ABSTRACT
Pre-mRNA splicing is a precise regulated process and is crucial for system development and homeostasis maintenance. Mutations in spliceosomal components have been found in various hematopoietic malignancies (HMs) and have been considered as oncogenic derivers of HMs. However, the role of spliceosomal components in normal and malignant hematopoiesis remains largely unknown. Pre-mRNA processing factor 31 (PRPF31) is a constitutive spliceosomal component, which mutations are associated with autosomal dominant retinitis pigmentosa. PRPF31 was found to be mutated in several HMs, but the function of PRPF31 in normal hematopoiesis has not been explored. In our previous study, we generated a prpf31 knockout (KO) zebrafish line and reported that Prpf31 regulates the survival and differentiation of retinal progenitor cells by modulating the alternative splicing of genes involved in mitosis and DNA repair. In this study, by using the prpf31 KO zebrafish line, we discovered that prpf31 KO zebrafish exhibited severe defects in hematopoietic stem and progenitor cell (HSPC) expansion and its sequentially differentiated lineages. Immunofluorescence results showed that Prpf31-deficient HSPCs underwent malformed mitosis and M phase arrest during HSPC expansion. Transcriptome analysis and experimental validations revealed that Prpf31 deficiency extensively perturbed the alternative splicing of mitosis-related genes. Collectively, our findings elucidate a previously undescribed role for Prpf31 in HSPC expansion, through regulating the alternative splicing of mitosis-related genes.
Subject(s)
RNA Splicing Factors , Zebrafish Proteins , Zebrafish , Animals , Embryonic Development , Mutation , RNA Precursors/metabolism , RNA Splicing Factors/metabolism , Stem Cells/metabolism , Zebrafish/genetics , Zebrafish/growth & development , Zebrafish/metabolism , Zebrafish Proteins/metabolismABSTRACT
Dysfunction of splicing factors often result in abnormal cell differentiation and apoptosis, especially in neural tissues. Mutations in pre-mRNAs processing factor 31 (PRPF31) cause autosomal dominant retinitis pigmentosa, a progressive retinal degeneration disease. The transcriptome-wide splicing events specifically regulated by PRPF31 and their biological roles in the development and maintenance of retina are still unclear. Here, we showed that the differentiation and viability of retinal progenitor cells (RPCs) are severely perturbed in prpf31 knockout zebrafish when compared with other tissues at an early embryonic stage. At the cellular level, significant mitotic arrest and DNA damage were observed. These defects could be rescued by the wild-type human PRPF31 rather than the disease-associated mutants. Further bioinformatic analysis and experimental verification uncovered that Prpf31 deletion predominantly causes the skipping of exons with a weak 5' splicing site. Moreover, genes necessary for DNA repair and mitotic progression are most enriched among the differentially spliced events, which may explain the cellular and tissular defects in prpf31 mutant retinas. This is the first time that Prpf31 is demonstrated to be essential for the survival and differentiation of RPCs during retinal neurogenesis by specifically modulating the alternative splicing of genes involved in DNA repair and mitosis.
Subject(s)
Alternative Splicing , Neural Stem Cells/metabolism , Neurogenesis/genetics , Retina/embryology , Zebrafish Proteins/physiology , Animals , Apoptosis , CRISPR-Cas Systems , Cell Survival , DNA Damage , DNA Repair , Exons , Gene Knockout Techniques , M Phase Cell Cycle Checkpoints , Neural Stem Cells/cytology , Retinal Neurons/cytology , Retinal Neurons/metabolism , Spindle Apparatus/ultrastructure , Tumor Suppressor Protein p53/metabolism , Zebrafish/embryology , Zebrafish/genetics , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Accurate and fine-grained prediction of PM2.5 concentration is of great significance for air quality control and human physical and mental health. Traditional approaches, such as time series, recurrent neural networks (RNNs) or graph convolutional networks (GCNs), cannot effectively integrate spatial-temporal and meteorological factors and manage dynamic edge relationships among scattered monitoring stations. In this paper, a spatial-temporal causal convolution network framework, ST-CCN-PM2.5, is proposed. Both the spatial effects of multi-source air pollutants and meteorological factors are considered via spatial attention mechanism. Time-dependent features in causal convolution networks are extracted by stacked dilated convolution and time attention. All the hyper-parameters in ST-CCN-PM2.5 are tuned by Bayesian optimization. Haikou air monitoring station data are employed with a series of baselines (AR, MA, ARMA, ANN, SVR, GRU, LSTM and ST-GCN). Final results include the following points: (1) For a single station, the RMSE, MAE and R2 values of ST-CCN-PM2.5 decreased by 27.05%, 10.38% and 3.56% on average, respectively. (2) For all stations, ST-CCN-PM2.5 achieve the best performance in win-tie-loss experiments. The numbers of winning stations are 68, 63, and 64 out of 95 stations in RMSE (MSE), MAE, and R2, respectively. In addition, the mean MSE, RMSE and MAE of ST-CCN-PM2.5 are 4.94, 2.17 and 1.31, respectively, and the R2 value is 0.92. (3) Shapley analysis shows wind speed is the most influencing factor in fine-grained PM2.5 concentration prediction. The effects of CO and temperature on PM2.5 prediction are moderately significant. Friedman test under different resampling further confirms the advantage of ST-CCN-PM2.5. The ST-CCN-PM2.5 provides a promising direction for fine-grained PM2.5 prediction.
ABSTRACT
Hematopoietic stem and progenitor cells (HSPCs) originate from the hemogenic endothelium via the endothelial-to-hematopoietic transition, are self-renewing, and replenish all lineages of blood cells throughout life. BCAS2 (breast carcinoma amplified sequence 2) is a component of the spliceosome and is involved in multiple biological processes. However, its role in hematopoiesis remains unknown. We established a bcas2 knockout zebrafish model by using transcription activator-like effector nucleases. The bcas2 -/- zebrafish showed severe impairment of HSPCs and their derivatives during definitive hematopoiesis. We also observed significant signs of HSPC apoptosis in the caudal hematopoietic tissue of bcas2 -/- zebrafish, which may be rescued by suppression of p53. Furthermore, we show that the bcas2 deletion induces an abnormal alternative splicing of Mdm4 that predisposes cells to undergo p53-mediated apoptosis, which provides a mechanistic explanation of the deficiency observed in HSPCs. Our findings revealed a novel and vital role for BCAS2 during HSPC maintenance in zebrafish.
Subject(s)
Embryo, Nonmammalian/embryology , Embryonic Development , Hematopoietic Stem Cells/metabolism , Neoplasm Proteins/metabolism , Zebrafish Proteins/metabolism , Zebrafish/embryology , Animals , Animals, Genetically Modified/embryology , Animals, Genetically Modified/genetics , Gene Knockdown Techniques , Neoplasm Proteins/genetics , Zebrafish/genetics , Zebrafish Proteins/geneticsABSTRACT
OBJECTIVE: Comorbid depression is common in schizophrenia, and sex differences are prominent in many aspects of schizophrenia. However, few studies have investigated sex difference in comorbid depression in schizophrenia. This large sample study aimed to investigate sex differences in first-episode drug-naive (FEDN) patients with schizophrenia comorbid major depressive episode (SZ-MDE). METHODS: A total of 996 FEDN patients with schizophrenia (472 males/524 females) were recruited. The 17-item Hamilton Depression Rating Scale and Positive and Negative Syndrome Scale (PANSS) were applied. RESULTS: There was no difference in the prevalence of comorbid MDE between male and female patients with schizophrenia. Among SZ-MDE patients, men had more severe psychotic symptoms (scores of PANSS total scale, negative scale, and general psychopathology scale), more severe depressive symptoms, and higher proportion of severe depression than women (all p < .001). The early onset age of schizophrenia, smoking, and PANSS positive score were the risk factors for comorbid MDE only in female patients with schizophrenia (all p < .05). Furthermore, in female patients with SZ-MDE, smoking was associated with the severity category of depression (p = .001, odds ratio = 2.70). Multiple variable regression demonstrated that the Hamilton Depression Rating Scale score correlated with PANSS general psychopathology (p = .01) and total scores (p = .04) in female SZ-MDE. CONCLUSIONS: Our results indicate sex differences in proportion of severe depression, clinical symptoms, and factors of comorbid MDE in FEDN patients with schizophrenia. These sex differences have clinical implications for the treatment of depression as related to the nature and severity of psychopathological symptoms in patients with schizophrenia.
Subject(s)
Depressive Disorder, Major , Pharmaceutical Preparations , Schizophrenia , Depression/epidemiology , Depressive Disorder, Major/complications , Depressive Disorder, Major/epidemiology , Female , Humans , Male , Psychiatric Status Rating Scales , Schizophrenia/complications , Schizophrenia/epidemiology , Sex CharacteristicsABSTRACT
Hematopoietic stem and progenitor cells (HSPCs) have the ability to self-renew and differentiate into various blood cells, thus playing an important role in maintenance of lifelong hematopoiesis. Brahma-related gene 1 (BRG1), which acts as the ATP subunit of mammalian SWI-SNF-related chromatin remodeling complexes, is involved in human acute myeloid leukemia and highly expresses in short-term HSPCs. But its role and regulatory mechanism for HSPC development have not yet been well established. Here, we generated a brg1 knockout zebrafish model using TALEN technology. We found that in brg1-/- embryo, the primitive hematopoiesis remained well, while definitive hematopoiesis formation was significantly impaired. The number of hemogenic endothelial cells was decreased, further affecting definitive hematopoiesis with reduced myeloid and lymphoid cells. During embryogenesis, the nitric oxide (NO) microenvironment in brg1-/- embryo was seriously damaged and the reduction of HSPCs could be partially rescued by a NO donor. Chromatin immunoprecipitation (ChIP) assays showed that BRG1 could bind to the promoter of KLF2 and trigger its transcriptional activity of NO synthase. Our findings show that Brg1 promotes klf2a expression in hemogenic endothelium and highlight a novel mechanism for HSPC formation and maintenance.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Embryo, Nonmammalian/embryology , Hematopoiesis , Hematopoietic Stem Cells/metabolism , Stem Cell Niche , Zebrafish Proteins/metabolism , Zebrafish/embryology , Adaptor Proteins, Signal Transducing/genetics , Animals , Gene Expression Regulation, Developmental , Gene Knockout Techniques , Hematopoietic Stem Cells/cytology , Kruppel-Like Transcription Factors/biosynthesis , Kruppel-Like Transcription Factors/genetics , Nitric Oxide/genetics , Nitric Oxide/metabolism , Response Elements , Transcription, Genetic , Zebrafish/genetics , Zebrafish Proteins/biosynthesis , Zebrafish Proteins/geneticsABSTRACT
Mutations in human prominin 1 (PROM1), encoding a transmembrane glycoprotein localized mainly to plasma membrane protrusions, have been reported to cause retinitis pigmentosa, macular degeneration, and cone-rod dystrophy. Although the structural role of PROM1 in outer-segment (OS) morphogenesis has been demonstrated in Prom1-knockout mouse, the mechanisms underlying these complex disease phenotypes remain unclear. Here, we utilized a zebrafish model to further investigate PROM1's role in the retina. The Prom1 orthologs in zebrafish include prom1a and prom1b, and our results showed that prom1b, rather than prom1a, plays an important role in zebrafish photoreceptors. Loss of prom1b disrupted OS morphogenesis, with rods and cones exhibiting differences in impairment: cones degenerated at an early age, whereas rods remained viable but with an abnormal OS, even at 9 months postfertilization. Immunofluorescence experiments with WT zebrafish revealed that Prph2, an ortholog of the human transmembrane protein peripherin 2 and also associated with OS formation, is localized to the edge of OS and is more highly expressed in the cone OS than in the rod OS. Moreover, we found that Prom1b deletion causes mislocalization of Prph2 and disrupts its oligomerization. We conclude that the variation in Prph2 levels between cones and rods was one of the reasons for the different PROM1 mutation-induced phenotypes of these retinal structures. These findings expand our understanding of the phenotypes caused by PROM1 mutations and provide critical insights into its function.
Subject(s)
AC133 Antigen/metabolism , Photoreceptor Cells/metabolism , Rod Cell Outer Segment/metabolism , AC133 Antigen/genetics , Animals , Cone-Rod Dystrophies/genetics , Disease Models, Animal , HeLa Cells , Humans , Macular Degeneration/metabolism , Membrane Proteins/metabolism , Morphogenesis , Mutation , Peripherins/genetics , Retina/metabolism , Retina/physiology , Retinal Cone Photoreceptor Cells/metabolism , Retinal Degeneration/genetics , Retinal Degeneration/physiopathology , Retinal Rod Photoreceptor Cells/metabolism , Retinitis Pigmentosa/genetics , Sequence Deletion , Zebrafish/metabolism , Zebrafish Proteins/metabolismABSTRACT
In humans, CERKL mutations cause widespread retinal degeneration: early dysfunction and loss of rod and cone photoreceptors in the outer retina and, progressively, death of cells in the inner retina. Despite intensive efforts, the function of CERKL remains obscure and studies in animal models have failed to clarify the disease mechanism of CERKL mutations. To address this gap in knowledge, we have generated a stable CERKL knockout zebrafish model by TALEN technology and a 7bp deletion in CERKL cDNA that caused the premature termination of CERKL. These CERKL-/- animals showed progressive degeneration of photoreceptor outer segments (OSs) and increased apoptosis of retinal cells, including those in the outer and inner retinal layers. Additionally, we confirmed by immunofluorescence and western-blot that rod degeneration in CERKL-/- zebrafish occurred earlier and was more significant than that in cone cells. Accumulation of shed OSs in the interphotoreceptor matrix was observed by transmission election microscopy (TEM). This suggested that CERKL may regulate the phagocytosis of OSs by the retinal pigment epithelium (RPE). We further found that the phagocytosis-associated protein MERTK was significantly reduced in CERKL-/- zebrafish. Additionally, in ARPE-19 cell lines, knockdown of CERKL also decreased the mRNA and protein level of MERTK, as well as the ox-POS phagocytosis. We conclude that CERKL deficiency in zebrafish may cause rod-cone dystrophy, but not cone-rod dystrophy, while interfering with the phagocytosis function of RPE associated with down-regulation of the expression of MERTK.
Subject(s)
Phosphotransferases (Alcohol Group Acceptor)/genetics , Phosphotransferases (Alcohol Group Acceptor)/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolism , Animals , Cell Line , Down-Regulation , Gene Knockout Techniques/methods , Humans , Mutation , Phagocytosis/genetics , Photoreceptor Cells , RNA, Messenger/metabolism , Receptor Protein-Tyrosine Kinases/metabolism , Retina/metabolism , Retinal Cone Photoreceptor Cells/metabolism , Retinal Degeneration/genetics , Retinal Pigment Epithelium/metabolism , Retinitis Pigmentosa/metabolism , Zebrafish/geneticsABSTRACT
Mutations in retinitis pigmentosa 2 (RP2) account for 10-20% of X-linked retinitis pigmentosa (RP) cases. The encoded RP2 protein is implicated in ciliary trafficking of myristoylated and prenylated proteins in photoreceptor cells. To date >70 mutations in RP2 have been identified. How these mutations disrupt the function of RP2 is not fully understood. Here we report a novel in-frame 12-bp deletion (c.357_368del, p.Pro120_Gly123del) in zebrafish rp2 The mutant zebrafish shows reduced rod phototransduction proteins and progressive retinal degeneration. Interestingly, the protein level of mutant Rp2 is almost undetectable, whereas its mRNA level is near normal, indicating a possible post-translational effect of the mutation. Consistent with this hypothesis, the equivalent 12-bp deletion in human RP2 markedly impairs RP2 protein stability and reduces its protein level. Furthermore, we found that a majority of the RP2 pathogenic mutations (including missense, single-residue deletion, and C-terminal truncation mutations) severely destabilize the RP2 protein. The destabilized RP2 mutant proteins are degraded via the proteasome pathway, resulting in dramatically decreased protein levels. The remaining non-destabilizing mutations T87I, R118H/R118G/R118L/R118C, E138G, and R211H/R211L are suggested to impair the interaction between RP2 and its protein partners (such as ARL3) or with as yet unknown partners. By utilizing a combination of in silico, in vitro, and in vivo approaches, our work comprehensively indicates that loss of RP2 protein structural stability is the predominating pathogenic consequence for most RP2 mutations. Our study also reveals a role of the C-terminal domain of RP2 in maintaining the overall protein stability.
Subject(s)
Base Sequence , Eye Proteins/metabolism , Intracellular Signaling Peptides and Proteins/metabolism , Membrane Proteins/metabolism , Retinal Degeneration , Sequence Deletion , Zebrafish Proteins/metabolism , Zebrafish/metabolism , Animals , Eye Proteins/genetics , GTP-Binding Proteins , Humans , Intracellular Signaling Peptides and Proteins/genetics , Membrane Proteins/genetics , Protein Domains , Protein Stability , Retinal Degeneration/genetics , Retinal Degeneration/metabolism , Zebrafish/genetics , Zebrafish Proteins/geneticsABSTRACT
Most cases of Usher syndrome type II (USH2) are due to mutations in the USH2A gene. There are no effective treatments or ideal animal models for this disease, and the pathological mechanisms of USH2 caused by USH2A mutations are still unknown. Here, we constructed a ush2a knockout (ush2a-/-) zebrafish model using TALEN technology to investigate the molecular pathology of USH2. An early onset auditory disorder and abnormal morphology of inner ear stereocilia were identified in the ush2a-/- zebrafish. Consequently, the disruption of Ush2a in zebrafish led to a hearing impairment, like that in mammals. Electroretinography (ERG) test indicated that deletion of Ush2a affected visual function at an early stage, and histological analysis revealed that the photoreceptors progressively degenerated. Rod degeneration occurred prior to cone degeneration in ush2a-/- zebrafish, which is consistent with the classical description of the progression of retinitis pigmentosa (RP). Destruction of the outer segments (OSs) of rods led to the down-regulation of phototransduction cascade proteins at late stage. The expression of Ush1b and Ush1c was up-regulated when Ush2a was null. We also found that disruption of fibronectin assembly at the retinal basement membrane weakened cell adhesion in ush2a-/- mutants. In summary, for the first time, we generated a ush2a knockout zebrafish line with auditory disorder and retinal degeneration which mimicked the symptoms of patients, and revealed that disruption of fibronectin assembly may be one of the factors underlying RP. This model may help us to better understand the pathogenic mechanism and find treatment for USH2 in the future.
Subject(s)
Extracellular Matrix Proteins , Gene Knockout Techniques , Usher Syndromes , Zebrafish Proteins , Zebrafish , Animals , Disease Models, Animal , Electroretinography , Extracellular Matrix Proteins/genetics , Extracellular Matrix Proteins/metabolism , Humans , Usher Syndromes/genetics , Usher Syndromes/metabolism , Usher Syndromes/pathology , Usher Syndromes/physiopathology , Zebrafish/genetics , Zebrafish/metabolism , Zebrafish Proteins/genetics , Zebrafish Proteins/metabolismABSTRACT
Retinitis pigmentosa (RP) affects about 1.8 million individuals worldwide. X-linked retinitis pigmentosa (XLRP) is one of the most severe forms of RP. Nearly 85% of XLRP cases are caused by mutations in the X-linked retinitis pigmentosa 2 (RP2) and RPGR. RP2 has been considered to be a GTPase activator protein for ARL3 and to play a role in the traffic of ciliary proteins. The mechanism of how RP2 mutations cause RP is still unclear. In this study, we generated an RP2 knockout zebrafish line using transcription activator-like effector nuclease technology. Progressive retinal degeneration could be observed in the mutant zebrafish. The degeneration of rods' outer segments (OSs) is predominant, followed by the degeneration of cones' OS. These phenotypes are similar to the characteristics of RP2 patients, and also partly consistent with the phenotypes of RP2 knockout mice and morpholino-mediated RP2 knockdown zebrafish. For the first time, we found RP2 deletion leads to decreased protein levels and abnormal retinal localizations of GRK1 and rod transducin subunits (GNAT1 and GNB1) in zebrafish. Furthermore, the distribution of the total farnesylated proteins in zebrafish retina is also affected by RP2 ablation. These molecular alterations observed in the RP2 knockout zebrafish might probably be responsible for the gradual loss of the photoreceptors' OSs. Our work identified the progression of retinal degeneration in RP2 knockout zebrafish, provided a foundation for revealing the pathogenesis of RP caused by RP2 mutations, and would help to develop potential therapeutics against RP in further studies.
Subject(s)
G-Protein-Coupled Receptor Kinase 1/metabolism , Genetic Diseases, X-Linked/metabolism , Photoreceptor Cells, Vertebrate/metabolism , Retinitis Pigmentosa/metabolism , Transducin/metabolism , Zebrafish Proteins/deficiency , Animals , Eye Proteins , G-Protein-Coupled Receptor Kinase 1/genetics , Gene Knockdown Techniques , Genetic Diseases, X-Linked/genetics , Genetic Diseases, X-Linked/pathology , Mice , Photoreceptor Cells, Vertebrate/pathology , Retinitis Pigmentosa/genetics , Retinitis Pigmentosa/pathology , Transducin/genetics , ZebrafishSubject(s)
Retinal Degeneration/genetics , Zebrafish , Animals , Humans , Morphogenesis , Sequence DeletionABSTRACT
This Special Issue provides readers with up-to-date information on the recent progress in the structure transition, processing, characterization, and applications of metals, including ferrous and nonferrous metals [...].
ABSTRACT
Accurate long-term PM2.5 prediction is crucial for environmental management and public health. However, previous studies have mainly focused on short-term air quality point predictions, neglecting the importance of accurately predicting the long-term trends of PM2.5 and studying the uncertainty of PM2.5 concentration changes. The traditional approaches have limitations in capturing nonlinear relationships and complex dynamic patterns in time series, and they often overlook the credibility of prediction results in practical applications. Therefore, there is still much room for improvement in long-term prediction of PM2.5. This study proposes a novel long-term point and interval prediction framework for urban air quality based on multi-source spatial and temporal data, which further quantifies the uncertainty and volatility of the prediction based on the accurate PM2.5 point prediction. In this model, firstly, multi-source datasets from multiple monitoring stations are preprocessed. Subsequently, spatial clustering of stations based on POI data is performed to filter out strongly correlated stations, and feature selection is performed to eliminate redundant features. In this paper, the ConvFormer-KDE model is presented, whereby local patterns and short-term dependencies among multivariate variables are mined through a convolutional neural network (CNN), long-term dependencies among time-series data are extracted using the Transformer model, and a direct multi-output strategy is employed to realize the long-term point prediction of PM2.5 concentration. KDE is utilized to derive prediction intervals for PM2.5 concentration at confidence levels of 85%, 90%, and 95%, respectively, reflecting the uncertainty inherent in long-term trends of PM2.5. The performance of ConvFormer-KDE was compared with a list of advanced models. Experimental results showed that ConvFormer-KDE outperformed baseline models in long-term point- and interval-prediction tasks for PM2.5. The ConvFormer-KDE can provide a valuable early warning basis for future PM2.5 changes from the aspects of point and interval prediction.
ABSTRACT
Construction waste is unavoidable in the process of urban development, causing serious environmental pollution. Accurate assessment of municipal construction waste generation requires building construction waste identification models using deep learning technology. However, this process requires high-quality public datasets for model training and validation. This study utilizes Google Earth and GF-2 images as the data source to construct a specific dataset of construction waste landfills in the Changping and Daxing districts of Beijing, China. This dataset contains 3,653 samples of the original image areas and provides mask-labeled images in the semantic segmentation domains. Each pixel within a construction waste landfill is classified into 4 categories of the image areas, including background area, vacant landfillable area, engineering facility area, and waste dumping area. The dataset contains 237,115,531 pixels of construction waste and 49,724,513 pixels of engineering facilities. The pixel-level semantic segmentation labels are provided to quantify the construction waste yield, which can serve as the basic data for construction waste extraction and yield estimation both for academic and industrial research.
ABSTRACT
Objective: This study was designed to investigate the prevalence of religious belief and its relationship with psychiatric symptoms among Chinese adolescents. Methods: This study recruited 11,603 adolescents in Grades 7-9 from March 21 to 31, 2020 in five cities in China. The religious beliefs of adolescents were collected by asking whether they held religious beliefs and what type of religious beliefs they held. The Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 Scale (GAD-7) were used to assess depressive and anxiety symptoms in all adolescents. Demographics, religious beliefs, and mental health status were collected through the professional version of Wenjuanxing. Results: Of 11,069 valid questionnaires collected, 847 (7.7%) reported holding religious beliefs. Adolescents with religious beliefs showed significantly more severe symptoms of depression and anxiety compared to those without religious beliefs (both p<0.05). Logistic regression analysis revealed that religious belief was a risk factor for symptoms of depression (OR = 1.37, 95%CI: 1.16-1.61, p < 0.001) and anxiety (OR = 1.49, 95%CI: 1.23-1.79, p < 0.001) after controlling age, gender, and parental marital status. Conclusions: Our findings suggest that religiousness in adolescents was associated with a higher likelihood of depression/more intense depressive symptoms. In addition, religious Chinese adolescents should be provided with more resources to help them cope with mental health concerns.
ABSTRACT
Multi-walled carbon nanotube (MWCNT) induced respiratory toxicity has become a growing concern, with ferroptosis emerging as a novel mechanism implicated in various respiratory diseases. However, whether ferroptosis is involved in MWCNT-elicited lung injury and the underlying molecular mechanisms warrant further exploration. In this study, we found that MWCNT-induced ferroptosis is autophagy-dependent, contributing to its cellular toxicity. Inhibiting of autophagy by pharmacological inhibitors 3-MA or ATG5 gene knockdown significantly attenuated MWCNT-induced ferroptosis, concomitant with rescued mitochondrial biogenesis. Rapamycin, the autophagy agonist, exacerbated the mitochondrial damage and MWCNT-induced ferroptosis. Moreover, lentivirus-mediated overexpression of PGC-1α inhibited ferroptosis, while inhibition of PGC-1α aggravated ferroptosis. In summary, our study unveils ferroptosis as a novel mechanism underlying MWCNT-induced respiratory toxicity, with autophagy promoting MWCNT-induced ferroptosis by hindering PGC-1α-dependent mitochondrial biogenesis.
Subject(s)
Autophagy , Ferroptosis , Lung , Nanotubes, Carbon , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha , Nanotubes, Carbon/toxicity , Ferroptosis/drug effects , Autophagy/drug effects , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/metabolism , Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha/genetics , Humans , Lung/drug effects , Lung/metabolism , Lung/pathology , Lung/cytology , Epithelial Cells/metabolism , Epithelial Cells/drug effects , Mitochondria/metabolism , Mitochondria/drug effects , Organelle Biogenesis , Autophagy-Related Protein 5/metabolism , Autophagy-Related Protein 5/genetics , Animals , Sirolimus/pharmacology , Mice , Cell LineABSTRACT
In recent years, CO2 flooding has become one of the main enhanced oil recovery (EOR) methods, especially for tight formations in different oilfields around the world. Most of the CO2 flooding projects carried out in the world are based on miscible flooding, however, this technique is less effective in China because of the depth of the reservoirs and the heavy components of the crude oil. Near-miscible flooding and immiscible flooding have also been gradually applied to China's domestic oil fields, and have achieved certain oil increase effects, but there are still some challenges such as gas channeling, corrosion, and solid phase deposition in the process of CO2 flooding. In this paper, through a detailed review of recent domestic and foreign cases of enhanced oil recovery, the effects of development methods of low permeability and ultralow permeability reservoirs under different miscible degrees are analyzed, and the solutions to some of the existing problems in field tests and experience are systematically summarized. According to the results of field tests, both miscible flooding and near-miscible flooding have similar effects and can achieve better recovery increment, with a long effect period and slow gas breakthrough speed. In addition, the problems of gas channeling, corrosion, and solid phase deposition occurring in the process of CO2 flooding are analyzed, and solutions such as a change in injection methods and coatings are put forward, which effectively promote the development of CO2 flooding technology. Those suggestions are of great significance for improving the oil recovery rate of unconventional oil reservoirs, ensuring the national energy supply, and low-carbon emissions reduction in China.
ABSTRACT
Prevention of encrustation on the surface has always been the biggest challenge for urological implants. In the field of ureteral stent design, biodegradability has attracted much attention in recent years, because biodegradable ureteral stents not only avoid secondary intervention, but also prevent encrustation due to surface renewal by degradation process. Furthermore, researches have focus on some surface parameters to provide guidance for the development of stent materials, such as hydrophilicity or surface charge. In this work, we synthesized two types of poly(ester-carbonate)s, poly(L-lactide-co-5-amino-1,3-dioxan-2-one) (P(LA-co-AC)) containing amino, and poly (L-lactide-co-5-methyl-5-carboxyl-1,3-dioxan-2-one) (P(LA-co-MCC)) containing carboxyl. Blending P(LA-co-AC) and P(LA-co-MCC) with poly(L-lactide-co-Æ-caprolactone) (PLACL) respectively, two types of ureteral stent materials were prepared. Due to the influence of ions formed by the dissociation of amino and carboxyl, two types of materials show differences in surface charge analyses. We further developed a dynamic urinary extracorporeal circulation (DUEC) system to assess in vitro encrustation of materials with different surface charges. The results of this comparative study identified that the materials with strong negative surface charge were most favorable for use as ureteral stent, and provided a new approach to surmount the problems faced by urological surgery which complied with the future trend of biodegradable ureteral stent design.
Subject(s)
Ureter , StentsABSTRACT
Introduction: Pathogenic mutations in RPGR ORF15, one of two major human RPGR isoforms, were responsible for most X-linked retinitis pigmentosa cases. Previous studies have shown that RPGR plays a critical role in ciliary protein transport. However, the precise mechanisms of disease triggered by RPGR ORF15 mutations have yet to be clearly defined. There are two homologous genes in zebrafish, rpgra and rpgrb. Zebrafish rpgra has a single transcript homologous to human RPGR ORF15; rpgrb has two major transcripts: rpgrb ex1-17 and rpgrb ORF15, similar to human RPGR ex1-19 and RPGR ORF15, respectively. rpgrb knockdown in zebrafish resulted in both abnormal development and increased cell death in the dysplastic retina. However, the impact of knocking down rpgra in zebrafish remains undetermined. Here, we constructed a rpgra mutant zebrafish model to investigate the retina defect and related molecular mechanism. Methods: we utilized transcription activator-like effector nuclease (TALEN) to generate a rpgra mutant zebrafish. Western blot was used to determine protein expression. RT-PCR was used to quantify gene transcription levels. The visual function of embryonic zebrafish was detected by electroretinography. Immunohistochemistry was used to observe the pathological changes in the retina of mutant zebrafish and transmission electron microscope was employed to view subcellular structure of photoreceptor cells. Results: A homozygous rpgra mutant zebrafish with c.1675_1678delins21 mutation was successfully constructed. Despite the normal morphological development of the retina at 5 days post-fertilization, visual dysfunction was observed in the mutant zebrafish. Further histological and immunofluorescence assays indicated that rpgra mutant zebrafish retina photoreceptors progressively began to degenerate at 3-6 months. Additionally, the mislocalization of cone outer segment proteins (Opn1lw and Gnb3) and the accumulation of vacuole-like structures around the connecting cilium below the OSs were observed in mutant zebrafish. Furthermore, Rab8a, a key regulator of opsin-carrier vesicle trafficking, exhibited decreased expression and evident mislocalization in mutant zebrafish. Discussion: This study generated a novel rpgra mutant zebrafish model, which showed retinal degeneration. our data suggested Rpgra is necessary for the ciliary transport of cone-associated proteins, and further investigation is required to determine its function in rods. The rpgra mutant zebrafish constructed in this study may help us gain a better understanding of the molecular mechanism of retinal degeneration caused by RPGR ORF15 mutation and find some useful treatment in the future.