ABSTRACT
BACKGROUND: Crochetage sign is a specific electrocardiographic manifestation of ostium secundum atrial septal defects (ASDs), which is associated with the severity of the left-to-right shunt. Herein, we reported a case of selective his bundle pacing (S-HBP) that eliminated crochetage sign in a patient with ostium secundum ASD. CASE SUMMARY: A 77-year-old man was admitted with a 2-year history of chest tightness and shortness of breath. Transthoracic echocardiography revealed an ostium secundum ASD. Twelve-lead electrocardiogram revealed atrial fibrillation with a prolonged relative risk interval, incomplete right bundle branch block, and crochetage sign. The patient was diagnosed with an ostium secundum ASD, atrial fibrillation with a second-degree atrioventricular block, and heart failure. The patient was treated with selective his bundle pacemaker implantation. After the procedure, crochetage sign disappeared during his bundle pacing on the electrocardiogram. CONCLUSION: S-HBP eliminated crochetage sign on electrocardiogram. Crochetage sign may be a manifestation of a conduction system disorder.
ABSTRACT
BACKGROUND: The incidence of new-onset atrial fibrillation (NOAF) is increasing in the last decades. NOAF is associated with worse long-term prognosis. The C2HEST score has been recently proposed to stratify the risk of NOAF. Pooled data on the performance of the C2HEST score are lacking. METHODS: Systematic review and meta-analysis of observational studies reporting data on NOAF according to the C2HEST score. We searched PubMed, Web of Science and Google scholar databases without time restrictions until June 2023 according to PRISMA guidelines. Meta-analysis of the area under the curve (AUC) with 95% confidence interval (95% CI) and a sensitivity analysis according to setting of care and countries were performed. RESULTS: Of 360 studies, 17 were included in the analysis accounting for 11,067,496 subjects/patients with 307,869 NOAF cases. Mean age ranged from 41.3 to 71.2 years. The prevalence of women ranged from 10.6 to 54.75%. The pooled analysis gave an AUC of .70 (95% CI .66-.74). A subgroup analysis on studies from general population/primary care yielded an AUC of 0.69 (95% CI 0.64-0.75). In the subgroup of patients with cardiovascular disease, the AUC was .71 (.69-.79). The C2HEST score performed similarly in Asian (AUC .72, 95% CI .68-.77), and in Western patients (AUC .68, 95% CI .62-.75). The best performance was observed in studies with a mean age <50 years (n = 3,144,704 with 25,538 NOAF, AUC .78, 95% CI .76-.79). CONCLUSION: The C2HEST score may be used to predict NOAF in primary and secondary prevention patients, and in patients across different countries. Early detection of NOAF may aid prompt initiation of management and follow-up, potentially leading to a reduction of AF-related complications.
ABSTRACT
RNA modification is an essential component of the epitranscriptome, regulating RNA metabolism and cellular functions. Several types of RNA modifications have been identified to date; they include N6-methyladenosine (m6A), N1-methyladenosine (m1A), 5-methylcytosine (m5C), N7-methylguanosine (m7G), N6,2'-O-dimethyladenosine (m6Am), N4-acetylcytidine (ac4C), etc. RNA modifications, mediated by regulators including writers, erasers, and readers, are associated with carcinogenesis, tumor microenvironment, metabolic reprogramming, immunosuppression, immunotherapy, chemotherapy, etc. A novel perspective indicates that regulatory subunits and post-translational modifications (PTMs) are involved in the regulation of writer, eraser, and reader functions in mediating RNA modifications, tumorigenesis, and anticancer therapy. In this review, we summarize the advances made in the knowledge of different RNA modifications (especially m6A) and focus on RNA modification regulators with functions modulated by a series of factors in cancer, including regulatory subunits (proteins, noncoding RNA or peptides encoded by long noncoding RNA) and PTMs (acetylation, SUMOylation, lactylation, phosphorylation, etc.). We also delineate the relationship between RNA modification regulator functions and carcinogenesis or cancer progression. Additionally, inhibitors that target RNA modification regulators for anticancer therapy and their synergistic effect combined with immunotherapy or chemotherapy are discussed.
ABSTRACT
Epigenetic regulatory mechanisms are underappreciated, yet are critical for enteric nervous system (ENS) development and maintenance. We discovered that fetal loss of the epigenetic regulator Bap1 in the ENS lineage caused severe postnatal bowel dysfunction and early death in Tyrosinase-Cre Bap1fl/fl mice. Bap1-depleted ENS appeared normal in neonates; however, by P15, Bap1-deficient enteric neurons were largely absent from the small and large intestine of Tyrosinase-Cre Bap1fl/fl mice. Bowel motility became markedly abnormal with disproportionate loss of cholinergic neurons. Single-cell RNA sequencing at P5 showed that fetal Bap1 loss in Tyrosinase-Cre Bap1fl/fl mice markedly altered the composition and relative proportions of enteric neuron subtypes. In contrast, postnatal deletion of Bap1 did not cause enteric neuron loss or impaired bowel motility. These findings suggest that BAP1 is critical for postnatal enteric neuron differentiation and for early enteric neuron survival, a finding that may be relevant to the recently described human BAP1-associated neurodevelopmental disorder.
Subject(s)
Cell Differentiation , Enteric Nervous System , Tumor Suppressor Proteins , Ubiquitin Thiolesterase , Animals , Enteric Nervous System/metabolism , Enteric Nervous System/pathology , Mice , Ubiquitin Thiolesterase/genetics , Ubiquitin Thiolesterase/metabolism , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/metabolism , Neurons/metabolism , Neurons/pathology , Mice, Knockout , Female , Gastrointestinal Motility/genetics , HumansABSTRACT
In order to comprehensively evaluate the effects of vermicomposting on compost quality and the conversion of heavy metals under different control conditions, 109 studies were reviewed. The effects of earthworm species, pre-compost time, ventilation methods, initial C/N, initial pH, and initial moisture of the raw materials on compost quality and the heavy metal toxicity were quantitatively discussed during the vermicomposting process through Meta-analysis. The results showed that the six subgroups of factors all showed obvious influences on the compost quality and heavy metal toxicity. After vermicomposting, the contents of NO3--N (116.2%), TN (29.1%), TP (31.2%), and TK (15.0%) were significantly increased, whereas NH4+-N (-14.8%) and C/N (-36.3%) were significantly decreased. Meanwhile, the total amount of Cu and Cr of the final compost and their bioavailability were significantly reduced. Considering the influences of grouping factors on compost quality and heavy metals, it is recommended to adjust the initial moisture of pile materials to 70%-80%, C/N to 30-85, and pH to 6-7 and to conduct pre-composting for 0-15 d; additionally, vermicomposting should be naturally placed when the composting is aimed at promoting the compost quality. If the main purpose is to weaken the perniciousness of heavy metals in the raw material, it is recommended to adjust the initial moisture of the material to 50%-60%, C/N to less than 30, and pH to 7-8; to conduct no pre-compost; regularly turn the piles; and use the earthworm Eudrilus eugeniae for vermicomposting.
Subject(s)
Composting , Metals, Heavy , Oligochaeta , Animals , Soil/chemistry , Sewage/chemistry , Metals, Heavy/analysisABSTRACT
Electrocardiographic (ECG) abnormalities are seen in 70%-80% of patients with acute pulmonary embolism (PE). Rarely, acute PE presents with ST-segment elevation (STE) in leads II; III and aVF and V1-3 mimicking ST-segment elevation myocardial infarction (STEMI). Herein, we describe a case of acute PE presenting with STE in II; III and aVF and V1-3.
Subject(s)
Bradycardia , Electrocardiography , Pulmonary Embolism , Humans , Pulmonary Embolism/complications , Pulmonary Embolism/diagnosis , Bradycardia/diagnosis , Bradycardia/physiopathology , Diagnosis, Differential , Male , ST Elevation Myocardial Infarction/diagnosis , ST Elevation Myocardial Infarction/complications , ST Elevation Myocardial Infarction/physiopathology , Acute Disease , Female , Middle AgedABSTRACT
Carbonaceous aerosol, as an important component of atmospheric aerosol, has a significant impact on atmospheric environmental quality, human health, and global climate change. To investigate the characteristics and sources of carbonaceous aerosol in atmospheric fine particulate matter (PM2.5) in Huaxi District of Guiyang, an in-situ observational study was conducted during different seasons in 2020, and the carbonaceous components of PM2.5 were measured using a thermal-optical carbon analyzer (DRI Model 2015). The results of the study showed that the average concentrations of PM2.5, total carbonaceous aerosol (TCA), organic carbon (OC), secondary organic carbon (SOC), and elemental carbon (EC) concentrations during the observation period were (39.7±22.3), (14.1±7.2), (7.6±3.9), (4.4±2.6), and (2.0±1.0) µg·m-3, respectively, and the mean value of OC/EC was (3.9±0.8). ρ(PM2.5), ρ(TCA), ρ(OC), ρ(SOC), and ρ(EC) showed a seasonal variation pattern with the highest in winter [(52.6±28.6), (17.0±9.6), (9.1±5.2), (6.1±3.9), and (2.4±1.2) µg·m-3, respectively] and the lowest in summer [(25.1±7.1), (11.6±3.6), (6.3±1.9), (3.7±1.2), and (1.6±0.6) µg·m-3, respectively]. The seasonal variation in OC/EC showed summer (4.2±0.8) > winter (3.8±0.9) > autumn (3.8±0.5) > spring (3.7±0.9), indicating the presence of SOC generation in all seasons in Huaxi District. SOC showed a significant correlation with OC (R2 =0.9), and the SOC concentration tended to increase with the increase in atmospheric oxidation. OC showed a good correlation with EC in all seasons, with the highest in autumn (R2 =0.9) and lower correlations in the other three seasons (R2 ranged from 0.74 to 0.75), indicating a common source. According to OC/EC ratio range, it was preliminarily determined that carbonaceous aerosol came from vehicle exhaust emissions, coal burning emissions, and biomass combustion emissions. In order to further quantify the contribution of major emission sources to carbonaceous aerosol, the results of this study using PMF to analyze the sources of carbonaceous aerosol showed that the main sources of carbonaceous aerosol in Huaxi District of Guiyang were coal combustion sources (29.3%), motor vehicle emission sources (21.5%), and biomass combustion sources (49.2%).
ABSTRACT
BACKGROUND: Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) is one of the causes of tumor immune tolerance and failure of cancer immunotherapy. Here, we found that bladder cancer (BCa)-derived exosomal circRNA_0013936 could enhance the immunosuppressive activity of PMN-MDSCs by regulating the expression of fatty acid transporter protein 2 (FATP2) and receptor-interacting protein kinase 3 (RIPK3). However, the underlying mechanism remains largely unknown. METHODS: BCa-derived exosomes was isolated and used for a series of experiments. RNA sequencing was used to identify the differentially expressed circRNAs. Western blotting, immunohistochemistry, immunofluorescence, qRT-PCR, ELISA and Flow cytometry were performed to reveal the potential mechanism of circRNA_0013936 promoting the immunosuppressive activity of PMN-MDSC. RESULTS: CircRNA_0013936 enriched in BCa-derived exosomes could promote the expression of FATP2 and inhibit the expression of RIPK3 in PMN-MDSCs. Mechanistically, circRNA_0013936 promoted the expression of FATP2 and inhibited the expression of RIPK3 expression via sponging miR-320a and miR-301b, which directly targeted JAK2 and CREB1 respectively. Ultimately, circRNA_0013936 significantly inhibited the functions of CD8+ T cells by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway, and down-regulating RIPK3 through the circRNA_0013936/miR-301b/CREB1 pathway in PMN-MDSCs. CONCLUSIONS: BCa-derived exosomal circRNA_0013936 promotes suppressive immunity by up-regulating FATP2 through the circRNA_0013936/miR-320a/JAK2 pathway and down-regulating RIPK3 through the circRNA_0013936/miR-301b-3p/CREB1 pathway in PMN-MDSCs. These findings help to find new targets for clinical treatment of human bladder cancer.
Subject(s)
MicroRNAs , Myeloid-Derived Suppressor Cells , RNA, Circular , Urinary Bladder Neoplasms , Humans , CD8-Positive T-Lymphocytes/metabolism , Fatty Acids/metabolism , MicroRNAs/genetics , MicroRNAs/metabolism , Myeloid-Derived Suppressor Cells/metabolism , Protein Kinases/metabolism , RNA, Circular/genetics , RNA, Circular/metabolism , Urinary Bladder/metabolism , Urinary Bladder Neoplasms/pathology , Exosomes/genetics , Coenzyme A Ligases/genetics , Coenzyme A Ligases/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/genetics , Receptor-Interacting Protein Serine-Threonine Kinases/metabolismABSTRACT
Background: Triple-negative breast cancer (TNBC) is a subtype of BC with high rates of mortality. The mechanism of PTPRG-AS1 in ferroptosis of TNBC was investigated. Methods: Chromatin immunoprecipitation and dual-luciferase reporter assays were used to measure intermolecular relationships. MTT and colony formation assays detected cell viability and proliferation. Kits detected Fe2+ and reactive oxygen species levels. The role of PTPRG-AS1 in tumor growth was analyzed in vivo. Results: PTPRG-AS1 was increased in TNBC tissues and cells. PTPRG-AS1 silencing increased the reduction of glutathione and GPX4, increased Fe2+ and reactive oxygen species in erastin-treated cells and inhibited proliferation. POU2F2 transcriptionally upregulated PTPRG-AS1. PTPRG-AS1 targeted miR-376c-3p to upregulate SLC7A11. PTPRG-AS1 knockdown suppressed tumor growth in vivo. Conclusion: POU2F2 transcriptionally activates PTPRG-AS1 to modulate ferroptosis and proliferation by miR-376c-3p/SLC7A11, promoting TNBC.
Triple-negative breast cancer (TNBC) is a kind of breast cancer with high recurrence and low survival rates. Activation of the ferroptosis pathway can inhibit BC proliferation and distant metastasis. Therefore, identifying effective biomarkers and molecular mechanisms of ferroptosis in TNBC is important for its earlier detection and therapy. PTPRG-AS1 is a new type of lncRNA discovered in recent years that is increased in various diseases and is related to prognosis. In the present study, the authors found that POU2F2 promoted PTPRG-AS1 transcription. PTPRG-AS1 knockdown activated ferroptosis in TNBC and inhibited proliferation. Mechanistically, PTPRG-AS1 targeted miR-376c-3p to upregulate SLC7A11, thereby inhibiting ferroptosis and promoting TNBC development. These results indicate that PTPRG-AS1 is a possible therapeutic target in TNBC.
Subject(s)
Ferroptosis , MicroRNAs , Octamer Transcription Factor-2 , RNA, Long Noncoding , Triple Negative Breast Neoplasms , Humans , Amino Acid Transport System y+/genetics , Cell Line, Tumor , Cell Proliferation/genetics , Ferroptosis/genetics , Gene Expression Regulation, Neoplastic , MicroRNAs/genetics , Octamer Transcription Factor-2/genetics , Reactive Oxygen Species , Receptor-Like Protein Tyrosine Phosphatases, Class 5/genetics , RNA, Long Noncoding/genetics , Triple Negative Breast Neoplasms/genetics , Triple Negative Breast Neoplasms/pathology , Up-RegulationABSTRACT
Seed metabolites are the combination of essential compounds required by an organism across various potential environmental conditions. The seed metabolites screening framework based on the network topology approach can capture important biological information of species. This study aims to identify comprehensively the relationship between seed metabolites and pathogenic bacteria. A large-scale data set was compiled, describing the seed metabolite sets and metabolite sets of 124,192 pathogenic strains from 34 genera, by constructing genome-scale metabolic models. The enrichment analysis method was used to screen the specific seed metabolites of each species/genus of pathogenic bacteria. The metabolites of pathogenic microorganisms database (MPMdb) (http://qyzhanglab.hzau.edu.cn/MPMdb/) was established for browsing, searching, predicting, or downloading metabolites and seed metabolites of pathogenic microorganisms. Based on the MPMdb, taxonomic and phylogenetic analyses of pathogenic bacteria were performed according to the function of seed metabolites and metabolites. The results showed that the seed metabolites could be used as a feature for microorganism chemotaxonomy, and they could mirror the phylogeny of pathogenic bacteria. In addition, our screened specific seed metabolites of pathogenic bacteria can be used not only for further tapping the nutritional resources and identifying auxotrophies of pathogenic bacteria but also for designing targeted bactericidal compounds by combining with existing antimicrobial agents.IMPORTANCEMetabolites serve as key communication links between pathogenic microorganisms and hosts, with seed metabolites being crucial for microbial growth, reproduction, external communication, and host infection. However, the large-scale screening of metabolites and the identification of seed metabolites have always been the main technical bottleneck due to the low throughput and costly analysis. Genome-scale metabolic models have become a recognized research paradigm to investigate the metabolic characteristics of species. The developed metabolites of pathogenic microorganisms database in this study is committed to systematically predicting and identifying the metabolites and seed metabolites of pathogenic microorganisms, which could provide a powerful resource platform for pathogenic bacteria research.
Subject(s)
Anti-Infective Agents , Seeds , Phylogeny , Bacteria , Databases, Factual , Anti-Infective Agents/metabolismABSTRACT
Pruritus, also known as itching, is a complex sensation that involves the activation of specific physiological and cellular receptors. The skin is innervated with sensory nerves as well as some receptors for various sensations, and its immune system has prominent neurological connections. Sensory neurons have a considerable impact on the sensation of itching. However, immune cells also play a role in this process, as they release pruritogens. Disruption of the dermal barrier activates an immune response, initiating a series of chemical, physical, and cellular reactions. These reactions involve various cell types, including keratinocytes, as well as immune cells involved in innate and adaptive immunity. Collective activation of these immune responses confers protection against potential pathogens. Thus, understanding the molecular and cellular mechanisms that contribute to pruritus in host skin is crucial for the advancement of effective treatment approaches. This review provides a comprehensive analysis of the present knowledge concerning the molecular and cellular mechanisms underlying itching signaling in the skin. Additionally, this review explored the integration of these mechanisms with the broader context of itch mediators and the expression of their receptors in the skin.
Subject(s)
Pruritus , Skin , Humans , Pruritus/genetics , Pruritus/metabolism , Keratinocytes , Sensory Receptor Cells/metabolism , Signal TransductionABSTRACT
Platelets and M2 macrophages both play crucial roles in tumorigenesis, but their relationship and the prognosis value of the relative genes in bladder cancer (BLCA) remain obscure. In the present study, we found that platelets stimulated by BLCA cell lines could promote M2 macrophage polarization, and platelets were significantly associated with the infiltration of M2 macrophages in BLCA samples. Through the bioinformatic analyses, A2M, TGFB3, and MYLK, which were associated with platelets and M2 macrophages, were identified and verified in vitro and then included in the predictive model. A platelet and M2 macrophage-related gene signature was constructed to evaluate the prognosis and immunotherapeutic sensitivity, helping to guide personalized treatment and to disclose the underlying mechanisms.
Subject(s)
Blood Platelets , Immunotherapy , Macrophages , Urinary Bladder Neoplasms , Urinary Bladder Neoplasms/genetics , Urinary Bladder Neoplasms/therapy , Urinary Bladder Neoplasms/immunology , Urinary Bladder Neoplasms/pathology , Humans , Prognosis , Macrophages/immunology , Macrophages/metabolism , Blood Platelets/metabolism , Cell Line, Tumor , Immunotherapy/methods , Male , Female , Gene Expression Regulation, Neoplastic , Computational Biology/methods , Mice , Transcriptome , Middle Aged , Gene Expression Profiling/methodsABSTRACT
Rapid restoration of perfusion in ischemic myocardium is the most direct and effective treatment for coronary heart disease but may cause myocardial ischemia/reperfusion injury (MIRI). Cinnamaldehyde (CA, C9H8O), a key component in the well-known Chinese medicine cinnamomum cassia, has cardioprotective effects against MIRI. This study aimed to observe the therapeutic effect of CA on MIRI and to elucidate its potential mechanism. H9C2 rat cardiomyocytes were pretreated with CA solution at 0, 10, and 100 µM, respectively and subjected to oxygen-glucose deprivation/reoxygenation (OGD/R). Then the cell viability, the NF-κB and caspase3 gene levels, the reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio, superoxide dismutase (SOD) level, reactive oxygen species (ROS) generation, 4-hydroxynonenal (4-HNE), and malondialdehyde (MDA) were detected. The severity of DNA damage was assessed by tail moment (TM) values using alkaline comet assay. Besides, the DNA damage-related proteins and the key proteins of the Nrf2 pathway were detected by western blot. CA treatment increased the cell viability, GHS/GSSG ratio, SOD level, PARP1, Nrf2, PPAR-γ, and HO-1 protein levels of H9C2 cardiomyocytes, while reducing NF-κB, caspase3, ROS level, 4-HNE and MDA content, γ-H2AX protein level, and TM values. Inhibition of the Nrf2 pathway reversed the effect of CA on cell viability and apoptosis of OGD/R induced H9C2 cardiomyocytes. Besides, 100 µM CA was more effective than 10 µM CA. In the OGD/R-induced H9C2 cardiomyocyte model, CA can protect cardiomyocytes from MIRI by attenuating lipid peroxidation and repairing DNA damage. The mechanism may be related to the activation of the Nrf2 pathway.
Subject(s)
Acrolein , Myocytes, Cardiac , NF-E2-Related Factor 2 , Oxygen , Animals , Rats , Acrolein/analogs & derivatives , Acrolein/pharmacology , Apoptosis , DNA Damage , Glucose/pharmacology , Glutathione Disulfide/genetics , Glutathione Disulfide/metabolism , Glutathione Disulfide/pharmacology , Lipid Peroxidation , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , NF-E2-Related Factor 2/drug effects , NF-E2-Related Factor 2/metabolism , NF-kappa B/metabolism , Oxidative Stress , Oxygen/metabolism , Reactive Oxygen Species/metabolism , Superoxide Dismutase/metabolismABSTRACT
Ferroptosis is a non-apoptotic form of cell death characterized by iron-dependent lipid peroxidation and glutathione (GSH) depletion. Despite recent advances, challenges remain in understanding the bidirectional interactions or interplay between organelles during ferroptosis. In this study, we aimed to understand the interplay between mitochondria (Mito) and lysosomes (Lyso) in cell homeostasis and ferroptosis. For this purpose, we designed a single fluorescent probe that marks GSH in Mito and hypochlorous acid (HOCl) in Lyso with two distinct emissions. Using this dual-targeted single fluorescent probe (9-morphorino pyronine), we detected Mito-Lyso interplay in ferroptosis. We disclosed differences in Mito-Lyso interplay depending on the induction of ferroptosis. Although erastin treatment decreased GSH, RSL3 triggered a HOCl burst, and FIN56- and FINO2-induced ferroptosis increased GSH and HOCl. Additionally, we showed that only extracellular vesicles generated during erastin-induced ferroptosis could spontaneously move and dock to neighboring cells, resulting in accelerated cell death.
Subject(s)
Extracellular Vesicles , Ferroptosis , Fluorescent Dyes/metabolism , Lysosomes/metabolism , Mitochondria/metabolism , Extracellular Vesicles/metabolismABSTRACT
Phytoplankton is the most important component of water ecosystems, which could indicate the state of the water environment owing to its sensitivity to water environment variation. However, its response to the environment is influenced by classification methods. To understand the phytoplankton population(phyla and genera) and functional groups(FG) for driving response characteristics and applicability to the environment in Dongting Lake, a total of four samples were collected from the lake from March to December 2019, and the distribution characteristics of the phytoplankton population and functional groups and their responses to environmental factors were compared and analyzed. Meanwhile, the applicability of the TLI index, Shannon-Wiener index, and Q index was compared in Dongting Lake. The results showed that a total of 61 genera belonging to six phyla of phytoplankton were detected in Dongting Lake, which could be divided into 23 functional groups and nine dominant functional groups. The succession trend of functional groups was P/MP/D(March)âMP/P/J(June)âMP/H1(September)âY/P/MP(December). The results of hierarchical segmentation showed that the population distribution and change in phytoplankton were driven by environmental factors more than the area in Dongting Lake. The main environmental factors affecting phytoplankton population and functional groups were water temperature(WT), permanganate index, dissolved oxygen(DO), conductivity(Cond), water level(WL), and total phosphorus(TP). RDA analysis showed that phytoplankton functional groups identified phytoplankton response to environmental factors better than phytoplankton population. It was shown that using the Q index to evaluate water quality had better applicability in Dongting Lake.
Subject(s)
Phytoplankton , Water Quality , Lakes/analysis , Ecosystem , Environmental Monitoring/methods , Nitrogen/analysisABSTRACT
Roads are the main places where urban people are exposed to atmospheric particulate matter from outdoor activities, and certain oxidatively active substances contained in road particulate matter are important components that induce the generation of reactive oxygen species (ROS), which in turn endanger human health. Here, we explored the characteristics of organic matter composition in water-soluble (WSM) and methanol-soluble fractions (MSM) of road dust in Xi'an and its oxidation potential (OP). Additionally, we investigated the organic fractions and their distribution based on parallel factor analysis (PARAFAC) and analyzed the correlation between organic matter types and OP. The results showed that the water-insoluble fraction of road dust in Xi'an contained more chromophoric organic matter with an average total concentration of (4.71±1.27)×104 R.U., which was 12 times higher than that of WSM[(3.96±1.10)×103 R.U.], of which low-oxidizing humic-like substances (HULIS) were the main organic matter (34.8%-43.7% of the total organic matter). The results of cluster analysis showed that the important sources of organic matter in road dust in Xi'an were fuel combustion and industrial production. The mean value of dust oxidative toxicity was (0.34±0.08) pmol·(min·µg)-1, with the water-insoluble fraction providing 70% of the total oxidative toxicity of dust particles, which was 2.4 times higher than the water-soluble fraction. The main precursors of oxidative toxicity of dust particles were metal elements, and special types of organic substances were also one of the important oxidative toxicity precursors, among which chromophore organic matter was the main cause of OP production in the WSM fraction (r=0.35, P<0.01), and protein-like organic matter and highly oxidized HULIS in WSM may have been the main two types of organic substances for OP production. However, there was no significant correlation between organic matter concentration in MSM and water-insoluble OP (OPTotal-OPWSM) (r=-0.04, P>0.1), so the oxidative toxicity of the water-insoluble particulate matter fraction was mainly generated from non-organic matter.
ABSTRACT
N6-methyladenosine (m6A) modification plays important roles in bioprocesses and diseases. AlkB homolog 5 (ALKBH5) is one of two m6A demethylases. Here, we reveal that ALKBH5 is acetylated at lysine 235 (K235) by lysine acetyltransferase 8 and deacetylated by histone deacetylase 7. K235 acetylation strengthens the m6A demethylation activity of ALKBH5 by increasing its recognition of m6A on mRNA. RNA-binding protein paraspeckle component 1 (PSCP1) is a regulatory subunit of ALKBH5 and preferentially interacts with K235-acetylated ALKBH5 to recruit and facilitate the recognition of m6A mRNA by ALKBH5, thereby promoting m6A erasure. Mitogenic signals promote ALKBH5 K235 acetylation. K235 acetylation of ALKBH5 is upregulated in cancers and promotes tumorigenesis. Thus, our findings reveal that the m6A demethylation activity of ALKBH5 is orchestrated by its K235 acetylation and regulatory subunit PSPC1 and that K235 acetylation is necessary for the m6A demethylase activity and oncogenic roles of ALKBH5.
Subject(s)
Carcinogenesis , Cell Transformation, Neoplastic , Humans , Acetylation , RNA, Messenger/metabolism , Carcinogenesis/genetics , AlkB Homolog 5, RNA Demethylase/genetics , AlkB Homolog 5, RNA Demethylase/metabolism , Demethylation , RNA-Binding Proteins/metabolismABSTRACT
Mitochondrial (MT) dysfunction has been associated with several neurodegenerative diseases including Alzheimer's disease (AD). While MT-copy number differences have been implicated in AD, the effect of MT heteroplasmy on AD has not been well characterized. Here, we analyzed over 1800 whole genome sequencing data from four AD cohorts in seven different tissue types to determine the extent of MT heteroplasmy present. While MT heteroplasmy was present throughout the entire MT genome for blood samples, we detected MT heteroplasmy only within the MT control region for brain samples. We observed that an MT variant 10398A>G (rs2853826) was significantly associated with overall MT heteroplasmy in brain tissue while also being linked with the largest number of distinct disease phenotypes of all annotated MT variants in MitoMap. Using gene-expression data from our brain samples, our modeling discovered several gene networks involved in mitochondrial respiratory chain and Complex I function associated with 10398A>G. The variant was also found to be an expression quantitative trait loci (eQTL) for the gene MT-ND3. We further characterized the effect of 10398A>G by phenotyping a population of lymphoblastoid cell-lines (LCLs) with and without the variant allele. Examination of RNA sequence data from these LCLs reveal that 10398A>G was an eQTL for MT-ND4. We also observed in LCLs that 10398A>G was significantly associated with overall MT heteroplasmy within the MT control region, confirming the initial findings observed in post-mortem brain tissue. These results provide novel evidence linking MT SNPs with MT heteroplasmy and open novel avenues for the investigation of pathomechanisms that are driven by this pleiotropic disease associated loci.
Subject(s)
Heteroplasmy , Mitochondria , Mitochondria/genetics , Polymorphism, Single Nucleotide , Phenotype , Base Sequence , DNA, Mitochondrial/geneticsABSTRACT
Transporters are the main determinant for pharmacokinetics characteristics of drugs, such as absorption, distribution, and excretion of drugs in humans. However, it is difficult to perform drug transporter validation and structure analysis of membrane transporter proteins by experimental methods. Many studies have demonstrated that knowledge graphs (KG) could effectively excavate potential association information between different entities. To improve the effectiveness of drug discovery, a transporter-related KG was constructed in this study. Meanwhile, a predictive frame (AutoInt_KG) and a generative frame (MolGPT_KG) were established based on the heterogeneity information obtained from the transporter-related KG by the RESCAL model. Natural product Luteolin with known transporters was selected to verify the reliability of the AutoInt_KG frame, its ROC-AUC (1:1), ROC-AUC (1:10), PR-AUC (1:1), PR-AUC (1:10) are 0.91, 0.94, 0.91 and 0.78, respectively. Subsequently, the MolGPT_KG frame was constructed to implement efficient drug design based on transporter structure. The evaluation results showed that the MolGPT_KG could generate novel and valid molecules and that these molecules were further confirmed by molecular docking analysis. The docking results showed that they could bind to important amino acids at the active site of the target transporter. Our findings will provide rich information resources and guidance for the further development of the transporter-related drugs.