ABSTRACT
Persistent and unresolved inflammation is a common underlying factor observed in several and seemingly unrelated human diseases, including cardiovascular and neurodegenerative diseases. ...Particularly, in atopic conditions, acute inflammatory responses such as those triggered by insect venom, food or drug allergies possess also a life‐threatening potential. However, respiratory allergies predominantly exhibit late immune responses associated with chronic inflammation, that can eventually progress into a severe phenotype displaying similar features as those observed in other chronic inflammatory diseases, as is the case of uncontrolled severe asthma. This review aims to explore the different facets and systems involved in chronic allergic inflammation, including processes such as tissue remodelling and immune cell dysregulation, as well as genetic, metabolic and microbiota alterations, which are common to other inflammatory conditions. Our goal here was to deepen on the understanding of an entangled disease as is chronic allergic inflammation and expose potential avenues for the development of better diagnostic and intervention strategies.
The RNA polymerase II-associated protein 1 (RPAP1) is conserved across metazoa and required for stem cell differentiation in plants; however, very little is known about its mechanism of action or its ...role in mammalian cells. Here, we report that RPAP1 is essential for the expression of cell identity genes and for cell viability. Depletion of RPAP1 triggers cell de-differentiation, facilitates reprogramming toward pluripotency, and impairs differentiation. Mechanistically, we show that RPAP1 is essential for the interaction between RNA polymerase II (RNA Pol II) and Mediator, as well as for the recruitment of important regulators, such as the Mediator-specific RNA Pol II factor Gdown1 and the C-terminal domain (CTD) phosphatase RPAP2. In agreement, depletion of RPAP1 diminishes the loading of total and Ser5-phosphorylated RNA Pol II on many genes, with super-enhancer-driven genes among the most significantly downregulated. We conclude that Mediator/RPAP1/RNA Pol II is an ancient module, conserved from plants to mammals, critical for establishing and maintaining cell identity.
Display omitted
•RPAP1 is an RNA Pol II regulator, conserved from plants to mammals•RPAP1 depletion erases cell identity gene expression, triggering de-differentiation•Mechanistically, RPAP1 is critical for the Mediator-RNA Pol II interaction•RPAP1 preferentially contributes to enhancer-driven gene transcription
Lynch et al. report a regulator of RNA Pol II called RPAP1, displaying functional conservation from plants to mammals. RPAP1 is required to establish and maintain cell identity. Mechanistically, RPAP1 is critical for the Mediator-RNA Pol II interaction, thereby preserving normal transcription at enhancer-driven genes.
Based on mRNA expression, accRCC can be divided in four molecular subtypes (ccrcc1-4), associated with prognosis, angiogenic signature, immune phenotype and therapy response. miRNAs are master ...regulators of mRNA function. We assessed the correlation of miRNA expression with (1) ccrccc1-4 subtypes, (2) mRNA targets and (3) outcome.
We performed miRNome analysis of 128 accRCC. (1) Unsupervised hierarchical clustering was done using 50 miRNAs with the most variable expression across all samples. Results were validated on TCGA data (n=255). (2) For miRNAs with subtype-specific expression, we performed pathway analysis of predicted mRNA targets (IPA, KEGG) and assessed target-downregulation in TCGA. (3) We used Cox regression to correlate miRNA expression with overall survival (OS) since diagnosis. Hazard ratios (HR) were correlated with subtype-specific expression (Pearson).
(1) Samples separated in two miRNA clusters, that partially overlapped with molecular subtypes. Cluster 1 consisted of 69% favourable subtypes (ccrcc2 or 3), cluster 2 of 77% unfavourable (ccrcc1 or 4) (p<2.2e-16). (2) Pathway analysis of predicted mRNA targets and targets suppressed in TCGA, suggested that favourable subtypes exhibit more angiogenic signaling, whereas unfavourable subtypes activate pathways involved in tumor invasiveness. (3) Several miRNAs were significantly associated with OS. There was a robust correlation in the entire dataset between HR for OS and differential expression between favourable/unfavourable subtypes (r=0.322; p<0.0001).Table973PTablemiRNASubtype-specific expression log2FoldChange <0: higher in ccrcc1 or -4 (unfavourable) log2FoldChange >0: higher in ccrcc2 or -3 (favourable)*p<0.05 ** false discovery rate <0.05Overall survival (hazard ratio)182-5p-1,43**1,25**3529-3p-1,42**1,37**335-3p-1,33**1,25**34c-5p-1,22**1,25**193b-3p-1,17**1,31**370-3p-1,07**1,16**199b-5p-1,05**1,26**21-3p-0,89**1,47**574-5p-0,89**1,40**4792-0,88**0,88*let-7i-5p-0,81**1,66**652-3p-0,75**1,39**1301-3p-0,70**1,39**222-3p-0,66**1,31*320a-0,63**1,28**425-5p-0,62**1,66**149-5p-0,61**1,32*146b-5p-0,54*1,49**193b-5p-0,491,21**185-5p-0,49**1,42**21-5p-0,42*1,68**7641-0,330,80**320b-0,281,25**1260b-0,150,79**44540,150,80**6880-5p0,250,64**27b-3p0,36**0,71*1260a0,380,73**79770,390,73**23b-3p0,48**0,81**23920,550,80**194-5p0,55*0,74**30c-5p0,70**0,78*190a-5p0,86**0,83**204-5p1,23**0,71**135a-5p1,37**0,86**
accRCC molecular subtypes exhibit different miRNA expression patterns. Differentially expressed miRNAs are implicated in pathways driving tumor biology and strongly correlated with OS. These findings underscore the robustness of the molecular subtypes and are, to the best of our knowledge, the first to show an association of global miRNome expression with outcome.
The authors.
Fonds Wetenschappelijk Onderzoek Vlaanderen.
M. Albersen: Research grant / Funding (self): Ipsen. B. Beuselinck: Advisory / Consultancy, Research grant / Funding (self): Bristol Meyers Squibb; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Merck; Research grant / Funding (self): Pfizer. All other authors have declared no conflicts of interest.
Abstract
Background
Based on mRNA expression, accRCC can be divided in four molecular subtypes (ccrcc1-4), associated with prognosis, angiogenic signature, immune phenotype and therapy response. ...miRNAs are master regulators of mRNA function. We assessed the correlation of miRNA expression with (1) ccrccc1-4 subtypes, (2) mRNA targets and (3) outcome.
Methods
We performed miRNome analysis of 128 accRCC. (1) Unsupervised hierarchical clustering was done using 50 miRNAs with the most variable expression across all samples. Results were validated on TCGA data (n = 255). (2) For miRNAs with subtype-specific expression, we performed pathway analysis of predicted mRNA targets (IPA, KEGG) and assessed target-downregulation in TCGA. (3) We used Cox regression to correlate miRNA expression with overall survival (OS) since diagnosis. Hazard ratios (HR) were correlated with subtype-specific expression (Pearson).
Results
(1) Samples separated in two miRNA clusters, that partially overlapped with molecular subtypes. Cluster 1 consisted of 69% favourable subtypes (ccrcc2 or 3), cluster 2 of 77% unfavourable (ccrcc1 or 4) (p < 2.2e-16). (2) Pathway analysis of predicted mRNA targets and targets suppressed in TCGA, suggested that favourable subtypes exhibit more angiogenic signaling, whereas unfavourable subtypes activate pathways involved in tumor invasiveness. (3) Several miRNAs were significantly associated with OS. There was a robust correlation in the entire dataset between HR for OS and differential expression between favourable/unfavourable subtypes (r = 0.322; p < 0.0001).
Table:973PmiRNASubtype-specific expression log2FoldChange <0: higher in ccrcc1 or -4 (unfavourable) log2FoldChange >0: higher in ccrcc2 or -3 (favourable)*p<0.05 ** false discovery rate <0.05Overall survival (hazard ratio)182-5p-1,43**1,25**3529-3p-1,42**1,37**335-3p-1,33**1,25**34c-5p-1,22**1,25**193b-3p-1,17**1,31**370-3p-1,07**1,16**199b-5p-1,05**1,26**21-3p-0,89**1,47**574-5p-0,89**1,40**4792-0,88**0,88*let-7i-5p-0,81**1,66**652-3p-0,75**1,39**1301-3p-0,70**1,39**222-3p-0,66**1,31*320a-0,63**1,28**425-5p-0,62**1,66**149-5p-0,61**1,32*146b-5p-0,54*1,49**193b-5p-0,491,21**185-5p-0,49**1,42**21-5p-0,42*1,68**7641-0,330,80**320b-0,281,25**1260b-0,150,79**44540,150,80**6880-5p0,250,64**27b-3p0,36**0,71*1260a0,380,73**79770,390,73**23b-3p0,48**0,81**23920,550,80**194-5p0,55*0,74**30c-5p0,70**0,78*190a-5p0,86**0,83**204-5p1,23**0,71**135a-5p1,37**0,86**
Conclusions
accRCC molecular subtypes exhibit different miRNA expression patterns. Differentially expressed miRNAs are implicated in pathways driving tumor biology and strongly correlated with OS. These findings underscore the robustness of the molecular subtypes and are, to the best of our knowledge, the first to show an association of global miRNome expression with outcome.
Legal entity responsible for the study
The authors.
Funding
Fonds Wetenschappelijk Onderzoek Vlaanderen.
Disclosure
M. Albersen: Research grant / Funding (self): Ipsen. B. Beuselinck: Advisory / Consultancy, Research grant / Funding (self): Bristol Meyers Squibb; Speaker Bureau / Expert testimony: Ipsen; Speaker Bureau / Expert testimony: Merck; Research grant / Funding (self): Pfizer. All other authors have declared no conflicts of interest.
Desde sus primeros años como nación independiente, México no fue en modo alguno ajeno a la presencia e influencia de la filosofía kantiana. El pensamiento del filósofo prusiano fue relevante en la ...teoría del derecho, la pedagogía, la ética y la cultura en general que desarrollaron intelectuales, políticos, educadores y pensadores mexicanos. Estudiar el proceso de ingreso y asimilación, así como de exégesis y crítica, de la filosofía kantiana en México, posee un significado importante pues tiene que ver con condiciones objetivas de carácer nacional. ¿Cómo y en qué se dejó sentir el pensamiento kantiano en la vida del México? Esta es la pregunta que busco responder. A ello no me mueve otra cosa que reconocer el empeño de todos aquellos que han ayudado a apropiarnos el legado de la más importante filosofía escrita en los tiempos modernos.
El trabajo analiza cómo la escolarización produjo mecanismos de diferenciación de los educandos y una semántica para referirse a las formas de desigualdad interna generadas en función de los diversos ...recorridos escolares. Se adopta una perspectiva de análisis histórico centrada en las trayectorias conceptuales de las categorías: retraso escolar, repetición, reprobación y deserción entre la década del veinte, con el Informe de Torres Quintero, y la década del sesenta, con el Plan de Once Años. Se muestra el desenvolvimiento de estas categorías en ese periodo y se sostiene que, en tanto práctica de gobernación, el Plan de Once Años sistematizó formas de entender y modelar las trayectorias de los educandos así como de regular y administrar la escolarización que perduraron en las décadas siguientes.
El propósito de este artículo es discutir y comparar las concepciones de Rousseau y Kant sobre la paz perpetua. Como escritores de la Ilustración, ambos tuvieron el interés filosófico de establecer ...los fundamentos para un orden internacional justo que permitiera a las naciones coexistir y desarrollarse pacíficamente. En nuestro análisis nos centramos en las estrategias discursivas que ambos filósofos emplearon a fin de presentar y justificar sus proyectos. Asimismo, realizamos una comparación entre el procedimiento pragmático de Rousseau y la postura moral de Kant. Con ello ponemos de relieve los defectos de la postura de Rousseau y presentamos la postura kantiana como un proyecto robusto que puede presentar una base normativa adecuada de cara al fin de la paz perpetua. Palabras clave: Rousseau, Kant, Ilustración, filosofía política, paz perpetua The aim of this paper is to discuss and compare Rousseau's and Kant's conceptions of perpetual peace. As writers of the Enlightenment, both authors had the philosophical concern of providing the foundations for a just international order, which would allow nations to coexist and develop peacefully. In our argument we focus upon the discursive strategies that both philosophers employ in order to present and justify their projects. A comparison is drawn between Rousseau's pragmatic approach and Kant's moral stand, stressing thereby the shortcomings of the former's position and interpreting the latter's as a robust philosophical project that can render an adequate normative basis for the goal of a perpetual peace. Key words: Rousseau, Kant, Enlightenment, Political Philosophy, Perpetual Peace
PDF
