Tryptophan deficiency induced by indoleamine 2,3-dioxygenase 1 results in glucose transporter 1-dependent promotion of aerobic glycolysis in pancreatic cancer.

Indoleamine 2,3-dioxygenase 1 (IDO1), the key enzyme in the catabolism of the essential amino acid tryptophan (Trp) through kynurenine pathway, induces immune tolerance and is considered as a critical immune checkpoint, but its impacts as a metabolism enzyme on glucose and lipid metabolism are overlooked. We aim to clarify the potential role of IDO1 in aerobic glycolysis in pancreatic cancer (PC). Analysis of database revealed the positive correlation in PC between the expressions of IDO1 and genes encoding important glycolytic enzyme hexokinase 2 (HK2), pyruvate kinase (PK), lactate dehydrogenase A (LDHA) and glucose transporter 1 (GLUT1). It was found that IDO1 could modulate glycolysis and glucose uptake in PC cells, Trp deficiency caused by IDO1 overexpression enhanced glucose uptake by stimulating GLUT1 translocation to the plasma membrane of PC cells. Besides, Trp deficiency caused by IDO1 overexpression suppressed the apoptosis of PC cells via promoting glycolysis, which reveals the presence of IDO1-glycolysis-apoptosis axis in PC. IDO1 inhibitors could inhibit glycolysis, promote apoptosis, and exhibit robust therapeutic efficacy when combined with GLUT1 inhibitor in PC mice. Our study reveals the function of IDO1 in the glucose metabolism of PC and provides new insights into the therapeutic strategy for PC.

Functionalized PLGA Microsphere Loaded with Fusion Peptide for Therapy of Bone Defects.

The challenges in the treatment of extensive bone defects are infection control and bone regeneration. Bone tissue engineering is currently one of the most promising strategies. In this study, a short biopeptide with specific osteogenic ability is designed by fusion peptide technology and encapsulated with chitosan-modified poly(lactic acid-glycolic acid) (PLGA) microspheres. The fusion peptide (FP) mainly consists of an osteogenic functional sequence (P-15) and a bone-specific binding sequence (Asp-6), which can regulate bone formation accurately and efficiently. Chitosan-modified PLGA with antimicrobial and pro-healing effects is used to achieve the sustained release of fusion peptides. In the early stage, the antimicrobial and soft tissue healing effects can stop the wound infection as soon as possible, which is relevant for the subsequent bone regeneration process. Our data show that CS-PLGA@FP microspheres have antibacterial and pro-cell migration effects in vitro and excellent pro-wound-healing effects in vivo. In addition, CS-PLGA@FP microspheres promote the expression of osteogenic-related factors and show excellent bone regeneration in a rat defect model. Therefore, CS-PLGA@FP microspheres are an efficient biomaterial that can accelerate the recovery of bone defects.

SNHG14 Elevates NFAT5 Expression Through Sequestering miR-375-3p to Promote MPP + -Induced Neuronal Apoptosis, Inflammation, and Oxidative Stress in Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the loss of dopaminergic neurons. LncRNA small nucleolar RNA host gene 14 (SNHG14) was found to promote neuron injury in PD. Here, we investigated the mechanisms of SNHG14 in PD process. In vivo or in vitro PD model was established by using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mice or 1-methyl-4-phenylpyridinium (MPP +)-stimulated SK-N-SH cells. The expression of genes and proteins was measured by qRT-PCR and Western blot. In vitro assays were conducted using ELISA, CCK-8, colony formation, EdU, flow cytometry, and Western blot assays, respectively. The oxidative stress was evaluated by determining the production of superoxide dismutase (SOD) and malondialdehyde (MDA). The direct interactions between miR-375-3p and NFAT5 (Nuclear factor of activated T-cells 5) or SNHG14 was verified using dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. SNHG14 and NFAT5 were elevated, while miR-375-3p was decreased in MPTP-mediated PD mouse model and MPP + -induced SK-N-SH cells. Knockdown of SNHG14 or NFAT5, or overexpression of miR-375-3p reversed MPP + -induced neuronal apoptosis, inflammation, and oxidative stress. Mechanistically, SNHG14 directly bound to miR-375, which targeted NFAT5. Inhibition of miR-375-3p abolished the inhibitory activity of SNHG14 knockdown on MPP + -evoked neuronal damage. Besides that, NFAT5 up-regulation counteracted the effects of miR-375-3p on MPP + -mediated neuronal damage. SNHG14 contributed to MPP + -induced neuronal injury by miR-375/NFAT5 axis, suggesting a new insight into the pathogenesis of PD.

Biochar's dual role in greenhouse gas emissions: Nitrogen fertilization dependency and mitigation potential.

Biochar was popularly used for reducing greenhouse gas (GHG) emissions in vegetable production, but using biochar does not necessarily guarantee a reduction in GHG emissions. Herein, it's meaningful to elucidate the intricate interplay among biochar properties, soil characteristics, and GHG emissions in vegetable production to provide valuable insights for informed and effective mitigation strategies. Therefore, in current research, a meta-analysis of 43 publications was employed to address these issues. The boost-regression analysis results indicated that the performance of biochar in inhibiting N2O emissions was most affected by the N application rate both in high and low N application conditions. Besides, biochar had dual roles and showed well performance in reducing GHG emissions under low N input (≤300 kg N ha-1), while having the opposite effect during high N input (>300 kg N ha-1). Specifically, applying biochar under low N fertilization input could obviously reduce soil N2O emissions, CO2 emissions, and CH4 emissions by 18.7 %, 17.9 %, and 16.9 %, respectively. However, the biochar application under high N fertilization input significantly (P < 0.05) increased soil N2O emissions, CO2 emissions, and CH4 emissions by 39.7 %, 43.0 %, and 27.7 %, respectively. Except for the N application rate, the soil pH, SOC, biochar C/N ratio, biochar pH, and biochar pyrolysis temperature are also the key factors affecting the control of GHG emissions in biochar-amended soils. The findings of this study will contribute to deeper insights into the potential application of biochar in regulating GHG under consideration of N input, offering scientific evidence and guidance for sustainable agriculture management.

Effects of Near-Freezing Temperature Combined with Jujube Polysaccharides Treatment on Proteomic Analysis of 'Diaogan' Apricot (Prunus armeniaca L.).

This study involved the extraction of polysaccharides from jujube for application in apricot storage. Although near-freezing temperature (NFT) storage is commonly employed for preserving fresh fruit, its effectiveness is somewhat limited. Incorporating jujube polysaccharides was proposed to augment the preservative effect on apricots. Our findings demonstrated that the combined use of NFT and jujube polysaccharides can maintain fruit color, and effectively inhibit decay. Additionally, Tandem Mass Tag (TMT) quantitative proteomic technology was utilized to analyze protein variations in 'Diaogan' apricots during storage. This dual approach not only markedly lowered the activity of polyphenol cell wall-degrading enzymes (p < 0.05) but also revealed 1054 differentially expressed proteins (DEPs), which are related to sugar and energy metabolism, stress response and defense, lipid metabolism, and cell wall degradation. The changes in DEPs indicated that the combined use of NFT and jujube polysaccharides could accelerate the conversion of malic acid to oxaloacetic acid and regulate antioxidant ability, potentially extending the storage lifespan of apricot fruit.

An advanced treatment process for 3-high wastewater discharged from crude oil storage tanks.

The wastewater discharged from crude oil storage tanks (WCOST) contains high concentrations of salt and metal iron ions, and high chemical oxygen demand (COD). It belongs to "3-high" wastewater, which is difficult for purification. In this study, WCOST treatments were comparatively investigated via an advanced pretreatment and the traditional coagulation-microfiltration (CMF) processes. After WCOST was purified through the conventional CMF process, fouling occurred in the microfiltration (MF) membrane, which is rather harmful to the following reverse osmosis (RO) membrane unit, and the effluent featured high COD and UV254 values. The analysis confirmed that the MF fouling was due to the oxidation of ferrous ions, and the high COD and UV254 values were mainly attributable to the organic compounds with small molecular sizes, including aromatic-like and fulvic-like compounds. After the pretreatment of the advanced process consisting of aeration, manganese sand filtration, and activated carbon adsorption in combination with CMF process, the removal efficiencies of organic matter and total iron ions reached 97.3% and 99.8%, respectively. All the water indexes of the effluent, after treatment by the advanced multi-unit process, meet well the corresponding standard. The advanced pretreatment process reported herein displayed a great potential for alleviating the MF membrane fouling and enhanced the lifetime of the RO membrane system in the 3-high WCOST treatment.

Research on rainy day traffic sign recognition algorithm based on PMRNet.

The recognition of traffic signs is of great significance to intelligent driving and traffic systems. Most current traffic sign recognition algorithms do not consider the impact of rainy weather. The rain marks will obscure the recognition target in the image, which will lead to the performance degradation of the algorithm, a problem that has yet to be solved. In order to improve the accuracy of traffic sign recognition in rainy weather, we propose a rainy traffic sign recognition algorithm. The algorithm in this paper includes two modules. First, we propose an image deraining algorithm based on the Progressive multi-scale residual network (PMRNet), which uses a multi-scale residual structure to extract features of different scales, so as to improve the utilization rate of the algorithm for information, combined with the Convolutional long-short term memory (ConvLSTM) network to enhance the algorithm's ability to extract rain mark features. Second, we use the CoT-YOLOv5 algorithm to recognize traffic signs on the recovered images. In this paper, in order to improve the performance of YOLOv5 (You-Only-Look-Once, YOLO), the 3 × 3 convolution in the feature extraction module is replaced by the Contextual Transformer (CoT) module to make up for the lack of global modeling capability of Convolutional Neural Network (CNN), thus improving the recognition accuracy. The experimental results show that the deraining algorithm based on PMRNet can effectively remove rain marks, and the evaluation indicators Peak Signal-to-Noise Ratio (PSNR) and Structural Similarity Index Measure (SSIM) are better than the other representative algorithms. The mean Average Precision (mAP) of the CoT-YOLOv5 algorithm on the TT100k datasets reaches 92.1%, which is 5% higher than the original YOLOv5.

The biomineralization of silica induced stress tolerance in plants: a case study for aluminum toxicity.

Biomineralization in plant roots refers to the process of cell-induced self-assembly to form nanostructures on the root surface. Silicon (Si) is the second most abundant element in soils, and beneficial to plant growth. Meanwhile, silicon is shown to participate in the process of biomineralization, which is useful for improving mechanical strength and alleviating biotic and abiotic stress, for example silicic acid polymerizes to form amorphous silica (SiO2-nH2O) in the process of growing to resist fungi and environmental stress. This process alters physical and chemical properties of cell wall. However, the mechanistic basis of this process remains unclear. Aluminum toxicity is a major constraint affecting plant performance in acid soil. This paper summarizes recent research advances in the field of plant biomineralization and describes the effects of silicon biomineralization on plant aluminum tolerance and its adaptive significance, using aluminum toxicity as a case study.

Classification related to immunogenic cell death predicts prognosis, immune microenvironment characteristics, and response to immunotherapy in lower-grade gliomas.

Background: Immunogenic cell death (ICD) is a form of cell death that elicits immune responses against the antigens found in dead or dying tumor cells. Growing evidence implies that ICD plays a significant role in triggering antitumor immunity. The prognosis for glioma remains poor despite many biomarkers being reported, and identifying ICD-related biomarkers is imminent for better-personalized management in patients with lower-grade glioma (LGG). Materials and methods: We identified ICD-related differentially expressed genes (DEGs) by comparing gene expression profiles obtained across Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) cohorts. On the foundation of ICD-related DEGs, two ICD-related clusters were identified through consensus clustering. Then, survival analysis, functional enrichment analysis, somatic mutation analysis, and immune characteristics analysis were performed in the two ICD-related subtypes. Additionally, we developed and validated a risk assessment signature for LGG patients. Finally, we selected one gene (EIF2AK3) from the above risk model for experimental validation. Results: 32 ICD-related DEGs were screened, dividing the LGG samples from the TCGA database into two distinct subtypes. The ICD-high subgroup showed worse overall survival (OS), greater immune infiltration, more active immune response process, and higher expression levels of HLA genes than the ICD-low subgroup. Additionally, nine ICD-related DEGs were identified to build the prognostic signature, which was highly correlated with the tumor-immune microenvironment and could unambiguously be taken as an independent prognostic factor and further verified in an external dataset. The experimental results indicated that EIF2AK3 expression was higher in tumors than paracancerous tissues, and high-expression EIF2AK3 was enriched in WHO III and IV gliomas by qPCR and IHC, and Knockdown of EIF2AK3 suppressed cell viability and mobility in glioma cells. Conclusion: We established novel ICD-related subtypes and risk signature for LGG, which may be beneficial to improving clinical outcome prediction and guiding individualized immunotherapy.

Discovery of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles as potent tubulin polymerization inhibitors.

Tubulin/colchicine-binding site inhibitors (CBSIs) co-crystal structures play an important role in the exploration of novel small molecules for oncotherapy. Based on the analysis of the binding models of tubulin and reported CBSIs, a series of 6-aryl-2-(3,4,5-trimethoxyphenyl)thiazole[3,2-b][1,2,4]triazoles were designed as potential tubulin polymerization inhibitors by binding to distinct colchicine domain of tubulin. Among the compounds synthesized, 7w not only shown noteworthy potency against SGC-7901 cancer cell line (IC50 = 0.21 µM) but also exhibited lower cytotoxicity than colchicine in normal cell line (HUVEC). The mechanism studies elucidated that 7w could cause the apoptosis of cancer cells by inhibiting tubulin polymerization to trigger G2/M arrest. In 4T1-xenograft mice model, 7w significantly inhibited tumor growth without losing weight, demonstrating a promising potential for further development with a unique binding mode at the colchicine-binding site.

African swine fever virus pS273R antagonizes stress granule formation by cleaving the nucleating protein G3BP1 to facilitate viral replication.

Cytoplasmic stress granules (SGs) are generally triggered by stress-induced translation arrest for storing mRNAs. Recently, it has been shown that SGs are regulated by different stimulators including viral infection, which is involved in the antiviral activity of host cells to limit viral propagation. To survive, several viruses have been reported to execute various strategies, such as modulating SG formation, to create optimal surroundings for viral replication. African swine fever virus (ASFV) is one of the most notorious pathogens in the global pig industry. However, the interplay between ASFV infection and SG formation remains largely unknown. In this study, we found that ASFV infection inhibited SG formation. Through SG inhibitory screening, we found that several ASFV-encoded proteins are involved in inhibition of SG formation. Among them, an ASFV S273R protein (pS273R), the only cysteine protease encoded by the ASFV genome, significantly affected SG formation. ASFV pS273R interacted with G3BP1 (Ras-GTPase-activating protein [SH3 domain] binding protein 1), a vital nucleating protein of SG formation. Furthermore, we found that ASFV pS273R cleaved G3BP1 at the G140-F141 to produce two fragments (G3BP1-N1-140 and G3BP1-C141-456). Interestingly, both the pS273R-cleaved fragments of G3BP1 lost the ability to induce SG formation and antiviral activity. Taken together, our finding reveals that the proteolytic cleavage of G3BP1 by ASFV pS273R is a novel mechanism by which ASFV counteracts host stress and innate antiviral responses.

Deep learning for real-time detection of breast cancer presenting pathological nipple discharge by ductoscopy.

Objective: As a common breast cancer-related complaint, pathological nipple discharge (PND) detected by ductoscopy is often missed diagnosed. Deep learning techniques have enabled great advances in clinical imaging but are rarely applied in breast cancer with PND. This study aimed to design and validate an Intelligent Ductoscopy for Breast Cancer Diagnostic System (IDBCS) for breast cancer diagnosis by analyzing real-time imaging data acquired by ductoscopy. Materials and methods: The present multicenter, case-control trial was carried out in 6 hospitals in China. Images for consecutive patients, aged ≥18 years, with no previous ductoscopy, were obtained from the involved hospitals. All individuals with PND confirmed from breast lesions by ductoscopy were eligible. Images from Beijing Chao-Yang Hospital were randomly assigned (8:2) to the training (IDBCS development) and internal validation (performance evaluation of the IDBCS) datasets. Diagnostic performance was further assessed with internal and prospective validation datasets from Beijing Chao-Yang Hospital; further external validation was carried out with datasets from 5 primary care hospitals. Diagnostic accuracies, sensitivities, specificities, and positive and negative predictive values for IDBCS and endoscopists (expert, competent, or trainee) in the detection of malignant lesions were obtained by the Clopper-Pearson method. Results: Totally 11305 ductoscopy images in 1072 patients were utilized for developing and testing the IDBCS. Area under the curves (AUCs) in breast cancer detection were 0·975 (95%CI 0·899-0·998) and 0·954 (95%CI 0·925-0·975) in the internal validation and prospective datasets, respectively, and ranged between 0·922 (95%CI 0·866-0·960) and 0·965 (95%CI 0·892-0·994) in the 5 external validation datasets. The IDBCS had superior diagnostic accuracy compared with expert (0.912 [95%CI 0.839-0.959] vs 0.726 [0.672-0.775]; p<0.001), competent (0.699 [95%CI 0.645-0.750], p<0.001), and trainee (0.703 [95%CI 0.648-0.753], p<0.001) endoscopists. Conclusions: IDBCS outperforms clinical oncologists, achieving high accuracy in diagnosing breast cancer with PND. The novel system could help endoscopists improve their diagnostic efficacy in breast cancer diagnosis.

Characterization of prognostic value and immunological roles of RAB22A in hepatocellular carcinoma.

Background: The protein-coding gene RAB22A, a member of the RAS oncogene family, is amplified or overexpressed in certain cancers. However, its action mechanism in hepatocellular carcinoma (HCC) remains unclear. Here, we aimed to examine the connection between RAB22A and survival prognosis in HCC and explore the biological significance of RAB22A. Methods: A database-based pan-cancer expression analysis of RAB22A was performed. Kaplan-Meier analysis and Cox regression were performed to evaluate the association between RAB22A expression and survival prognosis in HCC. Using Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA), various potential biological functions and regulatory pathways of RAB22A in HCC were discovered. Tumor immune infiltration was studied using the single sample gene set enrichment analysis (ssGSEA) method. N6-methyladenosine modifications and the regulatory network of competitive endogenous RNA (ceRNA) were verified in the TCGA cohort. Results: RAB22A was upregulated in HCC samples and cell lines. A high RAB22A expression in HCC was strongly correlated with sex, race, age, weight, TNM stage, pathological stage, tumor status, histologic grade, TP53 mutation status, and alpha fetal protein (AFP) levels. Overexpression of RAB22A indicated a poor prognosis was related to overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI). GO and KEGG analyses revealed that the differentially expressed genes related to RAB22A might be involved in the proteasomal protein catabolic process, ncRNA processing, ribosome ribosomal subunit, protein serine/threonine kinase activity, protein serine kinase activity, Endocytosis, and non-alcoholic fatty liver disease. GSEA analyses revealed that the differentially expressed genes related to RAB22A might be involved in the T cell receptor, a co-translational protein, that binds to the membrane, axon guidance, ribosome, phagocytosis, and Eukaryotic translation initiation. RAB22A was correlated with N6-methyladenosine expression in HCC and established RAB22A-related ceRNA regulatory networks. Finally,RAB22A expression was positively connected the levels of infiltrating with T helper cells, Tcm cells, and Th2 cells,In contrast, we observed negatively correlations with cytotoxic cells, DCs, and pDCs cells.Moreover,RAB22A expression showed a strong correlation with various immunomarkergroups in HCC. Conclusions: RAB22A is a potential therapeutic target for improving HCC prognosis and is closely related to immune cell infiltration.

Identification of cuproptosis-related subtypes and the development of a prognostic model in glioma.

Introduction: A copper-dependent cell death, cuproptosis, involves copper binding with lipoylated tricarboxylic acid (TCA) cycle components. In cuproptosis, ferredoxin 1 (FDX1) and lipoylation act as key regulators. The mechanism of cuproptosis differs from the current knowledge of cell death, which may invigorate investigations into copper's potential as a cancer treatment. An extremely dismal prognosis is associated with gliomas, the most prevalent primary intracranial tumor. In patients with glioma, conventional therapies, such as surgery and chemotherapy, have shown limited improvement. A variety of cell death modes have been confirmed to be operative in glioma oncogenesis and participate in the tumor microenvironment (TME), implicated in glioma development and progression. In this study, we aimed to explore whether cuproptosis influences glioma oncogenesis. Methods: Gene expression profiles related to cuproptosis were comprehensively evaluated by comparing adjacent tissues from glioma tissues in The Cancer Genome Atlas (TCGA) (https://portal.gdc.cancer.gov/) database. Gene expression, prognostic, clinical, and pathological data of lower-grade gliomas (LGG) and glioblastoma were retrieved from TCGA and Gene Expression Omnibus (GEO) (https://www.ncbi.nlm.nih.gov/geo/) databases. The datasets were managed by "Combat" algorithm to eliminate batch effects and then combined. A consensus clustering algorithm based on the Partitioning Around Medoid (PAM) algorithm was used to classified 725 patients with LGG and glioblastoma multiforme (GBM) into two cuproptosis subtypes. According to the differentially expressed genes in the two cuproptosis subtypes, 725 patients were divided into 2 gene subtypes. Additionally, a scoring system that associated with TME was constructed to predict patient survival and patient immunotherapy outcomes. Furthermore, we constructed a prognostic CRG-score and nomogram system to predict the prognosis of glioma patients. 95 tissue specimens from 83 glioma patients undergoing surgical treatment were collected, including adjacent tissues. Using immunohistochemistry and RT-qPCR, we verified cuproptosis-related genes expression and CRG-score predictive ability in these clinical samples. Results: Our results revealed extensive regulatory mechanisms of cuproptosis-related genes in the cell cycle, TME, clinicopathological characteristics, and prognosis of glioma. We also developed a prognostic model based on cuproptosis. Through the verifications of database and clinical samples, we believe that cuproptosis affects the prognosis of glioma and potentially provides novel glioma research approaches. Conclusion: We suggest that cuproptosis has potential importance in treating gliomas and could be utilized in new glioma research efforts.

Boron supply restores aluminum-blocked auxin transport by the modulation of PIN2 trafficking in the root apical transition zone.

The supply of boron (B) alleviates the toxic effects of aluminum (Al) on root growth; however, the mechanistic basis of this process remains elusive. This study filled this knowledge gap, demonstrating that boron modifies auxin distribution and transport in Al-exposed Arabidopsis roots. In B-deprived roots, treatment with Al induced an increase in auxin content in the root apical meristem zone (MZ) and transition zone (TZ), whereas in the elongation zone (EZ) the auxin content was decreased beyond the level required for adequate growth. These distribution patterns are explained by the fact that basipetal auxin transport from the TZ to the EZ was disrupted by Al-inhibited PIN-FORMED 2 (PIN2) endocytosis. Experiments involving the modulation of protein biosynthesis by cycloheximide (CHX) and transcriptional regulation by cordycepin (COR) demonstrated that the Al-induced increase of PIN2 membrane proteins was dependent upon the inhibition of PIN2 endocytosis, rather than on the transcriptional regulation of the PIN2 gene. Experiments reporting on the profiling of Al3+ and PIN2 proteins revealed that the inhibition of endocytosis of PIN2 proteins was the result of Al-induced limitation of the fluidity of the plasma membrane. The supply of B mediated the turnover of PIN2 endosomes conjugated with indole-3-acetic acid (IAA), and thus restored the Al-induced inhibition of IAA transport through the TZ to the EZ. Overall, the reported results demonstrate that boron supply mediates PIN2 endosome-based auxin transport to alleviate Al toxicity in plant roots.

Integrative analysis of single-cell transcriptomics reveals age-associated immune landscape of glioblastoma.

Glioblastoma (GBM) is the most malignant tumor in center nervous system. Clinical statistics revealed that senior GBM patients had a worse overall survival (OS) comparing with that of patients in other ages, which is mainly related with tumor microenvironment including tumor-associated immune cells in particular. However, the immune heterogeneity and age-related prognosis in GBM are under studied. Here we developed a machine learning-based method to integrate public large-scale single-cell RNA sequencing (scRNA-seq) datasets to establish a comprehensive atlas of immune cells infiltrating in cross-age GBM. We found that the compositions of the immune cells are remarkably different across ages. Brain-resident microglia constitute the majority of glioblastoma-associated macrophages (GAMs) in patients, whereas dramatic elevation of extracranial monocyte-derived macrophages (MDMs) is observed in GAMs of senior patients, which contributes to the worse prognosis of aged patients. Further analysis suggests that the increased MDMs arisen from excessive recruitment and proliferation of peripheral monocytes not only lead to the T cell function inhibition in GBM, but also stimulate tumor cells proliferation via VEGFA secretion. In summary, our work provides new cues for the correlational relationship between the immune microenvironment of GBM and aging, which might be insightful for precise and effective therapeutic interventions for senior GBM patients.

miR-33b in human cancer: Mechanistic and clinical perspectives.

The microRNAs (miRNAs), an extensive class of small noncoding RNAs (∼22 nucleotides), have been shown to have critical functions in various biological processes during development. miR-33b (or hsa-miR-33b) is down-regulated in cancer of multiple systems. Notably, at least 27 protein-coding genes can be targeted by miR-33b. miR-33b regulates the cell cycle, cell proliferation, various metabolism pathways, epithelial-mesenchymal transition (EMT), cancer cell invasion and migration, etc. In prostate cancer, Cullin 4B (CUL4B) can be recruited to the promoter to inhibit the expression of miR-33b. In gastric cancer, the hypermethylation of the CpG island regulated the expression of miR-33b. Besides, miR-33b could be negatively regulated by 7 competing-endogenous RNAs (ceRNAs), which are all long non-coding RNAs (lncRNAs). There are at least 4 signaling pathways, including NF-κB, MAP8, Notch1, and Wnt/ß-catenin signaling pathways, which could be regulated partially by miR-33b. Additionally, low expression of miR-33b was associated with clinicopathology and prognosis in cancer patients. In addition, the aberrant expression of miR-33b was connected with the resistance of cancer cells to 5 anticancer drugs (cisplatin, docetaxel, bortezomib, paclitaxel, and daunorubicin). Importantly, our work systematically summarizes the aberrant expression of miR-33b in various neoplastic diseases and the effect of its downregulation on the biological behavior of cancer cells. Furthermore, this review focuses on recent advances in understanding the molecular regulation mechanisms of miR-33b. Moreso, the relationship between the miR-33b expression levels and the clinicopathological data and prognosis of tumor patients was summarized for the first time. Overall, we suggest that the current studies of miR-33b are insufficient but provide potential hints and direction for future miR-33b-related research.

m6A-related bioinformatics analysis and functional characterization reveals that METTL3-mediated NPC1L1 mRNA hypermethylation facilitates progression of atherosclerosis via inactivation of the MAPK pathway.

OBJECTIVE: Accumulating evidence has demonstrated that N6-methyladenosine (m6A) plays important roles in many major diseases, including atherosclerosis (AS). In the present study, we aimed to explore the transcriptomic m6A landscape of endothelial function-associated genes and identify potential regulators in AS progression. METHODS: The GEO data (GSE142386) from MeRIP-seq in human umbilical vein endothelial cells (HUVECs) with METTL3 knocked down or not were analyzed. RNA-seq was performed to identify differences in gene expression. Gene ontology (GO) functional and Kyoto encyclopedia of genes and genomes (KEGG) pathway analyses were conducted to evaluate the potential functions of the differentially expressed genes. MeRIP-qPCR was used to measure the m6A and mRNA levels of the top 8 downregulated genes, and NPC1L1 was selected as the candidate gene. Oxidized low-density lipoprotein (ox-LDL) was used to stimulate HUVECs, and METTL3 or NPC1L1 was silenced in ox-LDL-treated cells. And Transwell, ELISA, and cell apoptosis assays were performed to assess cell functional injury. ApoE-/- mice were fed with high-fat diet for 8 weeks to establish an AS model, and adenovirus-mediated NPC1L1 shRNA or NC shRNA was injected into the mice through the tail vein. Mouse aortic tissue damage and plaque deposition were evaluated by H&E, Oil Red O, and TUNEL staining. RESULTS: One hundred and ninety-four hypermethylated m6A peaks and 222 hypomethylated peaks were detected in response to knockdown of METTL3. Genes with altered m6A peaks were significantly involved in the histone modification, enzyme activity, and formation of multiple complexes and were predominantly enriched in the MAPK pathway. NPC1L1 was a most significantly downregulated transcript in response to knockdown of METTL3. Moreover, knockdown of NPC1L1 or de-m6A (METTL3 knockdown)-mediated downregulation of NPC1L1 could improve ox-LDL-induced dysfunction of HUVECs in vitro and high-fat diet-induced atherosclerotic plaque in vivo, which was associated with the inactivation of the MAPK pathway. CONCLUSION: METTL3-mediated NPC1L1 mRNA hypermethylation facilitates AS progression by regulating the MAPK pathway, and NPC1L1 may be a novel target for the treatment of AS.

Changes in arsenic accumulation and metabolic capacity after environmental management measures in mining area.

Due to the public health concern of arsenic, environmental management measures in mining areas had been implemented. To assess the effect of environmental management measures in the mining area comprehensively, arsenic accumulation in the urine, hair, nails, and urinary metabolites of residents in a realgar mining area in Hunan province, China were investigated in 2019, and the changes in arsenic levels in the biomarkers during 2012-2019 were tracked. The importance of confounding factors (age, sex, occupation, residence, clinical history, vegetable source, cooking fuel, smoking, alcohol consumption, BMI) was analyzed using the Boruta algorithm. After the implementation of environmental management measures (including ceasing mining and smelting activities, building landfills, adjusting the planting structure, and soil restoration), urine, hair, and nail arsenic concentration decreased drastically but were still excessive. Arsenic accumulation was highest in older male miners who were long settled in the mining area and consumed homegrown vegetables. The only factor for changes in urinary arsenic levels was the cooking fuel type; residents using wood as cooking fuel experienced sustained arsenic exposure. Occupation and sex were important for determining arsenic changes in the hair and nails. Short-term arsenic accumulation in urine was affected by arsenic exposure, while long-term accumulation in hair and nails by arsenic metabolic capacity. The percentage of urinary arsenic metabolism and arsenic methylation indices of the participants in the mining area were within the normal range (%iAs: 10-30 %, %MMA: 10-20 %, % DMA: 60-80 %); samples indicated worse metabolic capacity than the reference population. The arsenic metabolic capacity of male miners was relatively weak, probably aggravated by alcohol drinking and smoking. Without soil remediation, arsenic exposure will continue. Homegrown vegetables and biomass fuels should be abandoned; reduced cigarette and alcohol consumption is recommended. Urinary arsenic would be more proper for assessing environmental remediation in mining areas.

Saúde Cardiovascular e Fibrilação ou Flutter Atrial: Um Estudo Transversal do ELSA-Brasil / Cardiovascular Health and Atrial Fibrillation or Flutter: A Cross-Sectional Study from ELSA-Brasil

Resumo Fundamento A associação entre o status de saúde cardiovascular ideal ( ideal cardiovascular health ( ICVH) e diagnóstico de fibrilação ou flutter atrial (FFA) foi menos estudado em comparação a outras doenças cardiovasculares. Objetivos Analisar a associação entre o diagnóstico de FFA e métricas e escores de ICVH no Estudo Longitudinal de Saúde do Adulto (ELSA-Brasil). Métodos Este estudo analisou dados de 13141 participantes com dados completos. Os traçados eletrocardiográficos foram codificados de acordo com o Sistema de Minnesota, em um centro de leitura centralizado. As métricas do ICVH (dieta, atividade física, índice de massa corporal, tabagismo, glicemia de jeju, e colesterol total) e escores do ICVH foram calculados conforme proposto pela American Heart Association . Modelos de regressão logística bruta e ajustada foram construídos para analisar associações de métricas e escores do ICVH com diagnóstico de FFA. O nível de significância foi estabelecido em 0,05. Resultados A idade mediana da amostra foi de 55 anos, e 54,4% eram mulheres. Nos modelos ajustados, os escores de ICVH não apresentaram associação significativa com diagnóstico de FFA prevalente [odds ratio (OR):0,96; intervalo de confiança de 95% (IC95%):0,80-1,16; p=0,70). Perfis de pressão arterial ideal (OR:0,33; IC95%:0,1-0,74; p=0,007) e colesterol total ideal (OR:1,88; IC95%:1,19-2,98; p=0,007) foram significativamente associados com o diagnóstico de FFA. Conclusões Não foram identificadas associações significativas entre escores de ICVH global e diagnóstico de FFA após ajuste multivariado em nossas análises, devido, ao menos em parte, às associações antagônicas da FFA com métricas de pressão arterial e de colesterol total do ICVH. Nossos resultados sugerem que estimar a prevenção da FFA por meio de escore de ICVH global pode não ser adequado, e as métricas do ICVH devem ser consideradas separadamente.

Abstract Background The association between ideal cardiovascular health (ICVH) status and atrial fibrillation or flutter (AFF) diagnosis has been less studied compared to other cardiovascular diseases. Objective To analyze the association between AFF diagnosis and ICVH metrics and scores in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods This study analyzed data from 13,141 participants with complete data. Electrocardiographic tracings were coded according to the Minnesota Coding System, in a centralized reading center. ICVH metrics (diet, physical activity, body mass index, smoking, blood pressure, fasting plasma glucose, and total cholesterol) and scores were calculated as proposed by the American Heart Association. Crude and adjusted binary logistic regression models were built to analyze the association of ICVH metrics and scores with AFF diagnosis. Significance level was set at 0.05. Results The sample had a median age of 55 years and 54.4% were women. In adjusted models, ICVH scores were not significantly associated with prevalent AFF diagnosis (odds ratio [OR]:0.96; 95% confidence interval [95% CI]:0.80-1.16; p=0.70). Ideal blood pressure (OR:0.33; 95% CI:0.15-0.74; p=0.007) and total cholesterol (OR:1.88; 95% CI:1.19-2.98; p=0.007) profiles were significantly associated with AFF diagnosis. Conclusions No significant associations were identified between global ICVH scores and AFF diagnosis after multivariable adjustment in our analyses, at least partially due to the antagonistic associations of AFF with blood pressure and total cholesterol ICVH metrics. Our results suggest that estimating the prevention of AFF burden using global ICVH scores may not be adequate, and ICVH metrics should be considered in separate.