrence and progression of many human diseases, including cancer, fibrosis, and inflammation. Therefore, DDR1 represents a highly promising therapeutic target. Although no selective small-molecule inhibitors have reached clinical trials to date, many molecules have shown therapeutic effects in preclinical studies. For example, BK40143 has demonstrated significant promise in the therapy of neurodegenerative diseases. In this context, our perspective aims to provide an in-depth exploration of DDR1, encompassing its structure characteristics, biological functions, and disease relevance. Furthermore, we emphasize the importance of understanding the structure-activity relationship of DDR1 inhibitors and highlight the unique advantages of dual-target or multitarget inhibitors. We anticipate offering valuable insights into the development of more efficacious DDR1-targeted drugs.

Gene‒environment interaction effect of hypothalamic‒pituitary‒adrenal axis gene polymorphisms and job stress on the risk of sleep disturbances.

Background: Studies have shown that chronic exposure to job stress may increase the risk of sleep disturbances and that hypothalamic‒pituitary‒adrenal (HPA) axis gene polymorphisms may play an important role in the psychopathologic mechanisms of sleep disturbances. However, the interactions among job stress, gene polymorphisms and sleep disturbances have not been examined from the perspective of the HPA axis. This study aimed to know whether job stress is a risk factor for sleep disturbances and to further explore the effect of the HPA axis gene × job stress interaction on sleep disturbances among railway workers. Methods: In this cross-sectional study, 671 participants (363 males and 308 females) from the China Railway Fuzhou Branch were included. Sleep disturbances were evaluated with the Pittsburgh Sleep Quality Index (PSQI), and job stress was measured with the Effort-Reward Imbalance scale (ERI). Generalized multivariate dimensionality reduction (GMDR) models were used to assess gene‒environment interactions. Results: We found a significant positive correlation between job stress and sleep disturbances (P < 0.01). The FKBP5 rs1360780-T and rs4713916-A alleles and the CRHR1 rs110402-G allele were associated with increased sleep disturbance risk, with adjusted ORs (95% CIs) of 1.75 [1.38-2.22], 1.68 [1.30-2.18] and 1.43 [1.09-1.87], respectively. However, the FKBP5 rs9470080-T allele was a protective factor against sleep disturbances, with an OR (95% CI) of 0.65 [0.51-0.83]. GMDR analysis indicated that under job stress, individuals with the FKBP5 rs1368780-CT, rs4713916-GG, and rs9470080-CT genotypes and the CRHR1 rs110402-AA genotype had the greatest risk of sleep disturbances. Conclusions: Individuals carrying risk alleles who experience job stress may be at increased risk of sleep disturbances. These findings may provide new insights into stress-related sleep disturbances in occupational populations.

Inhibition of PTEN promotes osteointegration of titanium implants in type 2 diabetes by enhancing anti-inflammation and osteogenic capacity of adipose-derived stem cells.

Background: The low osteogenic differentiation potential and attenuated anti-inflammatory effect of adipose-derived stem cells (ADSCs) from animals with type 2 diabetes mellitus (T2DM) limits osseointegration of the implant. However, the underlying mechanisms are not fully understood. Methods: Western blotting and qRT-PCR analyses were performed to investigate the effects of PTEN on the osteogenic capacity of ADSCs of T2DM rats (TADSCs). We conducted animal experiments in T2DM-Sprague Dawley (SD) rats to evaluate the osteogenic capacity of modified TADSC sheets in vivo. New bone formation was assessed by micro-CT and histological analyses. Results: In this study, adipose-derived stem cells of T2DM rats exhibited an impaired osteogenic capacity. RNA-seq analysis showed that PTEN mRNA expression was upregulated in TADSCs, which attenuated the osteogenic capacity of TADSCs by inhibiting the AKT/mTOR/HIF-1α signaling pathway. miR-140-3p, which inhibits PTEN, was suppressed in TADSCs. Overexpression or inhibition of PTEN could correspondingly reduce or enhance the osteogenic ability of TADSCs by regulating the AKT/mTOR/HIF-1α signaling pathway. TADSCs transfected with PTEN siRNA resulted in higher and lower expressions of genes encoded in M2 macrophages (Arg1) and M1 macrophages (iNOS), respectively. In the T2DM rat model, PTEN inhibition in TADSC sheets promoted macrophage polarization toward the M2 phenotype, attenuated inflammation, and enhanced osseointegration around implants. Conclusion: Upregulation of PTEN, which was partially due to the inhibition of miR-140-3p, is important for the attenuated osteogenesis by TADSCs owing to the inhibition of the AKT/mTOR/HIF-1α signaling pathway. Inhibition of PTEN significantly improves the anti-inflammatory effect and osteogenic capacity of TADSCs, thus promoting peri-implant bone formation in T2DM rats. Our findings offer a potential therapeutic approach for modifying stem cells derived from patients with T2DM to enhance osseointegration.

ViComp: Video Compensation for Projector-Camera Systems.

Projector video compensation aims to cancel the geometric and photometric distortions caused by non-ideal projection surfaces and environments when projecting videos. Most existing projector compensation methods start by projecting and capturing a set of sampling images, followed by an offline compensation model training step. Thus, abundant user effort is required before the users can watch the video. Moreover, the sampling images have little prior knowledge of the video content and may lead to suboptimal results. To address these issues, this paper builds a video compensation system that can online adapt the compensation parameters. Our approach consists of five threads and can perform compensation, projection, capturing, and short-term and long-term model updates in parallel. Due to the parallel mechanism, rather than projecting and capturing hundreds of sampling images and training the model offline, we can directly use the projected and captured video frames for model updates on the fly. To quickly apply to the new environment, we introduce a deep learning-based compensation model that integrates a fixed transformer-based method and a novel CNN-based network. Moreover, for fast convergence and to reduce error accumulation during fine-tuning, we present a strategy that cooperates with short-term and long-term memory model updates. Experiments show that it significantly outperforms state-of-the-art baselines.

Psychodynamic profiles of major depressive disorder and generalized anxiety disorder in China.

Traditional clinical diagnoses relying on symptoms may overlook latent factors that illuminate mechanisms and potentially guide treatment. The Operationalized Psychodynamic Diagnosis (OPD) system may compensate for symptom-based diagnosis by measuring psychodynamic profiles underlying mental disorders through conflicts and structure axes. However, OPD has not been widely adopted in China, and it remains unclear whether OPD can be used as an effective approach to distinguish between depression and anxiety. The current study aims to adopt the OPD system to investigate the psychodynamic profiles of major depressive disorder (MDD) and generalized anxiety disorder (GAD) in China, targeting patients with "pure" symptoms without comorbidity. We recruited 42 MDD patients, 32 GAD patients, and 31 healthy controls (HC), and assessed their self-report depression and anxiety symptoms, along with their underlying psychodynamic profiles through OPD interviews. Overall, both MDD and GAD patients showed more prominent conflict issues and lower levels of structure than HC. The MDD and GAD groups yielded different conflict profiles and conflict processing modes when processing their second conflicts. Importantly, the multi-dimensional psychodynamic profiles achieved machine learning classification of clinical groups with an accuracy of 0.84, supporting successful distinction of MDD and GAD patients. In conclusion, the OPD demonstrated sensitivity in revealing distinct psychodynamic profiles underlying "pure" depression and anxiety clinical populations in China. This work calls for future incorporation of OPD as a tool to investigate psychodynamic formulations underlying mental disorders, compensating for traditional symptom-based diagnostic approaches to guide precise individualized interventions.

What influences the activity of Degrader-Antibody conjugates (DACs).

The targeted protein degradation (TPD) technology employing proteolysis-targeting chimeras (PROTACs) has been widely applied in drug chemistry and chemical biology for the treatment of cancer and other diseases. PROTACs have demonstrated significant advantages in targeting undruggable targets and overcoming drug resistance. However, despite the efficient degradation of targeted proteins achieved by PROTACs, they still face challenges related to selectivity between normal and cancer cells, as well as issues with poor membrane permeability due to their substantial molecular weight. Additionally, the noteworthy toxicity resulting from off-target effects also needs to be addressed. To solve these issues, Degrader-Antibody Conjugates (DACs) have been developed, leveraging the targeting and internalization capabilities of antibodies. In this review, we elucidates the characteristics and distinctions between DACs, and traditional Antibody-drug conjugates (ADCs). Meanwhile, we emphasizes the significance of DACs in facilitating the delivery of PROTACs and delves into the impact of various components on DAC activity. These components include antibody targets, drug-antibody ratio (DAR), linker types, PROTACs targets, PROTACs connections, and E3 ligase ligands. The review also explores the suitability of different targets (antibody targets or PROTACs targets) for DACs, providing insights to guide the design of PROTACs better suited for antibody conjugation.

Preparation of nanocellulose light porous material adsorbed with tannic acid and its application in fresh-keeping pad.

This study fabricated nanocellulose lightweight porous material (TOCNF-G-LPM-TA) as absorbent fresh-keeping pad for meat products, using TEMPO-oxidized cellulose nanofibril (TOCNF) and gelatin as structural skeleton and tannic acid (TA) as antibacterial component of TOCNF lightweight porous material (TOCNF-G-LPM). The adsorption kinetics, capacity and mechanism of TOCNF-G-LPM in different initial concentrations of TA solutions were investigated, the antioxidant and antibacterial properties of TOCNF-G-LPM-TA and its fresh-keeping effect on refrigerated pork at 4 ℃ were studied. Due to strong hydrogen bonding and porous structure, TOCNF-G-LPM exhibited excellent TA adsorption ability (230 mg/g) conforming with pseudo-second-order kinetic and Langmuir isotherm models. TA endowed TOCNF-G-LPM with good antioxidant and antibacterial activities. According to changes in appearance, pH and TVB-N values of pork during storage at 4 ℃, TOCNF-G-LPM-TA effectively extended the shelf life of refrigerated pork. This work provides a facile method for preparing nanocellulose based absorbent fresh-keeping pads.

Design, Synthesis, and Biological Evaluation of Dual Inhibitors of EGFRL858R/T790M/ACK1 to Overcome Osimertinib Resistance in Nonsmall Cell Lung Cancers.

Activation of the alternative pathways and abnormal signaling transduction are frequently observed in third-generation EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors)-resistant patients. Wherein, hyperphosphorylation of ACK1 contributes to EGFR-TKIs acquired resistance. Dual inhibition of EGFRL858R/T790M and ACK1 might improve therapeutic efficacy and overcome resistance in lung cancers treatment. Here, we identified a EGFRL858R/T790M/ACK1 dual-targeting compound 21a with aminoquinazoline scaffold, which showed excellent inhibitory activities against EGFRL858R/T790M (IC50 = 23 nM) and ACK1 (IC50 = 263 nM). The cocrystal and docking analysis showed that 21a occupied the ATP binding pockets of EGFRL858R/T790M and ACK1. Moreover, 21a showed potent antiproliferative activities against the H1975 cells, MCF-7 cells and osimertinib-resistant cells AZDR. Further, 21a showed significant antitumor effects and good safety in ADZR xenograft-bearing mice. Taken together, 21a was a potent dual inhibitor of EGFRL858R/T790M/ACK1, which is deserved as a potential lead for overcoming acquired resistance to osimertinib during the EGFR-targeted therapy.

Non-IL-2-blocking anti-CD25 antibody inhibits tumor growth by depleting Tregs and has synergistic effects with anti-CTLA-4 therapy.

CD25, also known as the interleukin-2 receptor α chain (IL-2Rα), is highly expressed on regulatory T cells (Tregs), but relatively lower on effector T cells (Teffs). This makes it a potential target for Treg depletion, which can be used in tumor immunotherapy. However, marketed anti-CD25 antibodies (Basiliximab and Daclizumab) were originally developed as immunosuppressive drugs to prevent graft rejection, because these antibodies can block IL-2 binding to CD25 on Teffs, which in turn destroys the function of Teffs. Recent studies have shown that non-IL-2-blocking anti-CD25 antibodies have displayed exciting antitumor effects. Here, we screened out a non-IL-2-blocking anti-CD25 monoclonal antibody (mAb) 7B7 by hybridoma technology, and confirmed its antitumor activity via depleting Tregs in a CD25 humanized mouse model. Subsequently, we verified that the humanized 7B7, named as h7B7-15S, has comparable activities to 7B7, and that its Treg depletion is further increased when combined with anti-CTLA-4, leading to enhanced remodeling of the tumor immune microenvironment. Moreover, our findings reveal that the Fab form of h7B7-15S has the ability to deplete Tregs, independent of the Fc region. Taken together, our studies expand the application of anti-CD25 in tumor immunotherapy and provide insight into the underlying mechanism.

U2-Net and ResNet50-Based Automatic Pipeline for Bacterial Colony Counting.

In this paper, an automatic colony counting system based on an improved image preprocessing algorithm and convolutional neural network (CNN)-assisted automatic counting method was developed. Firstly, we assembled an LED backlighting illumination platform as an image capturing system to obtain photographs of laboratory cultures. Consequently, a dataset was introduced consisting of 390 photos of agar plate cultures, which included 8 microorganisms. Secondly, we implemented a new algorithm for image preprocessing based on light intensity correction, which facilitated clearer differentiation between colony and media areas. Thirdly, a U2-Net was used to predict the probability distribution of the edge of the Petri dish in images to locate region of interest (ROI), and then threshold segmentation was applied to separate it. This U2-Net achieved an F1 score of 99.5% and a mean absolute error (MAE) of 0.0033 on the validation set. Then, another U2-Net was used to separate the colony region within the ROI. This U2-Net achieved an F1 score of 96.5% and an MAE of 0.005 on the validation set. After that, the colony area was segmented into multiple components containing single or adhesive colonies. Finally, the colony components (CC) were innovatively rotated and the image crops were resized as the input (with 14,921 image crops in the training set and 4281 image crops in the validation set) for the ResNet50 network to automatically count the number of colonies. Our method achieved an overall recovery of 97.82% for colony counting and exhibited excellent performance in adhesion classification. To the best of our knowledge, the proposed "light intensity correction-based image preprocessing→U2-Net segmentation for Petri dish edge→U2-Net segmentation for colony region→ResNet50-based counting" scheme represents a new attempt and demonstrates a high degree of automation and accuracy in recognizing and counting single-colony and multi-colony targets.

Plant-derived monoterpene S-linalool and ß-ocimene generated by CsLIS and CsOCS-SCZ are key chemical cues for attracting parasitoid wasps for suppressing Ectropis obliqua infestation in Camellia sinensis L.

Insect-induced plant volatile organic compounds (VOCs) may function as either direct defence molecules to deter insects or indirect defence signals to attract the natural enemies of the invading insects. Tea (Camellia sinensis L.), an important leaf-based beverage crop, is mainly infested by Ectropis obliqua which causes the most serious damage. Here, we report a mechanistic investigation of tea plant-derived VOCs in an indirect defence mechanism against E. obliqua. Parasitoid wasp Parapanteles hyposidrae, a natural enemy of E. obliqua, showed strong electrophysiological response and selection behaviour towards S-linalool and ß-ocimene, two monoterpenes with elevated emission from E. obliqua-damaged tea plants. Larvae frass of E. obliqua, which also released S-linalool and ß-ocimene, was found to attract both mated female or male Pa. hyposidrae according to gas chromatography-electroantennogram detection and Y-tube olfactometer assays. In a field setting, both S-linalool and ß-ocimene were effective in recruiting both female and male Pa. hyposidrae wasps. To understand the molecular mechanism of monoterpenes-mediated indirect defence in tea plants, two novel monoterpene synthase genes, CsLIS and CsOCS-SCZ, involved in the biosynthesis of S-linalool or ß-ocimene, respectively, were identified and biochemically characterised. When the expression of these two genes in tea plants was inhibited by antisense oligodeoxynucleotide, both volatile emission and attraction of wasps were reduced. Furthermore, gene expression analysis suggested that the expression of CsLIS and CsOCS-SCZ is regulated by the jasmonic acid signalling pathway in the tea plant.

C-X-C motif chemokine receptor 4 inhibition promotes the effect of plantamajoside in hepatocellular carcinoma.

BACKGROUND AND STUDY AIM: Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related mortality worldwide, and, more than half of these cases are diagnosed in China. However, effective treatment for HCC is still limited. MATERIAL AND METHODS: C-X-C motif chemokine receptor 4 (CXCR4) was first activated and inhibited in HepG2 cells using a pharmacological method. HepG2 cell proliferation was detected using the CCK-8 method. Metastasis and apoptosis of HepG2 cells were detected using wound healing and flow cytometry. The expression of each target molecule related to metastasis and invasion, such as MMPs, E-cadherin and the PI3K/AKT/Mcl-1/PARP signaling pathway was detected by western blotting. The secretion of molecular metastases was detected using competitive ELISA. RESULTS: This study constructed a CXCR4 activation and inhibition model in HepG2 cells. CXCR4 inhibition promoted the inhibitory effect of plantamajoside on the proliferation and metastasis of cells, which led to apoptosis. Furthermore, we found that the expression of apoptosis-related proteins was increased after treatment with plantamajoside combined with CXCR4 inhibition. In addition, the expression and secretion of pro-metastatic proteins, including MMPs and E-cadherin were decreased. We also noticed that this effect might be mediated by the PI3K/AKT/Mcl-1/PARP signaling pathway. CONCLUSION: CXCR4 inhibition may contribute to the treatment of HCC. Inhibition of CXCR4 expression contributes to the therapeutic effect of plantamajoside; the effect of plantamajoside might be mediated by the PI3K/AKT/Mcl-1/PARP signaling pathway; and CXCR4 might be a therapeutic target of HCC.

Exploring the adverse effects of 1,3,6,8-tetrabromo-9H-carbazole in atherosclerotic model mice by metabolomic profiling integrated with mechanism studies in vitro.

Given its wide distribution in the environment and latent toxic effects, 1,3,6,8-tetrabromo-9H-carbazole (1368-BCZ) is an emerging concern that has gained increasing attention globally. 1368-BCZ exposure is reported to have potential cardiovascular toxicity. Although atherosclerosis is a cardiovascular disease and remains a primary cause of mortality worldwide, no evidence has been found regarding the impact of 1368-BCZ on atherosclerosis. Therefore, we aimed to explore the deleterious effects of 1368-BCZ on atherosclerosis and the underlying mechanisms. Serum samples from 1368-BCZ-treated atherosclerotic model mice were subjected to metabolomic profiling to investigate the adverse influence of the pollutant. Subsequently, the molecular mechanism associated with the metabolic pathway of atherosclerotic mice that was identified following 1368-BCZ exposure was validated in vitro. Serum metabolomics analysis revealed that 1368-BCZ significantly altered the tricarboxylic acid cycle, causing a disturbance in energy metabolism. In vitro, we further validated general markers of energy metabolism based on metabolome data: 1368-BCZ dampened adenosine triphosphate (ATP) synthesis and increased reactive oxygen species (ROS) production. Furthermore, blocking the aryl hydrocarbon receptor (AhR) reversed the high production of ROS induced by 1368-BCZ. It is concluded that 1368-BCZ decreased the ATP synthesis by disturbing the energy metabolism, thereby stimulating the AhR-mediated ROS production and presumably causing aggravated atherosclerosis. This is the first comprehensive study on the cardiovascular toxicity and mechanism of 1368-BCZ based on rodent models of atherosclerosis and integrated with in vitro models.

Quantifying mitochondrial heteroplasmy diversity: A computational approach.

Biodiversity plays a pivotal role in sustaining ecosystem processes, encompassing diverse biological species, genetic types and the intricacies of ecosystem composition. However, the precise definition of biodiversity at the individual level remains a challenging endeavour. Hill numbers, derived from Rényi's entropy, have emerged as a popular measure of diversity, with a recent unified framework extending their application across various levels, from genetics to ecosystems. In this study, we employ a computational approach to exploring the diversity of mitochondrial heteroplasmy using real-world data. By adopting Hill numbers with q = 2, we demonstrate the feasibility of quantifying mitochondrial heteroplasmy diversity within and between individuals and populations. Furthermore, we investigate the alpha diversity of mitochondrial heteroplasmy among different species, revealing heterogeneity at multiple levels, including mitogenome components and protein-coding genes (PCGs). Our analysis explores large-scale mitochondrial heteroplasmy data in humans, examining the relationship between alpha diversity at the mitogenome components and PCGs level. Notably, we do not find a significant correlation between these two levels. Additionally, we observe significant correlations in alpha diversity between mothers and children in blood samples, exceeding the reported R2 value for allele frequency correlations. Moreover, our investigation of beta diversity and local overlay similarity demonstrates that heteroplasmy variant distributions in different tissues of children more closely resemble those of their mothers. Through systematic quantification and analysis of mitochondrial heteroplasmy diversity, this study enhances our understanding of heterogeneity at multiple levels, from individuals to populations, providing new insights into this fundamental dimension of biodiversity.