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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.
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Adenocarcinoma/genética , Carcinoma Ductal Pancreático/genética , Neoplasias Pancreáticas/genética , Proteogenómica , Adenocarcinoma/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Algoritmos , Carcinoma Ductal Pancreático/diagnóstico , Estudios de Cohortes , Células Endoteliales/metabolismo , Epigénesis Genética , Femenino , Dosificación de Gen , Genoma Humano , Glucólisis , Glicoproteínas/biosíntesis , Humanos , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Neoplasias Pancreáticas/diagnóstico , Fenotipo , Fosfoproteínas/metabolismo , Fosforilación , Pronóstico , Proteínas Quinasas/metabolismo , Proteoma/metabolismo , Especificidad por Sustrato , Transcriptoma/genéticaRESUMEN
To elucidate the deregulated functional modules that drive clear cell renal cell carcinoma (ccRCC), we performed comprehensive genomic, epigenomic, transcriptomic, proteomic, and phosphoproteomic characterization of treatment-naive ccRCC and paired normal adjacent tissue samples. Genomic analyses identified a distinct molecular subgroup associated with genomic instability. Integration of proteogenomic measurements uniquely identified protein dysregulation of cellular mechanisms impacted by genomic alterations, including oxidative phosphorylation-related metabolism, protein translation processes, and phospho-signaling modules. To assess the degree of immune infiltration in individual tumors, we identified microenvironment cell signatures that delineated four immune-based ccRCC subtypes characterized by distinct cellular pathways. This study reports a large-scale proteogenomic analysis of ccRCC to discern the functional impact of genomic alterations and provides evidence for rational treatment selection stemming from ccRCC pathobiology.
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Carcinoma de Células Renales/genética , Proteínas de Neoplasias/genética , Proteogenómica , Transcriptoma/genética , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Carcinoma de Células Renales/inmunología , Carcinoma de Células Renales/patología , Supervivencia sin Enfermedad , Exoma/genética , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Genoma Humano/genética , Humanos , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/inmunología , Fosforilación Oxidativa , Fosforilación/genética , Transducción de Señal/genética , Transcriptoma/inmunología , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Secuenciación del ExomaRESUMEN
To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC. VIDEO ABSTRACT.
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Proteínas de Neoplasias/genética , Neoplasias Quísticas, Mucinosas y Serosas/genética , Neoplasias Ováricas/genética , Proteoma , Acetilación , Inestabilidad Cromosómica , Reparación del ADN , ADN de Neoplasias , Femenino , Dosificación de Gen , Humanos , Espectrometría de Masas , Fosfoproteínas/genética , Procesamiento Proteico-Postraduccional , Análisis de SupervivenciaRESUMEN
Each vertebrate species appears to have a unique timing mechanism for forming somites along the vertebral column, and the process in human remains poorly understood at the molecular level due to technical and ethical limitations. Here, we report the reconstitution of human segmentation clock by direct reprogramming. We first reprogrammed human urine epithelial cells to a presomitic mesoderm (PSM) state capable of long-term self-renewal and formation of somitoids with an anterior-to-posterior axis. By inserting the RNA reporter Pepper into HES7 and MESP2 loci of these iPSM cells, we show that both transcripts oscillate in the resulting somitoids at ~5 h/cycle. GFP-tagged endogenous HES7 protein moves along the anterior-to-posterior axis during somitoid formation. The geo-sequencing analysis further confirmed anterior-to-posterior polarity and revealed the localized expression of WNT, BMP, FGF, and RA signaling molecules and HOXA-D family members. Our study demonstrates the direct reconstitution of human segmentation clock from somatic cells, which may allow future dissection of the mechanism and components of such a clock and aid regenerative medicine.
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Mesodermo , Somitos , Humanos , Somitos/metabolismo , Mesodermo/metabolismo , Transducción de Señal , Regulación del Desarrollo de la Expresión Génica , Tipificación del Cuerpo/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismoRESUMEN
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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Lespedeza potaninii, a xerophytic subshrub belonging to the legume family, is native to the Tengger Desert and is highly adapted to drought. It has important ecological value due to its drought adaptability, but the underlying molecular mechanisms remain largely unknown. Here, we report a 1.24 Gb chromosome-scale assembly of the L. potaninii genome (contig N50 = 15.75â Mb). Our results indicate that L. potaninii underwent an allopolyploid event with 2 subgenomes, A and B, presenting asymmetric evolution and B subgenome dominance. We estimate that the 2 diploid progenitors of L. potaninii diverged around 3.6 million years ago (MYA) and merged around 1.0 MYA. We revealed that the expansion of hub genes associated with drought responses, such as the binding partner 1 of accelerated cell death 11 (ACD11) (BPA1), facilitated environmental adaptations of L. potaninii to desert habitats. We found a novel function of the BPA1 family in abiotic stress tolerance in addition to the known role in regulating the plant immune response, which could improve drought tolerance by positively regulating reactive oxygen species homeostasis in plants. We revealed that bZIP transcription factors could bind to the BPA1 promoter and activate its transcription. Our work fills the genomic data gap in the Lespedeza genus and the tribe Desmodieae, which should provide theoretical support both in the study of drought tolerance and in the molecular breeding of legume crops.
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Adaptación Fisiológica , Sequías , Genoma de Planta , Adaptación Fisiológica/genética , Evolución Molecular , Fabaceae/genética , Fabaceae/fisiología , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Estrés Fisiológico/genética , Regulación de la Expresión Génica de las Plantas , FilogeniaRESUMEN
Viral infections can alter host transcriptomes by manipulating host splicing machinery. Despite intensive transcriptomic studies on SARS-CoV-2, a systematic analysis of alternative splicing (AS) in severe COVID-19 patients remains largely elusive. Here we integrated proteomic and transcriptomic sequencing data to study AS changes in COVID-19 patients. We discovered that RNA splicing is among the major down-regulated proteomic signatures in COVID-19 patients. The transcriptome analysis showed that SARS-CoV-2 infection induces widespread dysregulation of transcript usage and expression, affecting blood coagulation, neutrophil activation, and cytokine production. Notably, CD74 and LRRFIP1 had increased skipping of an exon in COVID-19 patients that disrupts a functional domain, which correlated with reduced antiviral immunity. Furthermore, the dysregulation of transcripts was strongly correlated with clinical severity of COVID-19, and splice-variants may contribute to unexpected therapeutic activity. In summary, our data highlight that a better understanding of the AS landscape may aid in COVID-19 diagnosis and therapy.
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COVID-19 , Empalme Alternativo/genética , COVID-19/genética , Prueba de COVID-19 , Humanos , Proteómica , SARS-CoV-2/genética , TranscriptomaRESUMEN
BACKGROUND AND AIMS: Patients with acute myeloid leukaemia (AML) suffer from severe myocardial injury during daunorubicin (DNR)-based chemotherapy and are at high risk of cardiac mortality. The crosstalk between tumour cells and cardiomyocytes might play an important role in chemotherapy-related cardiotoxicity, but this has yet to be demonstrated. This study aimed to identify its underlying mechanism and explore potential therapeutic targets. METHODS: Cardiac tissues were harvested from an AML patient after DNR-based chemotherapy and were subjected to single-nucleus RNA sequencing. Cardiac metabolism and function were evaluated in AML mice after DNR treatment by using positron emission tomography, magnetic resonance imaging, and stable-isotope tracing metabolomics. Plasma cytokines were screened in AML mice after DNR treatment. Genetically modified mice and cell lines were used to validate the central role of the identified cytokine and explore its downstream effectors. RESULTS: In the AML patient, disruption of cardiac metabolic homeostasis was associated with heart dysfunction after DNR-based chemotherapy. In AML mice, cardiac fatty acid utilization was attenuated, resulting in cardiac dysfunction after DNR treatment, but these phenotypes were not observed in similarly treated tumour-free mice. Furthermore, tumour cell-derived interleukin (IL)-1α was identified as a primary factor leading to DNR-induced cardiac dysfunction and administration of an anti-IL-1α neutralizing antibody could improve cardiac functions in AML mice after DNR treatment. CONCLUSIONS: This study revealed that crosstalk between tumour cells and cardiomyocytes during chemotherapy could disturb cardiac energy metabolism and impair heart function. IL-1α neutralizing antibody treatment is a promising strategy for alleviating chemotherapy-induced cardiotoxicity in AML patients.
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Daunorrubicina , Interleucina-1alfa , Leucemia Mieloide Aguda , Animales , Leucemia Mieloide Aguda/tratamiento farmacológico , Humanos , Interleucina-1alfa/metabolismo , Ratones , Cardiotoxicidad/etiología , Antibióticos Antineoplásicos/efectos adversos , Masculino , Miocitos Cardíacos/efectos de los fármacos , Miocitos Cardíacos/metabolismoRESUMEN
Protein-protein interactions (PPIs) are fundamental to understanding biological systems as protein complexes are the active molecular modules critical for carrying out cellular functions. Dysfunctional PPIs have been associated with various diseases including cancer. Systems-wide PPI analysis not only sheds light on pathological mechanisms, but also represents a paradigm in identifying potential therapeutic targets. In recent years, cross-linking mass spectrometry (XL-MS) has emerged as a powerful tool for defining endogenous PPIs of cellular networks. While proteome-wide studies have been performed in cell lysates, intact cells and tissues, applications of XL-MS in clinical samples have not been reported. In this study, we adopted a DSBSO-based in vivo XL-MS platform to map interaction landscapes from two breast cancer patient-derived xenograft (PDX) models. As a result, we have generated a PDX interaction network comprising 2,557 human proteins and identified interactions unique to breast cancer subtypes. Interestingly, most of the observed differences in PPIs correlated well with protein abundance changes determined by TMT-based proteome quantitation. Collectively, this work has demonstrated the feasibility of XL-MS analysis in clinical samples, and established an analytical workflow for tissue cross-linking that can be generalized for mapping PPIs from patient samples in the future to dissect disease-relevant cellular networks.
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Neoplasias de la Mama , Mapas de Interacción de Proteínas , Humanos , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Animales , Espectrometría de Masas/métodos , Ratones , Proteoma/metabolismo , Proteoma/análisis , Proteómica/métodos , Mapeo de Interacción de Proteínas/métodosRESUMEN
One of the sensitive markers for autoimmune thyroid disease (AITD) clinical identification is thyroid-stimulating hormone receptor antibodies (TRAbs). To quickly distinguish TRAb with distinct antigenic epitopes, a straightforward and uncomplicated technique has not yet been created. The objective of this study is to search for molecular diagnostic targets for different types of AITD {Graves' disease (GD), Graves' orbitopathy (GO), GD with third-degree goiter [GD(3)], hypothyroidism combined with positive TRAb [HT(TRAb+)]} as molecular diagnostic targets. Following action on thyroid cells, differential genes (DEGs) generated by TRAb with distinct antigenic epitopes were detected and identified by RNA sequencing (RNA-Seq), bioinformatics analysis, and quantitative reverse transcription-polymerase chain reaction (RT-qPCR) in the serum of patients with AITD. Using the 5-ethynyl-2'-deoxyuridine (EdU) assay, the effect of coculturing thyroid cells with different antigenic TRAb epitopes on the cells' capacity to proliferate was investigated. Bioinformatics analysis and RT-qPCR validation identified one GD key gene alpha 2-HS glycoprotein (AHSG), two GO key genes [adrenoceptor alpha 1D (ADRA1D) and H2B clustered histone 18 (H2BC18)], two GD(3) key genes [suppressor of cytokine signaling 1 (SOCS1) and cytochrome b-245 beta (CYBB)], and one HT(TRAb+) key gene (MASP2). Correlation analysis and ROC curves showed that the abovementioned genes could be used as molecular diagnostic targets for different types of AITD. Finally, EdU results showed that TRAb inhibited thyroid cell proliferation in the HT(TRAb+) group compared with the normal control group, whereas the remaining three groups promoted thyroid cell proliferation, with a statistically significant difference (P < 0.05). We identified six key genes for different types of AITD, which have diagnostic value for different types of AITD. Meanwhile, we found that TRAbs with different antigenic epitopes in AITD have different biological functions.NEW & NOTEWORTHY We identified six molecular targets of different types of AITD [GD, GO, GD(3), and HT(TRAb+)], which have diagnostic value for different types of AITD. Meanwhile, we found that TRAb with different antigenic epitopes extracted from the sera of patients with AITD had different biological functions, which also provided a new idea for further research on the mechanism of action of TRAb with different antigenic epitopes in AITD.
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Epítopos , Enfermedad de Graves , Receptores de Tirotropina , Humanos , Receptores de Tirotropina/inmunología , Receptores de Tirotropina/genética , Epítopos/inmunología , Enfermedad de Graves/inmunología , Enfermedad de Graves/sangre , Enfermedad de Graves/diagnóstico , Oftalmopatía de Graves/inmunología , Oftalmopatía de Graves/genética , Oftalmopatía de Graves/sangre , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Femenino , Masculino , Inmunoglobulinas Estimulantes de la Tiroides/sangre , Inmunoglobulinas Estimulantes de la Tiroides/inmunología , Glándula Tiroides/inmunología , Adulto , Persona de Mediana Edad , Proliferación Celular , Tiroiditis Autoinmune/inmunología , Tiroiditis Autoinmune/genética , Hipotiroidismo/inmunologíaRESUMEN
BACKGROUND: Neoadjuvant therapy followed by surgery has become the standard of care for locally advanced esophageal squamous cell carcinoma (ESCC) and accurate pathological response assessment is critical to assess the therapeutic efficacy. However, it can be laborious and inconsistency between different observers may occur. Hence, we aim to develop an interpretable deep-learning model for efficient pathological response assessment following neoadjuvant therapy in ESCC. METHODS: This retrospective study analyzed 337 ESCC resection specimens from 2020-2021 at the Pudong-Branch (Cohort 1) and 114 from 2021-2022 at the Puxi-Branch (External Cohort 2) of Fudan University Shanghai Cancer Center. Whole slide images (WSIs) from these two cohorts were generated using different scanning machines to test the ability of the model in handling color variations. Four pathologists independently assessed the pathological response. The senior pathologists annotated tumor beds and residual tumor percentages on WSIs to determine consensus labels. Furthermore, 1850 image patches were randomly extracted from Cohort 1 WSIs and binarily classified for tumor viability. A deep-learning model employing knowledge distillation was developed to automatically classify positive patches for each WSI and estimate the viable residual tumor percentages. Spatial heatmaps were output for model explanations and visualizations. RESULTS: The approach achieved high concordance with pathologist consensus, with an R^2 of 0.8437, a RAcc_0.1 of 0.7586, a RAcc_0.3 of 0.9885, which were comparable to two senior pathologists (R^2 of 0.9202/0.9619, RAcc_0.1 of 8506/0.9425, RAcc_0.3 of 1.000/1.000) and surpassing two junior pathologists (R^2 of 0.5592/0.5474, RAcc_0.1 of 0.5287/0.5287, RAcc_0.3 of 0.9080/0.9310). Visualizations enabled the localization of residual viable tumor to augment microscopic assessment. CONCLUSION: This work illustrates deep learning's potential for assisting pathological response assessment. Spatial heatmaps and patch examples provide intuitive explanations of model predictions, engendering clinical trust and adoption (Code and data will be available at https://github.com/WinnieLaugh/ESCC_Percentage once the paper has been conditionally accepted). Integrating interpretable computational pathology could help enhance the efficiency and consistency of tumor response assessment and empower precise oncology treatment decisions.
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BACKGROUND: Omics characterization of pancreatic adenocarcinoma tissue is complicated by the highly heterogeneous and mixed populations of cells. We evaluate the feasibility and potential benefit of using a coring method to enrich specific regions from bulk tissue and then perform proteogenomic analyses. METHODS: We used the Biopsy Trifecta Extraction (BioTExt) technique to isolate cores of epithelial-enriched and stroma-enriched tissue from pancreatic tumor and adjacent tissue blocks. Histology was assessed at multiple depths throughout each core. DNA sequencing, RNA sequencing, and proteomics were performed on the cored and bulk tissue samples. Supervised and unsupervised analyses were performed based on integrated molecular and histology data. RESULTS: Tissue cores had mixed cell composition at varying depths throughout. Average cell type percentages assessed by histology throughout the core were better associated with KRAS variant allele frequencies than standard histology assessment of the cut surface. Clustering based on serial histology data separated the cores into three groups with enrichment of neoplastic epithelium, stroma, and acinar cells, respectively. Using this classification, tumor overexpressed proteins identified in bulk tissue analysis were assigned into epithelial- or stroma-specific categories, which revealed novel epithelial-specific tumor overexpressed proteins. CONCLUSIONS: Our study demonstrates the feasibility of multi-omics data generation from tissue cores, the necessity of interval H&E stains in serial histology sections, and the utility of coring to improve analysis over bulk tissue data.
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Interleukin-17A (IL-17A) plays a pivotal role in the pathogenesis of Graves' disease (GD), an autoimmune disorder affecting thyroid function, but the detailed regulatory mechanisms remain elusive. Circular RNAs (circRNAs) have emerged as key regulators of IL-17A expression and secretion in autoimmune diseases, yet their specific role in GD, especially within CD4 + T lymphocytes, are not well understood. In this study, a circRNA, circPHF16 (hsa_circ_0090364) was found to be highly expressed in the peripheral blood mononuclear cells and serum of GD patients. In vitro experiments in Jurkat T cells revealed that silencing of circPHF16 suppressed IL-17A expression and secretion, while overexpression of circPHF16 had the opposite effect. Furthermore, bioinformatics analysis demonstrated a circPHF16/miR-378a-3p/IL6ST pathway, in which circPHF16 regulates IL6ST expression, which, in turn, influences IL-17A expression and secretion by interacting with miR-378a-3p. In vivo studies in a mouse model of GD showed similar trends in molecular expression levels, consistent with competitive endogenous RNA interactions. Together the results of the study identify circPHF16 as a potential target in the development of new strategies for GD diagnosis and treatment, and thus, offer a theoretical foundation for clinical therapeutic approaches in GD.
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Enfermedad de Graves , Interleucina-17 , MicroARNs , ARN Circular , MicroARNs/genética , MicroARNs/metabolismo , ARN Circular/genética , ARN Circular/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucina-17/genética , Enfermedad de Graves/genética , Enfermedad de Graves/metabolismo , Animales , Ratones , Células Jurkat , Masculino , Femenino , Regulación de la Expresión Génica , AdultoRESUMEN
OBJECTIVE: To explore the role of HIF-1α in hypercoagulable state of COPD induced by lipopolysaccharide plus smoking in rats. It also has to explore the regulatory mechanism of HIF-1α-EPO/EDN-1/VEGF pathway by using its activator and inhibitor. METHODS: 60 Sprague-Dawley rats (SD rats) were randomly divided into healthy control group, COPD hypercoagulable control group, activator group, and inhibitor group with 15 rats in each group. The healthy control group was fed freely. The other groups were given smoke and lipopolysaccharide by tracheal instillation to establish the experimental animal model of COPD hypercoagulability. After successful modeling, each experimental group was given 0.9 % sodium chloride solution and corresponding drugs by intraperitoneal injection for 7 days. Lung function was detected after drug administration. Hematoxylin-eosin staining was used to observe the pathological changes of lung tissue. Enzyme-linked immunosorbent assay was used to detect serum D-D,F (1 + 2),IL-6,TNF-α. The mRNA expressions of HIF-1α, EPO, EDN-1, and VEGF were detected by RT-PCR. Western-Blot and IHC were used to detect the expression of HIF-1α, EPO, EDN-1, and VEGF in lung tissue of rats. RESULTS: Compared with the healthy control group, rats in COPD hypercoagulable control group had COPD symptoms/signs, decreased lung function, increased the expression of serum D-D and F (1 + 2), increased the expression of inflammatory factors IL-6,TNF-α, and increased the expression of proteins HIF-1α, EPO, EDN-1 and VEGF. Compared with COPD hypercoagulable control group, lung function in activator group and inhibitor group had no obvious changes. The expressions of serum D-D,F (1 + 2),IL-6,TNF-α in activator group have increased noticeably. The expressions of proteins HIF-1α, EPO, EDN-1, and VEGF have further increased. Compared with COPD hypercoagulable control group, the expression of serum D-D, F (1 + 2), HIF-1α, EPO, EDN-1, and VEGF in the inhibitor group decreased. CONCLUSION: HIF-1α-EPO/EDN-1/VEGF pathway plays an important role in the hypercoagulable state of COPD. HIF-1α inhibitor can improve airway inflammation and reduce hypercoagulability in COPD model rats.
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Enfermedad Pulmonar Obstructiva Crónica , Trombofilia , Animales , Ratas , Subunidad alfa del Factor 1 Inducible por Hipoxia , Interleucina-6 , Lipopolisacáridos , Enfermedad Pulmonar Obstructiva Crónica/complicaciones , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
A detailed and accurate combustion reaction mechanism is crucial for understanding the nature of fuel combustion. In this work, a theoretical study of reaction HCCO+HO2 using M06-2X/6-311++G(d,p) for geometry optimization and combined methods based on spin-unrestricted CCSD(T)/CBS level of theory with basis set extrapolation from MP2/aug-cc-pVnZ (n=T and Q) for energy calculations were performed. The temperature- and pressure-dependent rate coefficients at 300-2000â K and 0.01-100â atm, suitable for combustion conditions, were derived using the Rice-Ramsberger-Kassel-Marcus/Master-Equation approach. Furthermore, temperature-dependent thermochemistry data of key species for the HCCO+HO2 system has also been studied. Finally, an updated ketene model is developed by supplementing the most recent theoretical work and the theoretical work in this paper. This updated model was tested to simulate the speciation of ketene oxidation in available experimental research. It is shown that the updated model for predicting ketene oxidation exhibits a high level of agreement with experimental data across a wide range of species profiles. An analysis was conducted to identify the crucial reactions that influence ketene ignition. This paper's research findings are essential for enhancing the combustion mechanism of ketene and other hydrocarbons and oxygenated hydrocarbon fuels.
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OBJECTIVES: Cardiovascular magnetic resonance (CMR) imaging is routinely performed for assessing right ventricular (RV) systolic but not diastolic function. We aimed to investigate CMR-based assessment of RV diastolic function in pediatric patients with repaired tetralogy of Fallot (rTOF), compared to transthoracic echocardiography (TTE) measurements. METHODS: A total of 130 consecutive pediatric patients with rTOF who underwent clinically indicated CMR and same-day TTE were included. Forty-three controls were recruited. Phase-contrast images were used to measure trans-tricuspid valve flow velocities during early (E) and late diastolic (A) phases (measured in cm/s). Feature tracking of the tricuspid annulus was performed to derive early (e') and late diastolic (a') myocardial velocities (measured in cm/s). RV diastolic function was evaluated by E/A ratio, E/e' ratio, and E-wave deceleration time (measured in milliseconds). Regression analyses were utilized to identify potential variables associated with RV diastolic dysfunction (DD). The performance of CMR-derived parameters in diagnosing RV DD was assessed using receiver-operating characteristic analyses. RESULTS: Good agreement was found between CMR and TTE measurements (ICC 0.70-0.89). Patients with RV DD (n = 67) showed significantly different CMR-derived parameters including E and e' velocities, and E/A and E/e' ratio, compared to patients without DD (n = 63) (all p < 0.05). CMR-derived E and e' velocities and E/e' ratio were independent predictors of RV DD. E/e' of 5.8 demonstrated the highest discrimination of RV DD (AUC 0.76, sensitivity 70%, specificity 86%). CONCLUSIONS: CMR-derived parameters showed good agreement with TTE parameters in determining RV DD. CMR-derived E/e' was proved to be the most effective in identifying RV DD. CLINICAL RELEVANCE STATEMENT: This study demonstrated the feasibility and efficacy of CMR in assessing diastolic function in pediatric patients. RV DD was presented in over half of patients according to current TTE guidelines, highlighting the need for assessing RV diastolic function during follow-up. KEY POINTS: ⢠Routinely acquired cine and phase-contrast cardiovascular magnetic resonance (CMR) images yielded right ventricular (RV) diastolic parameters which demonstrated good agreement with transthoracic echocardiography (TTE) measurements. ⢠There was a high prevalence of RV diastolic function impairment in pediatric patients with repaired tetralogy of Fallot (rTOF). ⢠CMR is a reliable complementary modality of TTE for RV diastolic function evaluation.
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Diástole , Ecocardiografía , Tetralogía de Fallot , Disfunción Ventricular Derecha , Humanos , Tetralogía de Fallot/cirugía , Tetralogía de Fallot/diagnóstico por imagen , Tetralogía de Fallot/fisiopatología , Masculino , Femenino , Niño , Ecocardiografía/métodos , Adolescente , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Disfunción Ventricular Derecha/etiología , Preescolar , Función Ventricular Derecha/fisiología , Imagen por Resonancia Cinemagnética/métodos , Imagen por Resonancia Magnética/métodosRESUMEN
Electron-rich and hindered aryl chlorides are the most challenging substrates in Suzuki-Miyaura cross-coupling (SMC) reactions. Herein, we report a highly efficient catalytic system for the SMC reaction using trace amounts of commercially available catalysts [Pd(PPh3)4/(t-Bu)PCy2; Pd loading as low as 9.5 × 10-5 mol%]. This catalytic system can efficiently couple deactivated and sterically hindered aryl chlorides with various substituted phenylboronic acids, even in one-pot multiple coupling reactions (yield of products up to 92%). The impact of solvents on SMC reactions and the mechanisms of by-product formation in aryl boronic acid couplings are analyzed using density functional theory (DFT). Utilizing trace amounts of commercially available catalysts avoids complex synthesis, reduces costs, and minimizes metal residues.
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BACKGROUND: Zygotic genome activation (ZGA) is an important event in the early embryo development, and human embryo developmental arrest has been highly correlated with ZGA failure in clinical studies. Although a few studies have linked maternal factors to mammalian ZGA, more studies are needed to fully elucidate the maternal factors that are involved in ZGA. METHODS AND RESULTS: In this study, we utilized published single-cell RNA sequencing data from a Dux-mediated mouse embryonic stem cell to induce a 2-cell-like transition state and selected potential drivers for the transition according to an RNA velocity analysis. CONCLUSIONS: An overlap of potential candidate markers of 2-cell-like-cells identified in this research with markers generated by various data sets suggests that Trim75 is a potential driver of minor ZGA and may recruit EP300 and establish H3K27ac in the gene body of minor ZGA genes, thereby contributing to mammalian preimplantation embryo development.
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Regulación del Desarrollo de la Expresión Génica , Cigoto , Animales , Humanos , Ratones , Embrión de Mamíferos , Desarrollo Embrionario/genética , Genoma/genética , Cigoto/metabolismoRESUMEN
When confronted with wastewater that is characterized by complex composition, stable molecular structure, and high concentration, relying solely on photocatalytic technology proves inadequate in achieving satisfactory degradation results. Therefore, the integration of other highly efficient degradation techniques has emerged as a viable approach to address this challenge. Herein, a novel strategy was employed whereby the exfoliated g-C3N4 nanosheets (CNs) with exceptional photocatalytic performance, were intimately combined with porous rod-shaped cobalt ferrite (CFO) through a co-calcination process to form the composite CFO/CNs, which exhibited remarkable efficacy in the degradation of various organic pollutants through the combination of photocatalysis and Fenton-like process synergistically, exemplified by the representative case of tetracycline hydrochloride (TCH, 200 mL, 50 mg/L). Specifically, under 1 mM of peroxymonosulfate (PMS) and illumination conditions, 50 mg of 1CFO/9CNs achieved a TCH removal ratio of â¼90% after 60 min of treatment. Furthermore, this work comprehensively investigated the influence of various factors, including catalyst and PMS dosages, solution pH, and the presence of anions and humate, on the degradation efficiency of pollutants. Besides, quenching experiments and EPR tests confirmed the establishment of an S-scheme heterojunction between CNs and CFO, which facilitated the effective spatial separation of photoexcited charge carriers and preserved the potent redox potential of photogenerated electrons and holes. This work offers a valuable reference for the integration of photocatalysis with the PMS-based Fenton-like process.