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Introduction: Inherited retinal diseases (IRDs) affect â¼4.5 million people worldwide. Elusive pathogenic variants in over 280 genes are associated with one or more clinical forms of IRDs. It is necessary to understand the complex interaction among retinal cell types and pathogenic genes by constructing a regulatory network. In this study, we attempt to establish a panoramic expression view of the cooperative work in retinal cells to understand the clinical manifestations and pathogenic bases underlying IRDs. Methods: Single-cell RNA sequencing (scRNA-seq) data on the retinas from 35 retina samples of 3 species (human, mouse, and zebrafish) including 259,087 cells were adopted to perform a comparative analysis across species. Bioinformatic tools were used to conduct weighted gene co-expression network analysis (WGCNA), single-cell regulatory network analysis, cell-cell communication analysis, and trajectory inference analysis. Results: The cross-species comparison revealed shared or species-specific gene expression patterns at single-cell resolution, such as the stathmin family genes, which were highly expressed specifically in zebrafish Müller glias (MGs). Thirteen gene modules were identified, of which nine were associated with retinal cell types, and Gene Ontology (GO) enrichment of module genes was consistent with cell-specific highly expressed genes. Many IRD genes were identified as hub genes and cell-specific regulons. Most IRDs, especially the retinitis pigmentosa (RP) genes, were enriched in rod-specific regulons. Integrated expression and transcription regulatory network genes, such as congenital stationary night blindness (CSNB) genes GRK1, PDE6B, and TRPM1, showed cell-specific expression and transcription characteristics in either rods or bipolar cells (BCs). IRD genes showed evolutionary conservation (GNAT2, PDE6G, and SAG) and divergence (GNAT2, MT-ND4, and PDE6A) along the trajectory of photoreceptors (PRs) among species. In particular, the Leber congenital amaurosis (LCA) gene OTX2 showed high expression at the beginning of the trajectory of both PRs and BCs. Conclusion: We identified molecular pathways and cell types closely connected with IRDs, bridging the gap between gene expression, genetics, and pathogenesis. The IRD genes enriched in cell-specific modules and regulons suggest that these diseases share common etiological bases. Overall, mining of interspecies transcriptome data reveals conserved transcriptomic features of retinas across species and promising applications in both normal retina anatomy and retina pathology.
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BACKGROUND: The effect of nonalcoholic fatty liver disease (NAFLD) on major adverse cardiovascular events (MACEs) can be influenced by the degree of coronary artery stenosis. However, the association between the severity of NAFLD and MACEs in patients who underwent coronary computed tomography angiography (CCTA) is unclear. METHODS: A total of 341 NAFLD patients who underwent CCTA were enrolled. The severity of NAFLD was divided into mild NAFLD and moderate-severe NAFLD by abdominal CT results. The degree of coronary artery stenosis was evaluated by using Coronary Artery Disease Reporting and Data System (CAD-RADS) category. Cox regression analysis and Kaplan-Meier analysis were used to assess poor prognosis. RESULTS: During the follow-up period, 45 of 341 NAFLD patients (13.20%) who underwent CCTA occurred MACEs. The severity of NAFLD (hazard ratio [HR] = 2.95[1.54-5.66]; p = 0.001) and CAD-RADS categories 3-5 (HR = 16.31[6.34-41.92]; p < 0.001) were independent risk factors for MACEs. The Kaplan-Meier analysis showed that moderate to severe NAFLD patients had a worsen prognosis than mild NAFLD patients (log-rank p < 0.001). Moreover, the combined receiver operating characteristic curve of the severity of NAFLD and CAD-RADS category showed a good predicting performance for the risk of MACEs, with an area under the curve of 0.849 (95% CI = 0.786-0.911). CONCLUSION: The severity of NAFLD was independent risk factor for MACEs in patients with obstructive CAD, having CAD-RADS 3-5 categories on CCTA.
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Angiografía por Tomografía Computarizada , Angiografía Coronaria , Enfermedad de la Arteria Coronaria , Estenosis Coronaria , Enfermedad del Hígado Graso no Alcohólico , Valor Predictivo de las Pruebas , Índice de Severidad de la Enfermedad , Humanos , Enfermedad del Hígado Graso no Alcohólico/diagnóstico por imagen , Enfermedad del Hígado Graso no Alcohólico/complicaciones , Masculino , Femenino , Persona de Mediana Edad , Factores de Riesgo , Medición de Riesgo , Enfermedad de la Arteria Coronaria/diagnóstico por imagen , Enfermedad de la Arteria Coronaria/mortalidad , Enfermedad de la Arteria Coronaria/complicaciones , Anciano , Pronóstico , Estenosis Coronaria/diagnóstico por imagen , Estenosis Coronaria/mortalidad , Estudios Retrospectivos , Factores de TiempoRESUMEN
Prenatal lethality associated with mouse knockout of Mettl16, a recently identified RNA N6-methyladenosine (m6A) methyltransferase, has hampered characterization of the essential role of METTL16-mediated RNA m6A modification in early embryonic development. Here, using cross-species single-cell RNA sequencing analysis, we found that during early embryonic development, METTL16 is more highly expressed in vertebrate hematopoietic stem and progenitor cells (HSPCs) than other methyltransferases. In Mettl16-deficient zebrafish, proliferation capacity of embryonic HSPCs is compromised due to G1/S cell cycle arrest, an effect whose rescue requires Mettl16 with intact methyltransferase activity. We further identify the cell-cycle transcription factor mybl2b as a directly regulated by Mettl16-mediated m6A modification. Mettl16 deficiency resulted in the destabilization of mybl2b mRNA, likely due to lost binding by the m6A reader Igf2bp1 in vivo. Moreover, we found that the METTL16-m6A-MYBL2-IGF2BP1 axis controlling G1/S progression is conserved in humans. Collectively, our findings elucidate the critical function of METTL16-mediated m6A modification in HSPC cell cycle progression during early embryonic development.
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Células Madre Hematopoyéticas , Metiltransferasas , Metilación de ARN , Proteínas de Unión al ARN , Factores de Transcripción , Pez Cebra , Animales , Humanos , Ratones , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Ciclo Celular , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Proliferación Celular , Desarrollo Embrionario/genética , Regulación del Desarrollo de la Expresión Génica , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/citología , Metiltransferasas/metabolismo , Metiltransferasas/genética , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Pez Cebra/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Proteínas de Pez Cebra/genética , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Metilación de ARN/genéticaRESUMEN
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.
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Factores de Empalme de ARN , Proteínas de Pez Cebra , Pez Cebra , Animales , Desarrollo Embrionario , Mutación , Precursores del ARN/metabolismo , Factores de Empalme de ARN/metabolismo , Células Madre/metabolismo , Pez Cebra/genética , Pez Cebra/crecimiento & desarrollo , Pez Cebra/metabolismo , Proteínas de Pez Cebra/metabolismoRESUMEN
In this study, the slurry diffusion in a cavity filled with coal gangue was studied by combining experimental and numerical simulation methods. By calibrating slurry and particle materials, the grouting process in coal gangue filling area is simulated successfully, and the change of slurry diffusion flow field and particle movement and settling process in different dimensions are deeply analyzed. Both experimental and numerical simulation results show that the particle settlement presents a bell-shaped curve, which is of great significance for understanding the particle movement and settlement behavior in the filling cavity. In addition, it is found that the grouting speed has a significant effect on the particle settlement during the slurry diffusion process. When the grouting speed increases from 0.1m /s to 0.2m /s, the particle settlement and diffusion range increases about twice. In the plane flow field, it is observed that the outward diffusion trend and speed of grouting are more obvious. It is worth noting that in the whole process of grouting, it is observed that with the increase of grouting distance and depth, both the velocity of slurry and particles show a trend of rapid initial decline and gradually slow down, and the flow velocity of slurry near the grouting outlet at a flow rate of 0.2m/s is 2-4 times that of 0.1m/s. This provides important enlightenment for the porous seepage effect at different grouting speeds.
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Carbón Mineral , Movimiento , Simulación por Computador , Difusión , PorosidadRESUMEN
BACKGROUND: To investigate whether CT-based radiomics can effectively differentiate between heterotopic pancreas (HP) and gastrointestinal stromal tumor (GIST), and whether different resampling methods can affect the model's performance. METHODS: Multi-phase CT radiological data were retrospectively collected from 94 patients. Of these, 40 with HP and 54 with GISTs were enrolled between April 2017 and November 2021. One experienced radiologist manually delineated the volume of interest and then resampled the voxel size of the images to 0.5 × 0.5 × 0.5 mm3, 1 × 1 × 1 mm3, and 2 × 2 × 2 mm3, respectively. Radiomics features were extracted using PyRadiomics, resulting in 1218 features from each phase image. The datasets were randomly divided into training set (n = 66) and validation set (n = 28) at a 7:3 ratio. After applying multiple feature selection methods, the optimal features were screened. Radial basis kernel function-based support vector machine (RBF-SVM) was used as the classifier, and model performance was evaluated using the area under the receiver operating curve (AUC) analysis, as well as accuracy, sensitivity, and specificity. RESULTS: The combined phase model performed better than the other phase models, and the resampling method of 0.5 × 0.5 × 0.5 mm3 achieved the highest performance with an AUC of 0.953 (0.881-1), accuracy of 0.929, sensitivity of 0.938, and specificity of 0.917 in the validation set. The Delong test showed no significant difference in AUCs among the three resampling methods, with p > 0.05. CONCLUSIONS: Radiomics can effectively differentiate between HP and GISTs on CT images, and the diagnostic performance of radiomics is minimally affected by different resampling methods.
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Tumores del Estroma Gastrointestinal , Humanos , Tumores del Estroma Gastrointestinal/diagnóstico por imagen , Radiómica , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Páncreas/diagnóstico por imagenRESUMEN
RATIONALE AND OBJECTIVES: Clinical assessment of abdominal aortic aneurysm (AAA) intervention and rupture risk relies primarily on maximum diameter, but studies have shown that sole dependence on diameter has limitations. CTA-based radiomics, aneurysm and lumen area change rates (AACR, LACR) are measured to predict potential AAA events. MATERIALS AND METHODS: Between January 2017 and November 2022, 260 AAA patients from four centers who underwent two preoperative CTA examinations were included in this retrospective study. The endpoint event is defined as AAA rupture or repair. Patients were categorized into event and no-event groups based on the occurrence of endpoint event during follow-up. AACR and LACR were assessed using baseline and follow-up CTA, with radiomics features extracted from the baseline images. C-statistics and the Kaplan-Meier analysis were used to evaluate the predictive performance. RESULTS: A total of 193 eligible infrarenal AAA patients were included, 176 (91.2%) were man and 17 (8.8%) were woman. The median follow-up was 33.4 (14.2, 57.4) months. Seven models were constructed, comprising the aneurysm-based Radscore model, lumen-based Radscore model, intraluminal thrombus (ILT)-based Radscore model, AACR model, LACR model, clinical model (including high-density lipoprotein, D-dimer, and baseline aneurysm diameter), and a merged model. On the external validation set, the C-index of seven models were 0.713 (0.574-0.853), 0.642 (0.499-0.786), 0.727 (0.600-0.854), 0.619 (0.484-0.753), 0.680 (0.530-0.830), 0.690 (0.557-0.824) and 0.760 (0.651-0.869), in that order. In the Kaplan-Meier analysis, the merged model was best-divided patients into high/low-risk groups with Log-rank p < 0.0001. The AARC and LARC between non-event and event groups have significant differences (AACR: 1.4 cm2/y vs. 2.3 cm2/y, p < 0.0001; LACR: 0.3 cm2/y vs. 1.1 cm2/y, p < 0.0001). CONCLUSION: CTA-based radiomics, AACR and LACR have good predictive value for outcome event in infrarenal AAA patients.
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An important question in neuroscience is how sensory systems change as animals grow and interact with the environment. Exploring sensory systems in animals as they develop can reveal how networks of neurons process information as the neurons themselves grow and the needs of the animal change. Here we compared the structure and function of peripheral parts of the olfactory pathway in newly hatched and adult locusts. We found that populations of olfactory sensory neurons (OSNs) in hatchlings and adults responded with similar tunings to a panel of odors. The morphologies of local neurons (LNs) and projection neurons (PNs) in the antennal lobes (ALs) were very similar in both age groups, though they were smaller in hatchlings, they were proportional to overall brain size. The odor evoked responses of LNs and PNs were also very similar in both age groups, characterized by complex patterns of activity including oscillatory synchronization. Notably, in hatchlings, spontaneous and odor-evoked firing rates of PNs were lower, and LFP oscillations were lower in frequency, than in the adult. Hatchlings have smaller antennae with fewer OSNs; removing antennal segments from adults also reduced LFP oscillation frequency. Thus, consistent with earlier computational models, the developmental increase in frequency is due to increasing intensity of input to the oscillation circuitry. Overall, our results show that locusts hatch with a fully formed olfactory system that structurally and functionally matches that of the adult, despite its small size and lack of prior experience with olfactory stimuli.
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Saltamontes , Neuronas Receptoras Olfatorias , Animales , Odorantes , Vías Olfatorias/fisiología , Neuronas Receptoras Olfatorias/fisiología , Interneuronas , Olfato/fisiologíaRESUMEN
Introduction: Poor oral hygiene is linked to high risks of many systemic diseases, including cancers. Oral dysbiosis is closely associated with poor oral hygiene, causing tooth loss, gingivitis, and periodontitis. We provide a summary of studies and discuss the risk factors for oesophageal squamous cell carcinoma (ESCC) from a microbial perspective in this review.Methods: A literature search of studies published before December 31, 2022 from PubMed, Web of Science, and The Cochrane Library was performed. The search strategies included the following keywords: (1) oral care, oral health, oral hygiene, dental health, dental hygiene, tooth loss, teeth loss, tooth absence, missing teeth, edentulism, tooth brushing, mouthwash, and tooth cleaning; (2) esophageal, esophagus, oesophagus, and oesophageal; (3) cancer, carcinoma, tumor, and neoplasm.Discussion: Poor oral health, indicated by infrequent tooth brushing, chronic periodontitis, and tooth loss, has been associated with an increased risk of squamous dysplasia and ESCC. Oral microbial diversity and composition are profoundly dysregulated during oesophageal tumorigenesis. Similar to the oral microbiota, the oesophageal microbiota varies distinctly in multiple bacterial taxa in ESCC and gastric cardia adenocarcinoma, both of which have high co-occurrence rates in the "Oesophageal Cancer Belt". In addition, the potential roles of oncogenic viruses in ESCC have also been discussed. We also briefly explore the potential mechanisms underlying the tumor-promoting role of dysregulated microbiota for the development of therapeutic targeting strategies.Conclusion: Poor oral health is an established risk indicator of ESCC. The dysbiosis of microbiota in upper gastrointestinal tract that highly resembles the oral microbial ecosystem but with distinct features at individual sites contributes to the development and progression of ESCC.